Cancer, Metabolism and Environment (CAMEEN)

Our team has identified a novel and compelling hypoxia-inducible factor (HIF)- and TP53/TP73-dependent molecular mechanism that involves direct contact between mitochondria and endolysosomes in cancer cells (breast, colon, kidney and lung cancers). This cross-contact involves enlarged mitochondria, exhibiting mitochondrial cristae remodeling, and truncation of the C-terminal voltage-dependent mitochondrial anion channel (VDAC1 to VDAC1-ΔC) by lysosomal peptidases (Legumain-LGM) in hypoxia. This results in increased metabolic regulation of both oxidative phosphorylation (OXPHOS) and glycolysis and increased resistance to chemotherapy. With its three isoforms, VDAC1, 2, and 3, the channel family constitutes the most abundant pore-forming proteins in the mitochondrial outer membrane (MOM) where they control the flow of ADP, ATP, ions, respiratory substrates, and metabolites through the organelle. By binding to VDAC, several cytoplasmic and cytoskeletal proteins, including tubulin, modulate MOM permeability and thus control a wide variety of mitochondrial functions and probably the response to chemotherapy. Aberrant VDAC expression or function has been reported in many tumors, indicating that targeting VDAC is of therapeutic importance for cancer treatment.
We have shown that the hypoxia-induced cleaved form of VDAC1 (i.e., VDAC1-ΔC) is a critical regulator of glycolysis and ciliogenesis, as the conversion of VDAC1 to VDAC1-ΔC correlates with the loss of primary cilium (PC) and increased glycolysis and mitochondrial respiration. Our studies demonstrate that VDAC1-ΔC reprograms PC-deficient cells to utilize more metabolites (i.e. lactate, mannitol, fructose, etc.) promoting cell growth in a hypoxic microenvironment.

The vast majority of "anti-cancer" molecules validated in the laboratory prove ineffective in clinical trials. This dramatic observation is due to the lack of relevance of the experimental models used in research (mice and cell lines). For example, genetically modified mouse models do not reflect the histological complexity and genetic heterogeneity of human cancers. The spectacular development of 3D cell culture technologies and the creation, from progenitor cells or human "tumor stem cells," of self-organizing organotypic structures such as organoids/tumoroids, is revolutionizing translational medicine. The goal of "precision medicine" is to deliver each patient a specific treatment that can be tested "a priori" on tumor cells derived from their own tumor. In this context, we have developed in the laboratory the production and culture of organoids/tumoroids derived from cells of prostate cancer patients. This strategy allows us to obtain, for each patient, populations of organoids (healthy areas) and tumoroids (cancerous areas) from fresh surgical specimens.

7th Yamada Symposium

From 25 to 30 Août 2024 - Kobe (Japon)

https://smartconf.jp/content/icbrp2024/

From 22 to 24 november 2023 - Nice (France)

https://www.metabolism-cancer.com/

From 16th to 18th December 2024 - Le Croisic (France)

https://www.cancer-fstm.fr/

Metabolic and Immunosuppressive ASPECTS of prostate cancer

20 November 2024 - Palais des Congrès de Paris - 2 place de la Porte Maillot - 75017 Paris

https://www.c3m-nice.fr/admin-thuria/?loggedout=true&wp_lang=fr_FR