Cancer associated fibroblast FAK regulates malignant cell metabolism

Abstract

Emerging evidence suggests that cancer cell metabolism can be regulated by cancerassociated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.

FAK activity in cancer‐associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer

“…A recent publication identified, using molecular and functional analyses of several patient‐derived CAF primary cultures, four CAF sub‐groups that co‐exist within a tumour, each featuring specific phenotype and prognostic value (Neuzillet et al , 2019). While we were preparing this manuscript, the Hodivala‐Dilke's group showed that FAK depletion in a subpopulation of CAFs (FSP1‐positive) metabolically increases pancreatic tumour growth in mice and that low FAK gene expression within CAFs is associated with poor PDAC patient survival (Demircioglu et al , 2020). FAK role depends on both its scaffolding and kinase activities, and our FAK ‐inactivating strategy mimics the pharmacological inhibition as FAK‐KD mutant retains the cytoplasmic and nuclear scaffolding functions of FAK, which is not the case when FAK gene is invalidated (Demircioglu et al , 2020).…”

“…While we were preparing this manuscript, the Hodivala‐Dilke's group showed that FAK depletion in a subpopulation of CAFs (FSP1‐positive) metabolically increases pancreatic tumour growth in mice and that low FAK gene expression within CAFs is associated with poor PDAC patient survival (Demircioglu et al , 2020). FAK role depends on both its scaffolding and kinase activities, and our FAK ‐inactivating strategy mimics the pharmacological inhibition as FAK‐KD mutant retains the cytoplasmic and nuclear scaffolding functions of FAK, which is not the case when FAK gene is invalidated (Demircioglu et al , 2020). Another explanation for differences between ours and published results (Demircioglu et al , 2020) is that FAK expression and/or signalling may be heterogeneous across patient tumours and within different CAF subsets in a same tumour, putatively explaining different biological consequences for FAK targeting.…”

“…FAK role depends on both its scaffolding and kinase activities, and our FAK ‐inactivating strategy mimics the pharmacological inhibition as FAK‐KD mutant retains the cytoplasmic and nuclear scaffolding functions of FAK, which is not the case when FAK gene is invalidated (Demircioglu et al , 2020). Another explanation for differences between ours and published results (Demircioglu et al , 2020) is that FAK expression and/or signalling may be heterogeneous across patient tumours and within different CAF subsets in a same tumour, putatively explaining different biological consequences for FAK targeting. Accordingly, we observed that fibroblastic FAK activity is highly heterogeneous between PDAC patients, and showed that the fibroblastic pY397 FAK score is an independent prognosis marker that would help to identify patients with high risk of early relapse after surgery, and with the most benefit of receiving an adjuvant protocol including a FAK inhibitor.…”

Mitochondria at Center of Exchanges between Cancer Cells and Cancer-Associated Fibroblasts during Tumor Progression

“…Some CAFs subpopulations have also been shown to reorganize cancer cell metabolism via secreting cytokines that favor glycolysis and TCA cycle intermediates production, resulting in tumor growth and invasion in breast and pancreatic cancers [ 21 ]. A similar cytokine-based interaction was shown in ovarian cancer, implying IL-6, CXCL-5 and CXCL-10, which promotes self-stored glycogen utilization by cancer cells to fuel glycolysis and subsequent mitochondrial activity [ 22 ].…”

Long Non-Coding RNAs as Regulators of Interactions between Cancer-Associated Fibroblasts and Cancer Cells in the Tumor Microenvironment

“…CAFs also modulate glycolytic metabolism in cancer cells. Downregulation of focal adhesion kinase in CAFs increases CCL6 and CCL12 expression, leading to elevated glycolysis in cancer cells [ 47 ]. CAFs educated by neighboring cancer cells reversely secrete cytokines to stimulate glycogen metabolism in cancer cells, which accelerates energy production and tumor progression [ 48 ].…”