FPU2023- Targeting the microenvironment in liver cancer

Molecular therapies targeting the microenvironment in hepatocellular carcinoma and metastasis Hepatocellular carcinoma (HCC) is mostly induced in individuals with underlying chronic liver disease, with the tumor/stroma crosstalk being critical in its progression. Changes in extracellular matrix (ECM) during chronic liver injury and cytokines that recruit inflammatory cells participate in the pro-tumor microenvironment promoting the development of liver tumors and the appearance of metastatic nodules. Liver inflammation by fatty diet or toxic substances activates hepatic stellate cells (HSC) (Barcena et al, J Hepatol 2015, Tutusaus et al, CMGH 2020), induces reprogramming and remodeling of the ECM, favoring HCC progression by a sex-dependent mechanism (Cuño-Gomiz et al, Biol Sex Differ 2023). Specific inhibitors and gene silencing that reduce the pro-tumor microenvironment in the liver provide new strategies for clinical use and combined with current chemotherapeutic and enhance their effectiveness in HCC therapy (Cucarull et al, Cancers 2022). Our research reveals how multikinase inhibitors such as sorafenib or cabozantinib alter mitochondrial functionality and signaling, providing novel therapeutic targets (Tutusaus et al, Oncotarget 2018, Cucarull et al, Cancers 2020, Cucarull et al, Antioxidants 2021). Therapies with mitochondrial drugs causing cellular changes in immune response will be tested, studied in 3D tumoroid systems and evaluated in preclinical animal models.