TY - JOUR

T1 - Metabolic reprogramming by driver mutation-tumor microenvironment interplay in pancreatic cancer

T2 - new therapeutic targets

AU - Andersen, Henriette Berg

AU - Ialchina, Renata

AU - Pedersen, Stine Falsig

AU - Czaplinska, Dominika

N1 - Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2021

Y1 - 2021

N2 - Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers globally with a mortality rate exceeding 95% and very limited therapeutic options. A hallmark of PDAC is its acidic tumor microenvironment, further characterized by excessive fibrosis and depletion of oxygen and nutrients due to poor vascularity. The combination of PDAC driver mutations and adaptation to this hostile environment drives extensive metabolic reprogramming of the cancer cells toward non-canonical metabolic pathways and increases reliance on scavenging mechanisms such as autophagy and macropinocytosis. In addition, the cancer cells benefit from metabolic crosstalk with nonmalignant cells within the tumor microenvironment, including pancreatic stellate cells, fibroblasts, and endothelial and immune cells. Increasing evidence shows that this metabolic rewiring is closely related to chemo- and radioresistance and immunosuppression, causing extensive treatment failure. Indeed, stratification of human PDAC tumors into subtypes based on their metabolic profiles was shown to predict disease outcome. Accordingly, an increasing number of clinical trials target pro-tumorigenic metabolic pathways, either as stand-alone treatment or in conjunction with chemotherapy. In this review, we highlight key findings and potential future directions of pancreatic cancer metabolism research, specifically focusing on novel therapeutic opportunities.

AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers globally with a mortality rate exceeding 95% and very limited therapeutic options. A hallmark of PDAC is its acidic tumor microenvironment, further characterized by excessive fibrosis and depletion of oxygen and nutrients due to poor vascularity. The combination of PDAC driver mutations and adaptation to this hostile environment drives extensive metabolic reprogramming of the cancer cells toward non-canonical metabolic pathways and increases reliance on scavenging mechanisms such as autophagy and macropinocytosis. In addition, the cancer cells benefit from metabolic crosstalk with nonmalignant cells within the tumor microenvironment, including pancreatic stellate cells, fibroblasts, and endothelial and immune cells. Increasing evidence shows that this metabolic rewiring is closely related to chemo- and radioresistance and immunosuppression, causing extensive treatment failure. Indeed, stratification of human PDAC tumors into subtypes based on their metabolic profiles was shown to predict disease outcome. Accordingly, an increasing number of clinical trials target pro-tumorigenic metabolic pathways, either as stand-alone treatment or in conjunction with chemotherapy. In this review, we highlight key findings and potential future directions of pancreatic cancer metabolism research, specifically focusing on novel therapeutic opportunities.

KW - Acidosis

KW - Clinical trials

KW - Glycolysis

KW - Lipid metabolism

KW - Metabolic subtypes

KW - PDAC

U2 - 10.1007/s10555-021-10004-4

DO - 10.1007/s10555-021-10004-4

M3 - Review

C2 - 34855109

AN - SCOPUS:85120572135

VL - 40

SP - 1093

EP - 1114

JO - Cancer and Metastasis Reviews

JF - Cancer and Metastasis Reviews

SN - 0167-7659

IS - 4

ER -