CELLULAR SIGNALING MECHANISMS IN HEPATIC, CARDIOVASCULAR AND CANCER DISEASES
CELLULAR SIGNALING MECHANISMS IN HEPATIC, CARDIOVASCULAR AND CANCER DISEASES
UCM RESEARCH GROUP 920359
Our main interest is the study of signal transduction pathways and mechanisms controlling different physio-pathological processes such as cancer, cardiovascular and liver diseases, as well as liver repair and regeneration upon injury. The group comprises different related research lines leadered by various researchers.
Group directors:
Almudena Porras Gallo and Aránzazu Sánchez Muñoz
Group members, PhDs:
Almudena Porras Gallo, Aránzazu Sánchez Muñoz, Cesáreo Roncero Romero, Blanca Herrera González, Paloma Bragado Domingo, Álvaro Gutiérrez Uzquiza, Ángel Cuesta Martínez.
Group members, PhD students: Cristina Baquero Mayo, Nerea Palao Treviño, María Rodrigo Faus, Carlos González Corralejo, Juan García Sáez.
More information: https://cancerdormancygrowth.com/
RESEARCH LINES
Characterization of C3G function in cancer and liver physiopathology. Role of platelet C3G protein.
C3G is a guanine nucleotide exchange factor (GEF) for different proteins from Ras supefamily, mainly Rap1. However, its actions are not mediated by its GEF activity in many cases, but rather depend on protein-protein interactions. C3G regulates several cellular functions such as proliferation, differentiation and apoptosis. However, a number of its effects, as well as the mechanisms involved remain unknown. Our group, in collaboration with Dra. Guerrero (Cancer Center, Salamanca), found years ago a functional relationship between C3G and p38α MAPK, involved in the regulation of apoptosis in different cell models, such as chronic leukemia myeloid cells. Thus, C3G through the negative regulation of p38α activity regulates apoptosis and other processes such as migration and invasion in mouse embryonic fibroblasts (MEFs) and colorectal cancer (CRC) cells. Nevertheless, C3G and p38α promote CRC tumor growth through independent mechanisms.
The function of C3G in cancer is controversial, as it can act as a tumor promoter or supressor depending on tumor type and stage. Our group has demonstrated that in hepatocarcinoma (HCC), C3G expression increases up to the levels of liver progenitor cells, promoting tumor growth. This together with the correlation between high C3G levels in HCC patient samples and a lower patient survival, support the potential relevance of C3G in HCC.
Our studies on glioblastoma (GBM) indicate that, unlike HCC, C3G levels decrease in this tumor, facilitating its dissemination. Moreover, C3G regulates GBM progenitor capacity. Taking all this into account, we are currently characterizing the mechanisms involved in the regulation of the invasice capacity of GBM cells by C3G and its effect on metabolism.
C3G is also relevant for differentiation of megakaryocytes and platelets, as well as for platelet activation and the release of pro-angiogenic factors, which favors tumor growth, metastasis and angiogenesis. Taking all this into account, we are currently analyzing the in vivo function of platelet C3G protein on age inflammation and fibrosis induced by chronic liver damage. In addition, we are characterizing the role of C3G in liver cell progenitors (oval cells) and in the hepatocytes, in vitro and in vivo.
In vivo models:
- Transgenic mice overexpressing C3G full lenght or C3G∆Cat (a mutant lacking the catalitic domain) in megakaryocytes and platelets.
- Megakaryocytes and platelets-specific C3G Knock-out mice.
- Liver (hepatocytes) specific C3G Knock-out mice.
In vitro models:
- C3G, p38a MAPK and C3G/p38a-silenced CRC HCT116 cell lines.
- Human and mouse C3G-silenced HCC cell lines.
- Human C3G-silenced and C3G Knock-out generated by CRISPR/Cas9 technology GBM cell lines.
- C3G-silenced mouse oval cell lines.
- C3G-silenced, p38a MAPK Knock-out and C3G-silenced/ p38a MAPK Knock-out MEFs.
Researchers involved:
Dra. Almudena Porras Gallo
Principal Investigator and Full Professor at Biochemistry and Molecular Biology Deparment. Faculty of Pharmacy. UCM.
Dr. Angel Cuesta Martínez
Scientist and Assistant Professor at Biochemistry and Molecular Biology Deparment. Faculty of Pharmacy. UCM.
Nerea Palao Treviño
Postdoctoral Researcher, FPU.
Mechanisms of liver regeneration in chronic liver disease and regulation of liver adult progenitor cell biology and function
Chronic liver diseases (CLDs) constitute a major medical and public health problem worldwide. Currently, liver diseases are the tenth most common cause of death and this situation is unlikely to change in the next decade according to World Health Organization projections. CLD refers to a disease process that involves progressive destruction and regeneration of liver parenchyma leading to fibrosis and cirrhosis. Cirrhosis can be considered a premalignant condition, a platform for hepatocellular carcinoma (HCC) development. HCC ranks as the sixth most common cancer and the third most common cause of cancer deaths in 2020, causing over 800 thousand deaths worldwide. The large number of people affected worldwide and the lack of effective anti-fibrotic treatment make necessary a deeper understanding of the mechanisms driving CLD in order to deliver novel and more effective therapies.
In the context of chronic liver injury an activation and expansion of adult liver progenitor cells, known as oval cells (OC) in rodent models, occurs in an attempt to push regeneration and re-establish liver function. Evidences support opposite roles for oval cells either promoting liver repopulation and repair or promoting fibrogenesis, which together with their proposed role as a cell of origin of a subset of HCC emphasize the need to elucidate the complex signaling network implicated in regulation of oval cells activation, expansion and differentiation. In this line of work, the main objective of our research is to study the relevance of the signaling triggered by the Receptor Tyrosine Kinases (RTKs) Met and EGFR and their interaction with other signaling pathways, particularly those mediated by TGF-β and BMP9, in oval cell biology, function and fate in liver diseases. This objective aims to offer new clues on the regulation of the multifaceted behaviour of oval cells and to provide solid bases for developing new therapies for the treatment of liver diseases.
To develop these tasks, we use both in vitro and in vivo approaches. Experimental models currently available in our laboratory are:
Mouse models:
- A transgenic mouse model expressing a dominant negative mutant EGFR in the liver (DEGFR).
