Research lines

• Translational research in liver cancer

  Our scientific contributions to advancing knowledge in liver cancer during the last 15 years are summarized as follows: we contributed to the classification of hepatocellular carcinoma (HCC) from the molecular and immune standpoints, developed predictors of response to immunotherapy, provided a molecular characterization of NASH-related HCC, dissected the role of several signaling pathways in the pathogenesis of HCC, discovered new drivers for HCC and cholangiocarcinoma, and provided transcriptomic and methylomic-based prognostic signatures in HCC.  

• Molecular and immune classification of HCC

  The group contributed to the molecular classification of HCC (Hoshida, NEJM 2008, Chiang Cancer Research 2008) and to the generation of gene signatures with predictive and prognostic capacity (Nault Gastroenterology 2013, Pinyol Hepatology 2018, Moeini Gastroenterology 2019).  

  We defined the HCC immune classes (Sia Gastroenterology 2017) and defined an Inflamed class of tumors with potential for benefit from immunotherapy (Montironi Gut 2023).  

• Identification of determinants of response to immunotherapy in HCC

  We developed an 11-gene signature able to predict response to immune checkpoint inhibitors in HCC (Haber Gastroenterology 2022). We also contributed to a study that indicates that immunotherapies are significantly less effective in non-viral HCC etiologies, particularly NASH (Pfister Nature 2021). 

  In the pre-clinical context, we contributed to the evaluation of a neutrophil-targeting agent to sensitize NASH-HCC to immune checkpoint inhibitors (Leslie Gut 2022). Furthermore, we elucidated the mechanism of action of immunotherapy-based combinations such as lenvatinib combined with anti-PD-1 (Torrens Hepatology 2021) and cabozantinib combined with anti-PD-1 (Esteban-Fabró CCR 2022).  

• Molecular characterization of human NASH-HCC

  We have molecularly characterized human NASH-HCC at the genomic and molecular levels (Pinyol Journal of Hepatology 2021). 

• Identification of drivers of oncogenesis as targets for therapies in HCC

  Several studies led to the identification of Akt/mTOR pathway [Villanueva Gastroenterology, 2008), EGFR pathway (Keng, Nature Biotech 2009), IGF pathway ([Martinez-Quetglas, Gastroenterology 2016], Wnt Pathway (Lachenmeyer, CCR 2012), Notch pathway (Villanueva, Gastroenterology 2012), AEG (Yoo, J Clin Invest 2009), UHRF1 (Mudbhary R,Cancer Cell 2014)  and miRNAs (Viswanathan, Nature Genetics 2009, Toffanin, Gastroenterology 2011]. Also identification of mutational signatures associated with genotoxic (alcohol and tobacoo) in HCC (Schulze, Nature Genetics 2015). 

• Establishment of a molecular diagnosis and classification of HCC

  Gene-set (three genes) based diagnosis of HCC reported in Llovet, Gastroenterology 2006, and included in EASL-EORTC guidelines. In addition, we proposed a molecular classification of HCC based on the results reported in different publications. 

• Molecular characterization and identification of drivers of oncogenesis in cholangiocarcinoma

  We have contributed to the molecular classification of iCCA (Sia, Gastroenterology 2013) and eCCA (Montal, Journal of Hepatology 2020). 

  We identified IDH mutations as gatekeeper drivers in progenitor cells (Saha, Nature 2014) and FGFR2 fusion proteins as oncodrivers and novel targets for therapies in iCCA (Sia, Nature Communications 2015).  

• Establishment of sorafenib, regorafenib and ramucirumab as standard of care in patients with advanced HCC

  The international RCT showing survival benefits for sorafenib vs placebo, presented at plenary session in ASCO (Llovet, New Engl J Med 2008) was a breakthrough achievement established sorafenib as first line treatment for advanced HCC, and represents the first identification of survival advantages with systemic treatments. Adopted by American (AASLD) and European (EASL-EORTC) guidelines of management of HCC. 

  Establishment of regorafenib and ramucirumab as second-line treatment options (Bruix Lancet 2017, Zhu Lancet Oncology 2019).