TGF-βRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation

Abstract

Cancer-associated fibroblasts (CAFs) are highly heterogeneous and differentiated stromal cells that promote tumor progression via remodeling of extracellular matrix, maintenance of stemness, angiogenesis, and modulation of tumor metabolism. Aerobic glycolysis is characterized by an increased uptake of glucose for conversion into lactate under sufficient oxygen conditions, and this metabolic process occurs at the site of energy exchange between CAFs and cancer cells. As a hallmark of cancer, metabolic reprogramming of CAFs is defined as reverse Warburg effect (RWE), characterized by increased lactate, glutamine, and pyruvate, etc. derived from aerobic glycolysis. Given that the TGF-β signal cascade plays a critical role in RWE mainly through metabolic reprogramming related proteins including pyruvate kinase muscle isozyme 2 (PKM2), however, the role of nuclear PKM2 in modifying glycolysis remains largely unknown. In this study, using a series of in vitro and in vivo experiments, we provide evidence that TGF-βRII overexpression suppresses glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth. This study highlights a novel pathway that explains the role of TGF-βRII in CAFs glucose metabolism and suggests that targeting TGF-βRII in CAFs might represent a therapeutic approach for oral cancer.

‘Reverse Warburg effect’ of cancer‑associated fibroblasts (Review)

“…This demonstrates that IDH3α is a key metabolic switch in CAFs (84). A recent study revealed that TGF-β type II receptor (TGF-βRII) nuclear translocation of PKM2 inhibits glucose metabolism in CAFs, thereby inhibiting oral cancer tumor growth (85).…”

TGF-β signaling in the tumor metabolic microenvironment and targeted therapies

“…In addition, TGF-β treatment decreases the flow of pyruvate to the TCA cycle by directly activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1), and this enzyme inactivates the TCA cycle enzyme pyruvate dehydrogenase in mouse and human fibroblasts, a human Burkitt’s lymphoma cell line, and human renal cell carcinoma cell lines [ 169 , 170 ]. Our research team successfully separated and cultured human oral CAFs from human cancer [ 156 ], and verified the upregulated glycolysis via PFKFB3 and PKM2 overexpression in oral CAFs [ 157 , 158 ]. However, we found that TGF-βRII was downregulated in oral CAFs and thus promoted PKM2 nuclear translocation via increasing p-ERK1/2, which was responsible for the elevated glycolysis in oral CAFs [ 157 , 171 ].…”

“…Our research team successfully separated and cultured human oral CAFs from human cancer [ 156 ], and verified the upregulated glycolysis via PFKFB3 and PKM2 overexpression in oral CAFs [ 157 , 158 ]. However, we found that TGF-βRII was downregulated in oral CAFs and thus promoted PKM2 nuclear translocation via increasing p-ERK1/2, which was responsible for the elevated glycolysis in oral CAFs [ 157 , 171 ]. This study demonstrates that TGFβRII is reversely correlated with glycolysis via activation of non-canonical TGF-β signaling.…”

Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas

“…GlyCAF share similar transcriptional profiles with previously identified myCAF 6 , 45 , 61 , which are driven by TGFβ signaling and implicated in CD8 + T cell exclusion. TGFβ also drives glycolytic metabolism in fibroblasts 62 – 64 , uncovering a potential role for TGFβ in glyCAF biogenesis, although this warrants further investigation. This work highlights the importance of considering the functional features of CAFs when developing therapeutic strategies targeting the tumor microenvironment 65 .…”