Tumor–stromal metabolic crosstalk in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a dire prognosis.Standard-of-care chemotherapy regimens offer marginal survival benefit and carry risk of severe toxicity, while immunotherapy approaches have uniformly failed in clinical trials.Extensive desmoplasia in the PDAC tumor microenvironment (TME) disrupts blood flow to and from the tumor, thereby creating a nutrient-depleted, hypoxic, and acidic milieu that suppresses the function of antitumor immune cells and imparts chemotherapy resistance.Additionally, recent seminal studies have demonstrated crucial roles for metabolic crosstalkthe exchange of metabolites between PDAC cells and stromal cell populations in the TMEin establishing and maintaining core malignant behaviors of PDAC: tumor growth, metastasis, immune evasion, and therapy resistance.In this review, we provide a conceptual overview of metabolic crosstalk and how it evolves under various selection pressures in the TME, analyze the landscape of proposed tumorigenic metabolic crosstalk pathways, and highlight potentially druggable nodes. Pancreatic cancer remodels the TME to favor tumor progressionPDAC is a deadly malignancy that carries a dismal prognosis.The extreme mortality is due to late diagnosis, early metastasis, recurrence, and poor response to existing therapies.A compelling body of emerging evidence suggests that the aggressive clinical behavior of PDAC is in significant part attributable to the ability of PDAC cells to cause changes in the TME that support its malignant capabilities (Box 1) [1][2][3][4][5].A variety of stromal cells in the TME, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), T regulatory cells (Tregs), and others, facilitate PDAC progression by various mechanisms [2,6].Deranged cancer cell metabolism has been recognized as a driver of malignant tumor behavior since at least the 1920s [7].Metabolic changes are initiated early in the preneoplastic lesions [8].More recently, major technological advances in experimental biology have facilitated the discovery of metabolite exchange networks involving cancer cells and various stromal cell types in the TME, which has been termed 'metabolic crosstalk'.Seminal studies have since proposed essential roles for metabolic crosstalk across disparate domains of PDAC biology, including tumor growth, survival of tumor cells under harsh microenvironments, immune evasion, metastasis, and chemothe rapy resistance.In this review, we provide a conceptual overview of metabolic crosstalk and analyze an illustrative cross-section of proposed mechanisms by which it enables PDAC disease progression, with an emphasis on metabolic crosstalk pathways that may represent tractable and efficacious targets suitable for clinical testing. Metabolic symbiosis enables tumor growth in the nutrient-poor PDAC TMEThe term 'metabolic symbiosis' refers to the mutually fitness-enhancing exchange of metabolites between malignant epithelial cells (hereafter referred to as 'PDAC cells') and other cell types in the