• Le 28 avril 2022
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Webinar by Lisa Nocquet PhD student Team 7

"Metabolic influence of cancer-associated fibroblasts on triple negative breast cancer cells sensitivity to apoptosis
Triple-negative breast cancer (TNBC) is an aggressive cancer with a poor prognosis that is particularly resistant to cytotoxic chemotherapeutic treatments, notably due to over-expression of anti-apoptotic proteins. Here we show that, additional to intrinsic resistance, cancer cells acquire resistance to apoptosis thanks to a dialogue with cancer-associated fibroblasts (CAFs) of the microenvironment."

We used BH3-mimetics (e.g. ABT-737) targeting anti-apoptotic proteins of the BCL-2 family as cell death inducers in the TNBC cell line MDA-MB-468 cultured with conditioned-media of primary culture of CAFs from patients with invasive carcinoma. We established a cross-talk relying on soluble metabolic mediators. By analyzing metabolic phenotypic profiles, we noted enhanced consumption of mitochondria-fueling metabolites in MDA-MB-468 cancer cells under CAFs influence. CAFs promote oxygen consumption by cancer cells while a supply of pyruvate is sufficient to reduce cancer cells sensitivity to ABT-737-induced apoptosis. This suggests a central role of pyruvate in the protective effect of CAFs on TNBC cells apoptosis. Consistently, we show that CAFs protective effect is reversed by the inhibition of the mitochondrial entry of pyruvate in cancer cells.
We thus established a link between pyruvate metabolism and apoptosis resistance which allows TNBC cells to exploit CAF metabolic properties and unravelled a new potential therapeutic target to improve TNBC cytotoxic treatment in an ecosystemic context.