- As a model of chronic liver injury associated to oval cell expansion we use the DDC diet (a diet supplemented with 3,5-diethoxycarbonyl-1,4-dihydrocollidine), which is a model of cholestatic liver injury.
Cell models:
- Oval cell lines expressing a functional (Met flx/flx) or non-functional (Met -/-) Met receptor, both normal and transformed (Ras-Met flx/flx and Ras-Met -/-).
- Oval cell lines with mesenchymal phenotype induced by chronic treatment with TGF-β (TβT-Met flx/flx).
- Oval cell lines lacking EGFR activity generated from the ÄEGFR transgenic mouse model and EGFR null oval cells generated using CRISPR/Cas9 and shRNA technologies.
- Primary and immortalized mouse hepatocytes.
- Human hepatic tumor cell lines.
Researchers involved:
Dr. Aránzazu Sánchez Muñoz
Principal Investigator and Lecturer at Biochemistry and Molecular Biology Deparment. Faculty of Pharmacy. UCM.
Dr. Blanca Herrera González
Principal Investigator and Lecturer at Biochemistry and Molecular Biology Deparment. Faculty of Pharmacy. UCM.
blancamh@ucm.es
Dr. Césareo Roncero Romero
Senior Scientist and Lecturer at Biochemistry and Molecular Biology Deparment. Faculty of Pharmacy. UCM.
Carlos González Corralejo
Predoctoral researcher
Juan García Sáez
Predoctoral researcher, supported by a Grant.
juangarsaez@gmail.com
Genome-scale screening to identify and validate novel genes essential for metastasis
Prostate cancer (PCa) remains the most common solid tumor in men and the third leading cause of cancer deaths among men in the European Union. Due to the improvement of tumor diagnosis techniques, the high majority of PCa patients have a 5-year survival rate, however, survival rate of patients with an advanced or metastatic stage (mPCa) of the disease is severely decreased. Since the survival of patients with mPCa is so poor, it is particularly important to establish whether newly essential genes controlling the metastasis might offer opportunities for personalized therapy. Comprehensive studies have identified high frequency alterations in mPCa (AR, TP53, PTEN, MYC) interestingly, most of these patients present co-occurrence mutations that includes transcriptions factor or master regulator of the transcription like histone modifiers or alterations in molecules that mediate DNA repair. Identification of these genes can be of an immense value as either predictive biomarker and or new therapeutic target.
The recent development of the CRISPR/Cas9 technology makes the identification of these new players possible by selective edition of the genome. This technology uses a single guide RNA to target a specific sequence favouring the introduction of premature stop codons abolishing the expression of the target gene. Cas9 can also modulate transcription, without modifying the genomic sequence, through fusing inactive Cas9 (dCas9) to transcriptional activation domains. Interestingly, several groups have developed CRISPR lentiviral libraries targeting thousands of genes that can facilitate both loss-of-function or activation screenings in mammalian cells to identify essential genes in different process on a genome-wide scale.
The main objective of this proposal is to unbiasedly identify and characterize metastasis-associated genes in prostate cancer, using a high-throughput genetic screening based on CRISPR/Cas9 libraries. In addition, it will be characterized their functional relevance in prostate metastasis and whether its modulation could represent a new therapeutic strategy to increase the efficacy of prostate cancer treatments. We combined GENOME-WIDE screenings (GECKO and SAM) developed by MIT with innovative screenings and powerful biostatistics analysis (MAGECK and CASTLE) to identify new genes essential for the metastatic process. Our lab is currently working in the identification and characterization of genes recently involved in metastasis.
This approach includes two main aims:
1) Functional characterization of previously identified candidate genes and the establishment of its clinical significance in PCa.
2) Identification of genes essential for cancer metastasis developing an in vitro and in vivo genome-scale genetic screening based on activation CRISPR/Cas9 library.
On the other hand, we will provide evidences that genome-wide Cas9 screens are a robust and cost-effective method to explore metastasis-associated genes in prostate cancer, which can be easily extrapolated to other type of malignancies.
https://gutierrezuzquiza.com/
CRISPR technology
We use the power of the CRISPR/Cas9 technology to unravel the molecular mechanism of cancer cells and other diseases. Our lab is fully equipped to work with plasmid and construct to modify the genome of mammalian cells at desired location. We have experience in the generation of CRISPR single KO, KI and CRISPR KO genome-wide libraries able to target 20,000 genes in a single shot. Technology available on the lab: https://gutierrezuzquiza.com/crispr-technology/
Cell models:
- Prostate cancer cell lines: RWPE-1, LNCaP, 22rv1, PC3, DU145.
- Human endothelial cell lines-Ea.Hy926.
- We have developed prostate cancer cell lines KO to several genes using CRISPR technologies (HGK, PRMT7, SYCP3, PRKCA)
Identification of new treatment for diseases
Agreement established between the Complutense University (UCM) and the company Arctic Therapeutics to identify new therapeutic strategies and small compounds for the treatments of angiopathies.
Researchers involved:
Dr. Álvaro Gutierrez-Uzquiza
Principal Investigator and Professor at Biochemistry and Molecular Biology Deparment. Faculty of Pharmacy. UCM.
https://gutierrezuzquiza.com/
María Rodrigo Faus
Predoctoral Researcher
marod42@ucm.es
Microenviromental regulation of tumor dormancy. Implications for metastasis
Despite the improvements in diagnosis and earlier detection, about 50% of cancer patients will still eventually develop metastatic disease which remains the main cause of cancer-related death. Hence, developing new therapies effective against metastatic disease is one of the major challenges faced by modern oncologists. Metastases arise mainly from clinically occult disseminated tumour cells (DTCs), shed by the primary tumor (PT) and present in secondary organs at the time of diagnosis. The fact that metastases appear years or even decades after treatment of the primary lesion, suggests that there is a pause in cancer progression after dissemination. Some groups, including ours, propose that this pause is due to the acquisition by these DTCs of a dormant or sleeping behaviour. In fact, head and neck cancer (HNSCC), luminal breast cancer (Bca) or prostate cancer (PCa) patients, among others, can develop metastasis 20 years after the diagnosis and treatment of the primary tumor.
