Ferroptosis as a druggable weakness of acidic cancer cells to prevent tumor relapse post-chemotherapy through aldehyde dehydrogenase inhibition

Details

Supervisors

Feron, Olivier

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Inefficient tumor perfusion and excessive cancer cell proliferation lead to a deficit in O2 levels (hypoxia) and the accumulation of metabolic wastes, including protons (acidosis). Our team and others have previously shown that hypoxia and acidosis do not completely overlap in tumors, giving rise to a largely unexplored tumor compartment made of acidic and non-hypoxic cancer cells. These acidic cells (i.e., cells bathing in an extracellular acidic medium) are associated with a higher aggressive phenotype and metastatic potential. Importantly, they also exhibit a preference for fatty acid metabolism, which makes them more sensitive to ferroptosis, a cell death associated with the lipid peroxidation of polyunsaturated fatty acid (PUFA) and harmful aldehyde generation. This master’s thesis work has its origins in the identification (in an RNAseq study carried out in the host laboratory) of the enrichment of genes from the aldehyde dehydrogenase (ALDH) family in acid cancer cells. These results further echoed other studies documenting increased ALDH expression in chemo-resistant and stem-like cancer cells. Here, given the role of ALDH in aldehyde detoxification, we examined how inhibiting its activity could represent a pro-ferroptotic strategy to be combined with chemotherapy. We used genetic (CRISPR-Cas9 KO) and pharmacological tools to explore this hypothesis, focusing in particular on ALDH1A1, the main ALDH isoform. Using a 3D spheroid model of colorectal cancer, we documented the increase in ALDH activity, mainly supported by overexpression of the ALDH1A1 isoform, in response to acidosis and different chemotherapeutic agents. We also provided initial evidence that PUFA supplementation may increase the efficacy of a combination of ALDH-reducing drugs and conventional chemotherapy.