👤 Laetitia Ligat

Glioblastomas (GBM) are aggressive tumors, which systematically relapse despite standard treatment associating surgery, chemotherapy and radiation therapy. More recently, GBM therapy now includes another therapeutic modality option, Tumor Treating Fields (TTFields) given in combination with Temozolomide (TMZ) following standard treatment. However even with the adjunction of TTFields, GBM remains a lethal disease due to treatment resistance. One of the causes of resistance is the presence of cancer stem cells (GSC) known to be chemo and radioresistant and responsible for tumor regrowth. Studying mechanisms of resistance of GSC to TTFields is thus a major issue to address. Fibroblast Growth Factor Receptors (FGFR) play a major role in numerous processes essential for cancer development, and dysregulation of FGFR signaling has been observed in many cancer types, including GBM. We have previously shown that tyrosine kinase receptor Fibroblast Growth Factor Receptor 1 (FGFR1) controls GBM aggressiveness and GSC radioresistance and that its inhibition leads to radiosensitization through increasing mitotic cell death and microenvironment modulation. Because one of the main mechanisms of action of TTFields is mitotic disturbance and because TTFields act synergistically in vitro with irradiation (IR), we hypothesize that targeting FGFR could sensitize GSC to TTFields. Here we show that, like IR, TTFields significantly decrease GSC growth. Treatment of GSC with pemigatinib (Pem), a FGFR1-3 inhibitor, alters FGFR signalling pathway. We demonstrate that Pem, sensitizes GSC to TTFields by synergistically decreasing their survival and clonogenic ability. Finally, the adjunction of Pem to treatment combining IR and TTFields could sensitize GSC by inducing, in some GSC, a further decrease in the repair of IR-induced DNA damages. Altogether, these results highlight the potential benefits of inhibiting FGFR with the concomitant application of TTFields in the first-line standard GBM treatment to improve patient prognosis. Show less

Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity. Show less