Having travelled far from the primary tumor, DTCs find themselves in a new tissue microenvironment. Hence, their inability to continue proliferating and the resulting entrance into a prolonged growth-arrested state may often be attributable to a microenvironment to which these cells are poorly adapted when they first arrive after extravasation. Importantly, a dormant state can also be actively imposed by certain microenvironmental signals encountered by DTCs in foreign tissues. In fact, our previous studies have discovered specific microenvironment-driven mechanisms controlling the growth arrest and survival of dormant tumour cells. We propose that identifying the balance of signals that affect DTC turnover and maintains DTCs in a viable quiescent state would provide valuable clues for therapeutic intervention.
There is increasing evidence suggesting that the nervous system itself, as well as neurotransmitters and neuropeptides present in the microenvironment, might influence tumour progression. In fact, the nervous system can modulate angiogenesis and immune functions and inflammatory pathways, all of which can influence DTCs fate at secondary organs. We have previously shown that neural related genes can regulate breast cancer initiation, and resistance to targeted therapies. Furthermore, using bioinformatic tools we have identified several neural related factors diferentially expressed among breast cancer subtypes. Interestingly, we found that neuropilin 2 (NRP2) is downregulated in BC luminal patients (the ones with longer metastasis free periods). Furthermore, our preliminary results have shown that neuropilins (NRPs) and plexins (PLXNs) are differentially expressed among dormant and proliferating DTCs derived cell lines.
Therefore, the general aim of my project is to decipher some of the microenvironmental mechanisms that controlled DTCs biology, in particular, we focus on neural mediators and fibroblasts role. We expect to define new dormancy markers and identify new therapeutic targets that could be used to either maintaining DTCs dormancy as a chronic asymptomatic condition or eradicating dormant DTCs to prevent metastasis
In vivo Models
Tumor growth and metastasis assay in chicken embryo chorioallantoic membrane (CAM): The CAM is a very efficient, time-saving and cost-effective system for initial screening purposes. We use the CAM of day 10 chicken embryos to inoculate tumor cells. We study tumor growth and tumor dissemination to liver, lungs and bone marrow.
In vitro Models
- Head and neck squamous carcinoma (HNSCC) cell lines: T-HEp3, SQ20, FaDu, SCC15.
- Breast cancer cell lines: MDAMB231, HCC1954, BT549, MDAMB453, MCF7, T47D, SKBR3, BT474, ZR751.
- Lung cancer cell lines: Human adenocarcinoma cell lines A549 and NCI-H1975. Human squamous-cell carcinoma cell lines: NCI-H520 and NCI-H157. Healthy lung fibroblasts IRM90.
- We have develop several HNSCC and BrCA cell lines knockout for NRP2. We also have lung cancer cell lines with stable inhibition of TRIB3.
- Cell lines derived from lung and BM DTCs: Lu-HEp3, BM-HEp3, MDAMB453-Lu.
- Cell lines resistant to trastuzumab and Lapatinib: MDAMB453-Tz, MDMB453-Lap, SKBR3-TZ, SKBR3-Lap,BT474-Tz, BT474-Lap.
- Primary fibroblasts isolated from reduction mamoplasties (RMFs) or breast primary tumors (TAFs), immortalized and tagged with GFP.
Researchers involved:
Dra. Paloma Bragado Domingo
Group leader and Assistant Professor at Biochemistry and Molecular Biology Deparment. Faculty of Pharmacy. UCM.
External Collaborators:
Dr. Jordi Alcaraz, Ph.D, Serra-Húnter Professor/Professor Agregat Serra-Húnter, University of Barcelona (UB), Group leader, associate group, Institute for Bioengineering of Catalonia (IBEC)
Researcher, Barcelona, Spain.
Dr. Julio Aguirre Ghiso, PhD, Endowed Mount Sinai Professor in Cancer Biology, Division of Hematology and Oncology, Departments of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
Artic therapeutics. www.arctictherapeutics.com
Dra. Katja Breitkopf-Heinlein. Heidelberg University, Mannheim, Germany.
Dra. Neus Carbó, PhD, Associate Professor - Grup Noves Estratègies en Càncer (NEC) Departament de Bioquímica i Biomedicina Molecular, UB, Barcelona, Spain.
Dr. Peter ten Dijke. Leiden University Medical Center, The Netherlands.
Dr. Steven Dooley. Heidelberg University, Mannheim, Germany.
Dra. Isabel Fabregat. TGF-beta and Cancer group, IDIBELL, Barcelona, Spain; CIBEREHD, Oncology Programme.
Dr. Mariano García Arranz. Jiménez Díaz Foundation, Madrid, Spain.
Dra. Carmen Guerrero. Cancer Research Center (CIC), Salamanca University-CSIC, Salamanca, Spain.
Dr. Marcelo Kazanietz. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
Dr. Flavio Maina. IBDM, CNRS-Marseille University, Marseille, France.
Dra. Ángela Martínez Valverde. Biomedical Research Institute (IIBM), Madrid, Spain.
Dr. Wolfgang Mikulits. University of Vienna, Austria.
Dr. Massimo Pancione. Department of Science and Technology, University of Sannio, Italy
Dr. Ignacio Rubio. Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital Jena, Germany.
Dr. José Carlos Segovia. CIEMAT, Madrid, Spain.
Our group is very active in research training, including supervision of national and international students at different research career stages: predoctoral, master and undergraduate.
If you are interested, please, contact us.
GRANTS
Under execution:
New functions of C3G intumor progression, liver physiology and megakaryocytes and platelets biology. Contribution of platelet C3G to pathologic neoangiogenesis patológica and liver damage.
Ministry of Science, Innovation and Universities. Ref. PID2019-104143-RB-C22. Project coordinated with that from Dra. C. Guerrero.
01/07/2020-30/6/2023.
PI: Dra. A. Porras
Role of C3G in hematopoietic tumors and in platelet mediated angiogenesis. Evaluation of its use as a therapeutic target.
Council of Education from Castilla and León. SA078P20 (Consolidated Research Unit from Castilla and León).
2021-2023.
PI: Dra. C. Guerrero
Narrowing down the actions and interactions of RTKs (Met, EGFR) and BMP9 during chronic cholestatic liver injury. Hepatic progenitor cells and inflammation at first line (OVALIN-CHOLIDIS)
Ministry of Science, Innovation and Universities. Ref. RTI2018-099098-B-100.
