Tumor mechanics and metabolic dysfunction

Abstract

Desmosplasia is a characteristic of most solid tumors and leads to fibrosis through abnormal extracellular matrix (ECM) deposition, remodeling and post translational modifications. The resulting stiff tumor stroma not only compromises vascular integrity to induce hypoxia and impede drug delivery, but also promotes aggressiveness by potentiating the activity of key growth, invasion, and survival pathways. Intriguingly, many of the pro-tumorigenic signaling pathways which are mechanically activated by ECM stiffness also promote glucose uptake and aerobic glycolysis, and an altered metabolism is a recognized hallmark of cancer. Indeed, emerging evidence suggests that metabolic alterations and an abnormal ECM may cooperatively drive cancer cell aggression and treatment resistance. Accordingly, improved methods to monitor tissue mechanics and metabolism promise to improve diagnostics and treatments to ameliorate ECM stiffening and elevated mechanosignaling may improve patient outcome. Here we discuss the interplay between ECM mechanics and metabolism in tumor biology and suggest that monitoring these processes and targeting their regulatory pathways may improve diagnostics, therapy, and the prevention of malignant transformation.

Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension

“…Here, the identification of glutaminolysis as a mechanoactivated process coregulated with aerobic glycolysis advances our understanding of the regulatory hierarchy seen in the metabolic reprogramming in PH. Such an interface between stiffness and metabolism draws parallels to related reprogramming events proposed in tumors in relation to matrix remodeling (29). By its direct causative relation to metabolic dysregulation, it also reinforces the paradigm of vascular stiffness as an initiating pathogenic trigger of this disease rather than merely an end-stage feature.…”

18F-fluoromisonidazole PET and Activity of Neoadjuvant Nintedanib in Early HER2-Negative Breast Cancer: A Window-of-Opportunity Randomized Trial

“…Alternatively, when the TKIs do not exert vascular normalization or cause excessive vascular pruning, TKI treatment would add no benefit to chemotherapy. In a preclinical study, we demonstrated that measuring tumor hypoxia with 18 F-fluoromisonidazole PET mirrored the status of vascular normalization. We incorporated this technique in the neoadjuvant setting of breast cancer patients treated with the TKI nintedanib in combination with chemotherapy.…”

“…We hypothesized that tracing the tumor stromal oxygenation levels with 18 F-fluoromisonidazole-positron emission tomography (18F-FMISO-PET) during a WoO would allow detecting the patients that are or are not candidates for nintedanib therapy. The justification of this hypothesis is that it is widely accepted that abnormal stroma is hypoxic as well (5,(18)(19)(20)(21).…”

“…The justification of this hypothesis is that it is widely accepted that abnormal stroma is hypoxic as well (5,(18)(19)(20)(21). Thus, if hypoxia can be monitored, it could be possible to detect in which patients the stromal normalization phenomenon is occurring (i.e., continue nintedanib) or not (i.e., stop nintedanib).…”

Mesenchymal traits at the convergence of tumor-intrinsic and -extrinsic mechanisms of resistance to immune checkpoint blockers

“…It is now clearly evident that tumors contain various non-cancer cells including fibroblasts, vascular endothelial cells, immune cells -with T-cells as potent mediators of antitumor immunity -and soluble factors [2][3][4] that, in dynamic reciprocity with cancer cells, make up the tumor microenvironment (TME). TME is organ-specific in terms of interstitial cells and extracellular matrix (ECM), which condition tissue oxygen levels and pH, adding further layers of complexity [5,6].…”