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. Author manuscript; available in PMC: 2022 Feb 22.
Published in final edited form as: Nat Metab. 2021 Apr 19;3(4):456–468. doi: 10.1038/s42255-021-00384-w

Figure 4.

Figure 4.

Reciprocal regulation of mechanics and metabolism in cancer. (a) Under normal conditions, the compliant extracellular matrix suppresses JNK/p38 signaling, and promotes either retainment of inactive YAP/TAZ in the cytosol or its degradation by proteasomes. Cells show reduced actin cytoskeleton assembly and express normal levels of surface glycocalyx. (b) In cancer, extracellular matrix stiffening accelerates glycolysis through JNK/p38 and YAP/TAZ-mediated metabolic reprogramming, and induces cytoskeleton remodelling, resulting in the release of glycolytic enzymes in the cytosol, thereby promoting glucose metabolism. Transcriptional programs are perturbed, promoting metabolic reprogramming, including glucose and glutamine metabolism. Glutamine metabolic and glycolytic end-products feed into the TCA cycle, increasing the abundance of oncometabolites fumarate, succinate, and 2-HG (red). The surface glycocalyx is frequently overexpressed generating large entropic pressures that drive increased membrane curvature and tubulation. GLUT, glucose transporter; GLS1, glutaminase 1; Ub, ubiquitin.