Jan/2019-Sept/2022.
PI: Dra. A. Sánchez and Blanca Herrera.
Using CRISPR/Cas9 technology to identify new biomarkers in metastatic prostate cancer (CRISPCAN).
Ministerio de Ciencia e Innovación. PID2020-117650RA-I00 .
2021-2023
PI: Dr. A. Gutierrez Uzquiza
Genome-scale screening to identify and validate novel genes essential for prostate cancer metastasis.
Autonomous Community of Madrid. Ref. 2017-T1/BMD-5468
Feb/2018-Feb/2022
PI: Dr. A. Gutierrez Uzquiza
Deciphering the role of neuropilins and plexins in the regulation of disseminated tumour cells destiny and metastasis.
Ministry of Science, Innovation and Universities. Ref: PID2019-104991RB-I00
01/07/2020-30/6/2023
PI: Dra. P. Bragado
From last 10 years:
Function of C3G during tumor development and liver physiopathology. Implication of platelet C3G in angiogenesis and cardiovascular and liver diseases.
Ministry of Economy and Competitiveness. Ref. SAF-2016-76588-C2-1-R. Project coordinated with that from Dra. C. Guerrero.
2017-2020.
PI and Coordinator: Dra. A. Porras.
Metastasis clock: Circadian regulation of disseminated tumour cells
Fundación BBVA (Becas Leonardo). Ref: IN[18]_BBM_TRA_0041
2019-2020
PI: Dra. P. Bragado
New insights into the molecular mechanisms regulating hepatic progenitor cells expansion and fate during chronic liver disease.
Ministry of Economy and Competitiveness. Ref. SAF2015-69145-R.
2016-2018
PI: Dra. A. Sánchez
Role of C3G in the regulation of platelet function: Implications in angiogenesis and its use in diagnosis and treatment of thrombotic disease.
Council of Education from Castilla and León. SA017U16. (Consolidated Research Unit from Castilla and León).
22/03/2016-30/06/2018.
PI: Dra. C. Guerrero
In vitro an in vivo analysis of C3G function in different cell types and its impact on cardiovascular pathologies and metastasis.
Ministry of Economy and Competitiveness Ref. SAF-2013-48210-C02-02. Project coordinated with that from Dra. C. Guerrero.
2014-2016.
PI: Dra. A. Porras.
Strategy to inhibit TGF-beta in liver disease (IT-LIVER).
FP7-PEOPLE-2012-ITN (Initial Training Networks). Ref. 316549.
2012-2016
PI at UCM: Dra. A. Sánchez
Grant coordinator: Dr. I. Fabregat (IDIBELL, Barcelona)
Searching for biomarkers of progression toward HCC in obese patients.
X Call for Research Funding from “Mutua Madrileña” Foundation. Ref. AP115752013.
2013-2014
Principal Investigator: B. Herrera
Mitochondria and its implication in human pathology.
R&D Network, Community of Madrid. S2010/BMD-2402.
2012-2015
PI at UCM: Dra. A. Sánchez
Grant coordinator: Dr. J.M. Cuezva (CBMSO-CSIC/UAM, Madrid)
Role of BMP9 in liver physiology and pathology.
Health Strategic Action Funding from “Fondo de Investigaciones Sanitarias (FIS), Instituto Carlos III”. Ref. PI10/00274.
2011-2013
PI: Dra. B. Herrera
Analysis of the functional interaction between C3G and p38α MAPK in cell adhesion and migration, as well as its impact on tumor invasion. Role in angiogenesis.
Ministry of Science and Innovation. Ref. SAF-2010-20918-C02-01. Project coordinated with that from Dra. C. Guerrero.
2011-2013.
PI and Coordinator: Dra. A. Porras.
Regulation of death and differentiation/morphogenesis processes in liver adult progenitor cells. Role of Met and ErbB1 signaling pathways.
Ministry of Science and Innovation. Ref. SAF2009-12477.
2010-2013
PI: Dra. A. Sánchez
PUBLICATIONS (last 10 years)
C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells.
Manzano S, Gutierrez-Uzquiza A, Bragado P, Sequera C, Herranz Ó, Rodrigo-Faus M, Jauregui P, Morgner S, Rubio I, Guerrero C, Porras A.
Cell Death Dis. 2021 Apr 6;12(4):348. doi: 10.1038/s41419-021-03631-w. PMID: 33824275
Biological and Mechanical Synergies to Deal With Proton Therapy Pitfalls: Minibeams, FLASH, Arcs, and Gantryless Rooms.
Mazal A, Vera Sanchez JA, Sanchez-Parcerisa D, Udias JM, España S, Sanchez-Tembleque V, Fraile LM, Bragado P, Gutierrez-Uzquiza A, Gordillo N, Garcia G, Castro Novais J, Perez Moreno JM, Mayorga Ortiz L, Ilundain Idoate A, Cremades Sendino M, Ares C, Miralbell R, Schreuder N.
Front Oncol. 2021 Jan 21;10:613669. doi: 10.3389/fonc.2020.613669. eCollection 2020. “
NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients.
Michael E. March*, Alvaro Gutierrez-Uzquiza*, Asbjorg Osk Snorradottir, Leticia S. Matsuoka, et al.
Nature Communication. 2021. doi: 10.1038/s41467-021-22120-4
Compte M, Harwood SL, Martínez-Torrecuadrada J, Perez-Chacon G, González-García P, Tapia-Galisteo A, Van Bergen En Henegouwen PMP, Sánchez A, Fabregat I, Sanz L, Zapata JM, Alvarez-Vallina L.
Front Immunol. 2021;11:614363. doi: 10.3389/fimmu.2020.614363. eCollection 2020.
Editorial Special Issue TGF-beta/BMP Signaling Pathway.
Fabregat I, Herrera B, Sánchez A
Cells. 2020;9(11):2363. doi: 10.3390/cells9112363.
Sequera C, Bragado P, Manzano S, Arechederra M, Richelme S, Gutiérrez-Uzquiza A, Sánchez A, Maina F, Guerrero C, Porras A.
Cancers (Basel). 2020;12(8):2282. doi: 10.3390/cancers12082282.
