Resum
Liver cancer incidence has increased markedly in recent years, with high mortality rates and limited therapeutic options. Transforming Growth Factor-β (TGF-β) has emerged as a promising therapeutic target, particularly in combination with immune checkpoint inhibitors. However, TGF-β is a pleiotropic cytokine that can act as both a tumor suppressor and a tumor promoter, depending on tumor context and the microenvironment. Here, we developed novel in vitro and in vivo models to better characterize the role of TGF-β signaling in liver tumor and stromal cells and to assess whether TGF-β inhibition could represent an effective therapeutic strategy. We established new mouse liver cancer cell lines from tumors induced by hydrodynamic tail vein injection of a transposon vector (MYC-LucOS, CTNNB1, SB13). A syngeneic orthotopic model was generated by injecting tumor cells into the liver parenchyma of C57BL/6J mice. Galunisertib (a TGF-β receptor inhibitor, 150 mg/kg orally), anti-PD-L1 (5 mg/kg), and their combination were evaluated for their effects on tumor progression. Cells displaying an epithelial phenotype responded to TGF-β with growth inhibition, apoptosis, and induction of epithelial–mesenchymal transition (EMT). Chronic exposure to TGF-β (2 ng/mL for four weeks) generated a mesenchymal cell line resistant to the suppressive effects of TGF-β. Upon orthotopic implantation, mesenchymal cells exhibited more aggressive tumor progression than epithelial cells. Galunisertib monotherapy had no effect or exacerbated tumor growth in both models, whereas immunotherapy was particularly effective in epithelial-derived tumors. Notably, combined treatment with galunisertib and anti-PD-L1 significantly improved therapeutic efficacy in both models, leading to reduced tumor burden. These findings indicate that TGF-β inhibition alone may be ineffective or even detrimental. In contrast, its combination with immunotherapy provides therapeutic benefit in hepatocellular carcinoma (HCC), including tumors in which TGF-β retains tumor-suppressive functions.
Hosted by Ruth Rodriguez Barrueco – Breast cancer group
Biografia
Bachelor in Biological Sciences in 1980, and PhD in Biochemistry and Molecular Biology in 1983, Autonoma University of Madrid. My research line begins at the Faculty of Pharmacy, Complutense University (UCM), Madrid (1991) as Lecturer, after a postdoctoral stage in Dr. Enrique Rozengurt’s Lab at the Imperial Cancer Research Foundation (ICRF) in London (1989-1990). I completed my training with a second stay abroad, in the laboratory of Dr. Hyam L. Leffert (UCSD, San Diego, CA) during the years 1997-98, to strengthen my knowledge in the field of liver differentiation and cancer. In September 2005 I moved to IDIBELL as Senior Investigator, after causing leave of absence from the position of professor of the UCM.
My independent research line started with the aim of searching for new regulatory elements of hepatic cell proliferation and differentiation. We found that Transforming Growth Factor beta (TGF-β) induced intrinsic apoptosis in hepatocytes, a process that required the production of reactive oxygen species-ROS. However, it was very interesting to observe that some cells escaped death induced by TGF-β and responded to it by inducing epithelial-mesenchymal transition (EMT), a process of particular relevance in cancer. In fact, TGF-β induces both pro- and anti-apoptotic signals, the latter mediated by the transactivation of the Epidermal Growth Factor receptor (EGFR). We also found that TGF-β induces the expression of a NADPH oxidase, specifically NOX4, which is required for TGF-β -mediated cell death and the EGFR counteracts this process. All these advances placed us in a line of work where we tried to analyze how the TGF-β and EGFR pathways and the NADPH oxidases converge in a cross-linking of determinant signals for cell fate during liver regeneration, fibrosis and hepatocarcinogenesis. Recent works are also focused on exploring the inhibition of the TGF-β pathway as a potential therapeutic option in liver cancer, either alone or in combination with other strategies, particularly immunotherapy.