Macropinocytosis in Cancer-Associated Fibroblasts Is Dependent on CaMKK2/ARHGEF2 Signaling and Functions to Support Tumor and Stromal Cell Fitness

Abstract

Although pancreatic ductal adenocarcinoma (PDAC) cells are exposed to a nutrient-depleted tumor microenvironment, they can acquire nutrients via macropinocytosis, an endocytic form of protein scavenging that functions to support cancer metabolism. Here, we provide evidence that macropinocytosis is also operational in the pancreatic tumor stroma. We find that glutamine deficiency triggers macropinocytic uptake in pancreatic cancer–associated fibroblasts (CAF). Mechanistically, we decipher that stromal macropinocytosis is potentiated via the enhancement of cytosolic Ca2+ and dependent on ARHGEF2 and CaMKK2-AMPK signaling. We elucidate that macropinocytosis has a dual function in CAFs—it serves as a source of intracellular amino acids that sustain CAF cell fitness and function, and it provides secreted amino acids that promote tumor cell survival. Importantly, we demonstrate that stromal macropinocytosis supports PDAC tumor growth. These results highlight the functional role of macropinocytosis in the tumor stroma and provide a mechanistic understanding of how nutrient deficiency can control stromal protein scavenging. Significance: Glutamine deprivation drives stromal macropinocytosis to support CAF cell fitness and provide amino acids that sustain PDAC cell survival. Selective disruption of macropinocytosis in CAFs suppresses PDAC tumor growth. This article is highlighted in the In This Issue feature, p. 1601

Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting

“…Zhang et al have reported that glutamine deficiency triggers macropinocytic nutrient uptake in pancreatic CAFs by the enhancement of cytosolic Ca2 + and CaMKK2-AMPK signaling. Herein, macropinocytosis contributes to intracellular and extracellular amino acid pools that sustain CAF fitness and promote tumor cell survival [62].…”

Mesenchymal Lineage Heterogeneity Underlies Nonredundant Functions of Pancreatic Cancer–Associated Fibroblasts

“…Pancreatic ductal adenocarcinoma (PDAC) is defined in part by an exuberant stromal reaction, including abundant cancer-associated fibroblasts (CAFs) (1)(2)(3)(4). Diverse tumorsupportive functions have been ascribed to PDAC CAFs, including metabolic roles whereby nutrient transfer from CAFs to neighboring pancreatic cancer cells facilitates proliferation within a nutrient-poor microenvironment (5)(6)(7)(8)(9). In addition, PDAC CAFs produce cytokines and chemokines associated with immune suppression (10)(11)(12)(13), and CAF ablation in mice fosters efficacy of immune checkpoint inhibitors which are otherwise ineffective in PDAC (14,15).…”

Exploiting cancer’s drinking problem: regulation and therapeutic potential of macropinocytosis

“…By affording access to diverse sources of nutrients, macropinocytosis is emerging as a metabolic adaptation that contributes to multiple fitness determinants. There is also evidence to suggest that macropinocytosis is sensitive to nutrient availability [16,24,25]. These important observations invoke the idea that tumor cells can selectively tune macropinocytic activity to modulate nutrient scavenging according to their metabolic needs, further reinforcing the connection between macropinocytosis and metabolic fitness.…”