Unraveling the role of fibroblasts, FGF5 and FGFR2 in HER2-targeted therapies resistance and tumor progression.
Bragado P, Fernández-Nogueira P, Carbó N, Gascón P.
Oncotarget. 2020 Dec 8;11(49):4541-4543.
Addante A, Roncero C, Lazcanoiturburu N, Méndez R, Almalé L, García-Álvaro M, Ten Dijke P, Fabregat I, Herrera B, Sánchez A.
Cells. 2020; 9(3):752. doi: 10.3390/cells9030752.
C3G contributes to platelet activation and aggregation by regulating major signaling pathways. Gutiérrez-Herrero S, Fernández-Infante C, Hernández-Cano L, Ortiz-Rivero S, Guijas C, Martín-Granado V, González-Porras JR, Balsinde J, Porras A, Guerrero C.
Signal Transduction and Targeted Therapy 2020; 5(1):29. doi: 10.1038/s41392-020-0119-9.
Clathrin switches transforming growth factor-β role to pro-tumorigenic in liver cancer.
Caballero-Díaz D, Bertran E, Peñuelas-Haro I, Moreno-Càceres J, Malfettone A, López-Luque J, Addante A, Herrera B, Sánchez A, Alay A, Solé X, Serrano T, Ramos E, Fabregat I
J Hepatol. 2020;72(1):125-134. doi: 10.1016/j.jhep.2019.09.012.
Breast Mammographic Density: Stromal Implications on Breast Cancer Detection and Therapy.
Fernández-Nogueira P, Mancino M, Fuster G, Bragado P, Puig MP, Gascón P, Casado FJ, Carbó N.
J Clin Med. 2020 Mar 12;9(3):776. doi: 10.3390/jcm9030776. PMID: 32178425 Free PMC article. Review.
The novel proautophagy anticancer drug ABTL0812 potentiates chemotherapy in adenocarcinoma and squamous nonsmall cell lung cancer.
López-Plana A, Fernández-Nogueira P, Muñoz-Guardiola P, Solé-Sánchez S, Megías-Roda E, Pérez-Montoyo H, Jauregui P, Yeste-Velasco M, Gómez-Ferreria M, Erazo T, Ametller E, Recalde-Percaz L, Moragas-Garcia N, Noguera-Castells A, Mancino M, Morán T, Nadal E, Alfón J, Domènech C, Gascon P, Lizcano JM, Fuster G, Bragado P.
Int J Cancer. 2020 Aug 15;147(4):1163-1179. doi: 10.1002/ijc.32865. Epub 2020 Feb 6. PMID: 31943158
Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation.
Fernández-Nogueira P, Mancino M, Fuster G, López-Plana A, Jauregui P, Almendro V, Enreig E, Menéndez S, Rojo F, Noguera-Castells A, Bill A, Gaither LA, Serrano L, Recalde-Percaz L, Moragas N, Alonso R, Ametller E, Rovira A, Lluch A, Albanell J, Gascon P, Bragado P.
Clin Cancer Res. 2020 Mar 15;26(6):1432-1448. doi: 10.1158/1078-0432.CCR-19-0353. Epub 2019 Nov 7. PMID: 31699826
Epigenetic SMAD3 Repression in Tumor-Associated Fibroblasts Impairs Fibrosis and Response to the Antifibrotic Drug Nintedanib in Lung Squamous Cell Carcinoma.
Ikemori R, Gabasa M, Duch P, Vizoso M, Bragado P, Arshakyan M, Luis IC, Marín A, Morán S, Castro M, Fuster G, Gea-Sorli S, Jauset T, Soucek L, Montuenga LM, Esteller M, Monsó E, Peinado VI, Gascon P, Fillat C, Hilberg F, Reguart N, Alcaraz J.
Cancer Res. 2020 Jan 15;80(2):276-290. doi: 10.1158/0008-5472.CAN-19-0637. Epub 2019 Nov 6. PMID: 3169490
Almalé L, García-Álvaro M, Martínez-Palacián A, García-Bravo M, Lazcanoiturburu N, Addante A, Roncero C, Sanz J, de la O López M, Bragado P, Mikulits W, Factor VM, Thorgeirsson SS, Casal JI, Segovia JC, Rial E, Fabregat I, Herrera B, Sánchez A.
Stem Cells. 2019;37(8):1108-1118. doi: 10.1002/stem.3038.
JAK/Stat5-mediated subtype-specific lymphocyte antigen 6 complex, locus G6D (LY6G6D) expression drives mismatch repair proficient colorectal cancer.
Giordano G, Parcesepe P, Rosario D’Andrea M, Coppola L, Di Raimo T, Remo A, Manfrin E, Fiorini C, Scarpa A, Amoreo CA, Conciatori F, Milella M, Caruso FP, Cerulo L, Porras A and Pancione M. Journal of Experimental & Clinical Cancer Research. 2019; 38(1):28. doi: 10.1186/s13046-018-1019-5.
Immune Resistance and EGFR Antagonists in Colorectal Cancer.
Giordano, G, Remo, A, Porras, A and Pancione, M.
Cancers (Basel). 2019;11(8): 1089. doi: 10.3390/cancers11081089.
Preclinical Evaluation of AZ12601011 and AZ12799734, Inhibitors of Transforming Growth Factor β Superfamily Type 1 Receptors.
Spender LC, Ferguson GJ, Hughes GD, Davies BR, Goldberg FW, Herrera B, Taylor RG, Strathearn LS, Sansom OJ, Barry ST, Inman GJ
Mol Pharmacol. 2019;95(2):222-234. doi: 10.1124/mol.118.112946.
ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor.
Dong Li, Michael E. March, Alvaro Gutierrez-Uzquiza , Charlly Kao, Christoph Seiler, et al.
Nature Medicine. 2019 Jul;25(7):1116-1122
RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation.
Zhou N, Gutierrez-Uzquiza A, Zheng XY, Chang R, Vogl DT, Garfall AL, Bernabei L, Saraf A, Florens L, Washburn MP, Illendula A, Bushweller JH, Busino L.
Leukemia. 2019 Aug;33(8):2006-2021. doi: 10.1038/s41375-019-0403-2.
Glucocorticoids promote transition of ductal carcinoma in situ to invasive ductal carcinoma by inducing myoepithelial cell apoptosis.
