Cancer-Associated Fibroblast Diversity Shapes Tumor Metabolism in Pancreatic Cancer

Abstract

Despite extensive research, the 5-year survival rate of pancreatic cancer (PDAC) patients remains at only 9%. Patients often show poor treatment response, due partly to a highly complex tumor microenvironment (TME). Cancer-associated fibroblast (CAF) heterogeneity is characteristic of the pancreatic TME, where several CAF subpopulations have been identified, such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen presenting CAFs (apCAFs). In PDAC, cancer cells continuously adapt their metabolism (metabolic switch) to environmental changes in pH, oxygenation, and nutrient availability. Recent advances show that these environmental alterations are all heavily driven by stromal CAFs. CAFs and cancer cells exchange cytokines and metabolites, engaging in a tight bidirectional crosstalk, which promotes tumor aggressiveness and allows constant adaptation to external stress, such as chemotherapy. In this review, we summarize CAF diversity and CAF-mediated metabolic rewiring, in a PDAC-specific context. First, we recapitulate the most recently identified CAF subtypes, focusing on the cell of origin, activation mechanism, species-dependent markers, and functions. Next, we describe in detail the metabolic crosstalk between CAFs and tumor cells. Additionally, we elucidate how CAF-driven paracrine signaling, desmoplasia, and acidosis orchestrate cancer cell metabolism. Finally, we highlight how the CAF/cancer cell crosstalk could pave the way for new therapeutic strategies.

Keywords: CAF; PDAC; acidosis; cancer-associated fibroblast; desmoplasia; hypoxia; metabolism; pancreatic cancer; paracrine signaling.

Figure 1

Cancer-associated fibroblast (CAF) heterogeneity in PDAC, with focus on cell of origin, activator signals, species-dependent markers, and functions. (A) Myofibroblastic CAFs with high alpha-SMA expression. (B) Inflammatory CAFs showing abundant IL1 receptors. (C) Antigen-presenting CAFs that express MHC-II. (D) Metabolic CAFs bearing increased glycolysis. (E) Meflin⁺ CAFs with tumor-restraining properties.

Figure 2

Direct effects of cancer-associated fibroblasts on cancer cell metabolism via metabolite exchange in PDAC. CAFs influence cancer cell metabolism by secreting lactate (reverse Warburg effect), amino acids, lipids, and exosomes. Cancer cells shift towards amino acid metabolism, TCA cycle, and pentose phosphate pathways to support anabolic processes and growth.

Figure 3

Indirect effects of cancer-associated fibroblasts on cancer cell metabolism in PDAC. (A) CAFs secrete cytokines and growth factors to orchestrate cancer cell metabolism. (B) CAFs produce ECM (desmoplasia), leading to hypovascularization and hypoxia. Desmoplasia and hypoxia stabilize HIF1A, shifting cancer cell metabolism towards glycolysis and promoting drug efflux. (C) CAFs favor acidic pH_e (tumor acidosis) via increased H⁺ secretion. Acidosis promotes cancer cell invasion, glycolysis, and metabolic waste trafficking in PDAC.