Oncogenic KRAS-Driven Metabolic Reprogramming in Pancreatic Cancer Cells Utilizes Cytokines from the Tumor Microenvironment

Abstract

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic KRAS in protumorigenic signaling interactions between cancer cells and host cells. We show that KRAS mutation (KRAS*) drives cell-autonomous expression of type I cytokine receptor complexes (IL2r γ -IL4r α and IL2r γ -IL13r α 1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading Th2 cells in the microenvironment. Early neoplastic lesions show close proximity of cancer cells harboring KRAS* and Th2 cells producing IL4 and IL13. Activated IL2r γ -IL4r α and IL2r γ -IL13r α 1 receptors signal primarily via JAK1-STAT6. Integrated transcriptomic, chromatin occupancy, and metabolomic studies identifi ed MYC as a direct target of activated STAT6 and that MYC drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the KRAS*-driven metabolic reprogramming of PDAC. SIGNIFICANCE:Type II cytokines, secreted by Th2 cells in the tumor microenvironment, can stimulate cancer cell-intrinsic MYC transcriptional upregulation to drive glycolysis. This KRAS*-driven heterotypic signaling circuit in the early and advanced tumor microenvironment enables cooperative protumorigenic interactions, providing candidate therapeutic targets in the KRAS* pathway for this intractable disease.

Thymic Stromal Lymphopoietin and Cancer: Th2-Dependent and -Independent Mechanisms

“…At difference with the transplantable K14-TSLPtg mouse model reported above (30), very recently DePinho and collaborators (59), using a transgenic mouse model of pancreatic cancer carrying an inducible oncogenic KRAS mutation, demonstrated a tumor-promoting function for Th2 cytokines from the tumor microenvironment, thus recapitulating the human disease. In this model, activation of cancer cells carrying the mutated KRAS by IL-4 and IL-13, which were secreted by the Th2 cells present in the tumor microenvironment, triggered the JAK1-STAT6-MYC pathway that in turn activated glycolysis crucial for tumor progression.…”

Cancer Stemness Meets Immunity: From Mechanism to Therapy

“…In NSCLC, CD8 + T cells are the main sources of IFN-γ, where low levels of IFN-γ promote CSC stemness via activation of the PI3K/AKT/ NOTCH1 pathway and high levels of IFN-γ induce cancer cell apoptosis via activation of the Janus kinase 1 (JAK1)/STAT1/caspase pathway ( Song et al, 2019 ). In pancreatic cancer, infiltrating Th2 cells produce cytokines IL-4 and IL-13 to activate the JAK1/STAT6 pathway in cancer cells, which in turn increases MYC-driven glycolysis ( Dey et al, 2020 ), an anabolic process that supports CSC stemness ( Chen et al, 2020b ; Sancho et al, 2015 ). In addition to secretion of soluble factors, T cells can regulate CSC stemness via a direct cell-to-cell contact mechanism in breast cancer where cognate non-lytic interactions between CD8 + T cells and cancer cells can promote cancer cell stemness ( Stein et al, 2019 ).…”

Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer

“…In cancer cells, KRAS* activates glycolysis and glutamine flux to provide metabolic intermediates for anabolic metabolism and to maintain redox homeostasis, respectively (5,7). KRAS* also drives cell autonomous expression of type I cytokine receptor complexes to receive growth signals from the tumor microenvironment (TME) to enhance glycolysis (8). Moreover, KRAS* induces cancer cell macropinocytosis as an additional carbon source to fuel tumor growth (9).…”