Zubeldia-Plazaola A, Recalde-Percaz L, Moragas N, Alcaraz M, Chen X, Mancino M, Fernández-Nogueira P, Prats de Puig M, Guzman F, Noguera-Castells A, López-Plana A, Enreig E, Carbó N, Almendro V, Gascón P, Bragado P, Fuster G.
Breast Cancer Res. 2018 Jul 4;20(1):65. doi: 10.1186/s13058-018-0977-z. PMID: 29973218
C3G, through its GEF activity, induces megakaryocytic differentiation and proplatelet formation. Ortiz-Rivero S, Baquero C, Hernández-Cano L, Roldán-Etcheverry JJ, Gutiérrez-Herrero S, Fernández-Infante C, Martín-Granado V, Anguita E, de Pereda JM, Porras A, Guerrero C.
Cell Commun Signal. 2018; 16(1):101.
Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC-induced cholestatic liver injury.
Addante A, Roncero C, Almalé L, Lazcanoiturburu N, García-Álvaro M, Fernández M, Sanz J, Hammad S, Nwosu ZC, Lee SJ, Fabregat I, Dooley S, Ten Dijke P, Herrera B, Sánchez A.
Liver Int. 2018;38(9):1664-1675. doi: 10.1111/liv.13879.
González-Rodríguez Á, Valdecantos MP, Rada P, Addante A, Barahona I, Rey E, Pardo V, Ruiz L, Laiglesia LM, Moreno-Aliaga MJ, García-Monzón C, Sánchez A, Valverde ÁM.
Mol Metab. 2018;7:132-146. doi: 10.1016/j.molmet.2017.10.008.
TWEAK promotes migration and invasion in MEFs through a mechanism dependent on ERKs activation and Fibulin 3 down-regulation.
Sequera C, Vázquez-Carballo A, Arechederra M, Fernández-Veledo S, Porras A.
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How Rap and its GEFs control liver physiology and cancer development. C3G alterations in human hepatocarcinoma.
Sequera C, Manzano S, Guerrero C and Porras A.
Hepat Oncol. 2018; 5(1): HEP05. doi: 10.2217/hep-2017-0026.
Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly
Li D, Wenger TL, Seiler C, March M, Gutierrez-Uzquiza A, et al.
Human Molecular Genetics. (2018), Sep 15.
Histamine receptor 1 inhibition enhances antitumor therapeutic responses through extracellular signal-regulated kinase (ERK) activation in breast cancer.
Fernández-Nogueira P, Noguera-Castells A, Fuster G, Recalde-Percaz L, Moragas N, López-Plana A, Enreig E, Jauregui P, Carbó N, Almendro V, Gascón P, Bragado P, Mancino M.
Cancer Lett. 2018 Jun 28;424:70-83.
Emerging insight into MAPK inhibitors and immunotherapy in colorectal cancer.
Pancione M, Giordano G, Parcesepe P, Cerulo L, Coppola L, Curatolo AD, Conciatori F, Milella M, Porras A.
Curr Med Chem. 2017; 24(14):1383-1402.doi: 10.2174/0929867324666170227114356.
BMP Signalling at the Crossroad of Liver Fibrosis and Regeneration.
Herrera B, Addante A, Sánchez A.
Int J Mol Sci. 2017;19(1):39. doi: 10.3390/ijms19010039.
BMP-9 interferes with liver regeneration and promotes liver fibrosis.
Breitkopf-Heinlein K, Meyer C, König C, Gaitantzi H, Addante A, Thomas M, Wiercinska E, Cai C, Li Q, Wan F, Hellerbrand C, Valous NA, Hahnel M, Ehlting C, Bode JG, Müller-Bohl S, Klingmüller U, Altenöder J, Ilkavets I, Goumans MJ, Hawinkels LJ, Lee SJ, Wieland M, Mogler C, Ebert MP, Herrera B, Augustin H, Sánchez A, Dooley S, Ten Dijke P
Gut. 2017;66(5):939-954. doi: 10.1136/gutjnl-2016-313314.
Hurst LA, Dunmore BJ, Long L, Crosby A, Al-Lamki R, Deighton J, Southwood M, Yang X, Nikolic MZ, Herrera B, Inman GJ, Bradley JR, Rana AA, Upton PD, Morrell NW.
Nat Commun. 2017;8:14079. doi: 10.1038/ncomms14079.
C3G knock-down enhances migration and invasion by increasing Rap1-mediated p38 activation, while it impairs tumor growth through p38α-independent mechanisms.
Priego, N., Arechederra, M., Sequera, C., Bragado, P., Vázquez, A., Gutiérrez-Uzquiza, A., Martín-Granado, V., Ventura, JJ., Kazanietz, M., Guerrero,C. and Porras, A.
Oncotarget 2016; 7(29):45060-45078. doi: 10.18632/oncotarget.9911.
De Petrocellis L, Arroyo FJ, Orlando P, Schiano Moriello A, Vitale RM, Amodeo P, Sánchez A, Roncero C, Bianchini G, Martín MA, López-Alvarado P, Menéndez JC
J Med Chem. 2016 Jun 23;59(12):5661-83. doi: 10.1021/acs.jmedchem.5b01448. Correction in: J Med Chem. 2016 Aug;59(16):7697. doi: 10.1021/acs.jmedchem.6b01091.
The rationale for targeting TGF-β in chronic liver diseases.
Giannelli G, Mikulits W, Dooley S, Fabregat I, Moustakas A, ten Dijke P, Portincasa P, Winter P, Janssen R, Leporatti S, Herrera B, Sanchez A.
Eur J Clin Invest. 2016;46(4):349-61. doi: 10.1111/eci.12596.
TGF-β signalling and liver disease.
Fabregat I, Moreno-Càceres J, Sánchez A, Dooley S, Dewidar B, Giannelli G, Ten Dijke P; IT-LIVER Consortium.
FEBS J. 2016;283(12):2219-32. doi: 10.1111/febs.13665.
López-Luque J, Caballero-Díaz D, Martinez-Palacián A, Roncero C, Moreno-Càceres J, García-Bravo M, Grueso E, Fernández A, Crosas-Molist E, García-Álvaro M, Addante A, Bertran E, Valverde AM, González-Rodríguez Á, Herrera B, Montoliu L, Serrano T, Segovia JC, Fernández M, Ramos E, Sánchez A, Fabregat I.
Hepatology. 2016;63(2):604-19. doi: 10.1002/hep.28134.
Differential expression of neurogenes among breast cancer subtypes identifies high risk patients.
Fernández-Nogueira P, Bragado P, Almendro V, Ametller E, Rios J, Choudhury S, Mancino M, Gascón P.
Oncotarget. 2016 Feb 2;7(5):5313-26. doi: 10.18632/oncotarget.6543. PMID: 26673618 Free
The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase.
Erazo T, Lorente M, López-Plana A, Muñoz-Guardiola P, Fernández-Nogueira P, García-Martínez JA, Bragado P, Fuster G, Salazar M, Espadaler J, Hernández-Losa J, Bayascas JR, Cortal M, Vidal L, Gascón P, Gómez-Ferreria M, Alfón J, Velasco G, Domènech C, Lizcano JM.
Clin Cancer Res. 2016 May 15;22(10):2508-19. doi: 10.1158/1078-0432.CCR-15-1808.
Down-regulates Fibulin 3 Expression through Methylation of Gene Regulatory Sequences: ROLE IN MIGRATION AND INVASION.
Arechederra M, Priego N, Vázquez-Carballo A, Sequera C, Gutiérrez-Uzquiza Á, Cerezo-Guisado MI, Ortiz-Rivero S, Roncero C, Cuenda A, Guerrero C, Porras, A.
J Biol Chem. 2015; 290(7), 4383-4397. doi: 10.1074/jbc.M114.582239.
BMP9-Induced Survival Effect in Liver Tumor Cells Requires p38MAPK Activation.
García-Álvaro M, Addante A, Roncero C, Fernández M, Fabregat I, Sánchez A, Herrera B.
Int J Mol Sci. 2015;16(9):20431-48. doi: 10.3390/ijms160920431.
Suárez-Causado A, Caballero-Díaz D, Bertrán E, Roncero C, Addante A, García-Álvaro M, Fernández M, Herrera B, Porras A, Fabregat I, Sánchez A.
Biochim Biophys Acta. 2015;1853(10 Pt A):2453-63. doi: 10.1016/j.bbamcr.2015.05.017.
PKCε Is an Essential Mediator of Prostate Cancer Bone Metastasis
Gutierrez-Uzquiza A, Lopez-Haber C, Jernigan DL, Fatatis A, Kazanietz M.
Mol Cancer Res. 2015, Sep;13(9):1336-46.
NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes.
Sosa MS, Parikh F, Maia AG, Estrada Y, Bosch A, Bragado P, Ekpin E, George A, Zheng Y, Lam HM, Morrissey C, Chung CY, Farias EF, Bernstein E, Aguirre-Ghiso JA.
Nat Commun. 2015 Jan 30;6:6170. doi: 10.1038/ncomms7170
Potential roles of bone morphogenetic protein (BMP)-9 in human liver diseases.
Herrera B, Dooley S, Breitkopf-Heinlein K.
Int J Mol Sci. 2014;15(4):5199-220. doi: 10.3390/ijms15045199.
Marhenke S, Buitrago-Molina LE, Endig J, Orlik J, Schweitzer N, Klett S, Longerich T, Geffers R, Sánchez Muñoz A, Dorrell C, Katz SF, Lechel A, Weng H, Krech T, Lehmann U, Dooley S, Rudolph KL, Manns MP, Vogel A.
Gut. 2014;63(9):1501-12. doi: 10.1136/gutjnl-2013-304829.
The NADPH oxidase NOX4 inhibits hepatocyte proliferation and liver cancer progression.
Crosas-Molist E, Bertran E, Sancho P, López-Luque J, Fernando J, Sánchez A, Fernández M, Navarro E, Fabregat I
Free Radic Biol Med. 2014;69:338-47. doi: 10.1016/j.freeradbiomed.2014.01.040.
TWEAK prevents TNF-α-induced insulin resistance through PP2A activation in human adipocytes.
Vázquez-Carballo A, Ceperuelo-Mallafré V, Chacón MR, Maymó-Masip E, Lorenzo M, Porras A, Vendrell J, Fernández-Veledo S.
Am J Physiol Endocrinol Metab. 2013; 305(1):E101-12. doi: 10.1152/ajpendo.00589.2012.
Transcriptional regulation of oncogenic protein kinase Cε (PKCε) by STAT1 and Sp1 proteins
Wang H, Gutierrez-Uzquiza A, Garg R, Barrio-Real L, Abera MB, Lopez-Haber C, Rosemblit C, Lu H, Abba M, Kazanietz MG. (2014).
J Biol Chem. 2014 Jul 11;289(28):19823-38. doi: 10.1074/jbc.M114.548446
β3-Chimaerin, a novel member of the chimaerin Rac-GAP family
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Molecular Biology reports. 2014;41(4):2067-76. doi: 10.1007/s11033-014-3055-3.
Mechanisms of disseminated cancer cell dormancy: an awakening field.
Sosa MS, Bragado P, Aguirre-Ghiso JA.
Nat Rev Cancer. 2014 Sep;14(9):611-22. doi: 10.1038/nrc3793. PMID: 25118602
C3G forms complexes with Bcr-Abl and p38alpha MAPK at the focal adhesions in chronic myeloid leukemia cells: implication in the regulation of leukemic cell adhesion.
Maia, V, Ortiz-Rivero, S, Sanz, M, Gutierrez-Berzal, J, Alvarez-Fernández, I, Gutierrez-Herrero, S, de Pereda, JM, Porras, A, Guerrero, C.
Cell Commun Signal. 2013; 11(1),9. doi: 10.1186/1478-811X-11-9
BMP9 is a proliferative and survival factor for human hepatocellular carcinoma cells.
Herrera B, García-Álvaro M, Cruz S, Walsh P, Fernández M, Roncero C, Fabregat I, Sánchez A, Inman GJ.
PLoS One. 2013;8(7):e69535. doi: 10.1371/journal.pone.0069535.
Martínez-Palacián A, del Castillo G, Suárez-Causado A, García-Álvaro M, de Morena-Frutos D, Fernández M, Roncero C, Fabregat I, Herrera B, Sánchez A.
PLoS One. 2013;8(1):e53108. doi: 10.1371/journal.pone.0053108.
Met signaling in cardiomyocytes is required for normal cardiac function in adult mice.
Arechederra M, Carmona R, González-Nuñez M, Gutiérrez-Uzquiza A, Bragado P, Cruz-González I, Cano E, Guerrero C, Sánchez A, López-Novoa JM, Schneider MD, Maina F, Muñoz-Chápuli R, Porras A
Biochim Biophys Acta. 2013;1832(12):2204-15. doi: 10.1016/j.bbadis.2013.08.008.
Amigo I, Traba J, González-Barroso MM, Rueda CB, Fernández M, Rial E, Sánchez A, Satrústegui J, Del Arco A.
J Biol Chem. 2013;288(11):7791-802. doi: 10.1074/jbc.M112.409144.
Gutierrez-Uzquiza A., Colon-Gonzalez F., Leonard T. A., Canagarajah B. J., Wang HB, Bruce J. Mayer B.J., Hurley J.H. and Kazanietz M.G. (2013).
Nature Communication. (2013) 4:1849.
Rac signaling in breast cancer: a tale of GEFs and GAPs.
Wertheimer E., Gutierrez-Uzquiza A., Rosemblit C., Lopez-Haber C., Sosa M.S., Kazanietz M.G. (2012).
Cell Signaling. 2012, Feb;24(2):353-62.
TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling.
Bragado P, Estrada Y, Parikh F, Krause S, Capobianco C, Farina HG, Schewe DM, Aguirre-Ghiso JA.
Nat Cell Biol. 2013 Nov;15(11):1351-61.
Metastasis awakening: targeting dormant cancer.
Aguirre-Ghiso JA, Bragado P, Sosa MS.
Nat Med. 2013 Mar;19(3):276-7. doi: 10.1038/nm.3120.
Regulation of tumor cell dormancy by tissue microenvironments and autophagy.
Sosa MS, Bragado P, Debnath J, Aguirre-Ghiso JA.
Adv Exp Med Biol. 2013;734:73-89. doi: 10.1007/978-1-4614-1445-2_5.
C3G transgenic mouse models with specific expression in platelets reveal a new role for C3G in platelet clotting through its GEF activity.
Gutiérrez-Herrero, S, Maia, V, Gutiérrez-Berzal, J, Calzada, N, Sanz, M , González-Manchón, C, Pericacho, M, Ortiz-Rivero, S, González-Porras, J. R., Arechederra, M, Porras, A, Guerrero, C.
BBA Mol Cel Res. 2012;1823(8), 1366-1377
Bretón-Romero R, González de Orduña C, Romero N, Sánchez-Gómez FJ, de Álvaro C, Porras A, Rodríguez-Pascual F, Laranjinha J, Radi R, Lamas S.
Free Radic Biol Med. 2012, 52, 1093-1100
p38[alpha]mediates cell survival in response to oxidative stress via induction of antioxidant genes. Effect on the p70S6K pathway.
Gutierrez-Uzquiza A, Arechederra M, Bragado P, Aguirre-Ghiso JA, Porras A.
J Biol Chem. 2012, 287, 2632-2642
BMPS and liver: more questions than answers.
Herrera B, Sánchez A, Fabregat I.
Curr Pharm Des. 2012;18(27):4114-25. doi: 10.2174/138161212802430503
Martínez-Palacián A, del Castillo G, Herrera B, Fernández M, Roncero C, Fabregat I, Sánchez A.
Cell Signal. 2012;24(2):505-13. doi: 10.1016/j.cellsig.2011.09.031.
Sancho P, Mainez J, Crosas-Molist E, Roncero C, Fernández-Rodriguez CM, Pinedo F, Huber H, Eferl R, Mikulits W, Fabregat I.
PLoS One. 2012;7(9):e45285. doi: 10.1371/journal.pone.0045285.
Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer.
Kim RS, Avivar-Valderas A, Estrada Y, Bragado P, Sosa MS, Aguirre-Ghiso JA, Segall JE.
PLoS One. 2012;7(4):e35569.
Microenvironments dictating tumor cell dormancy.
Bragado P, Sosa MS, Keely P, Condeelis J, Aguirre-Ghiso JA.
Recent Results Cancer Res. 2012;195:25-39. doi: 10.1007/978-3-642-28160-0_3.
PMID: 22527492 Free PMC article. Review.
Analysis of marker-defined HNSCC subpopulations reveals a dynamic regulation of tumor initiating properties.
Bragado P, Estrada Y, Sosa MS, Avivar-Valderas A, Cannan D, Genden E, Teng M, Ranganathan AC, Wen HC, Kapoor A, Bernstein E, Aguirre-Ghiso JA.
PLoS One. 2012;7(1):e29974. doi: 10.1371/journal.pone.0029974. Epub 2012 Jan 20.
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ERK1/2 and p38α/β signaling in tumor cell quiescence: opportunities to control dormant residual disease.
Sosa MS, Avivar-Valderas A, Bragado P, Wen HC, Aguirre-Ghiso JA.
Clin Cancer Res. 2011 Sep 15;17(18):5850-7. doi: 10.1158/1078-0432.CCR-10-2574. Epub 2011 Jun 14. PMID: 21673068
Gutiérrez-Uzquiza A, Arechederra M, Molina I, Baños R, Maia V, Benito M, Guerrero C, Porras A.
Cell Signal. 2010, 22, 533-542
Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter.
Hannigan A, Smith P, Kalna G, Lo Nigro C, Orange C, O'Brien DI, Shah R, Syed N, Spender LC, Herrera B, Thurlow JK, Lattanzio L, Monteverde M, Maurer ME, Buffa FM, Mann J, Chu DC, West CM, Patridge M, Oien KA, Cooper JA, Frame MC, Harris AL, Hiller L, Nicholson LJ, Gasco M, Crook T, Inman GJ.
J Clin Invest. 2010;120(8):2842-57. doi: 10.1172/JCI36125.
Growth factor- and cytokine-driven pathways governing liver stemness and differentiation.
Sánchez A, Fabregat I.
World J Gastroenterol. 2010;16(41):5148-61. doi: 10.3748/wjg.v16.i41.5148.