Hypoxia-Driven Oncometabolite L-2HG Maintains Stemness-Differentiation Balance and Facilitates Immune Evasion in Pancreatic Cancer

Abstract

In pancreatic cancer, the robust fibroinflammatory stroma contributes to immune suppression and renders tumors hypoxic, altering intra-tumoral metabolic pathways and leading to poor survival. One metabolic enzyme activated during hypoxia is lactate dehydrogenase A (LDHA). As a result of its promiscuous activity under hypoxia, LDHA produces L-2 hydroxyglutarate, an epigenetic modifier, that regulates the tumor transcriptome. However, the role of L-2HG in remodeling the pancreatic tumor microenvironment is not known. Here we used mass spectrometry to detect L-2HG in serum samples from pancreatic cancer patients, comprising tumor cells as well as stromal cells. Both hypoxic pancreatic tumors as well as serum from pancreatic cancer patients accumulated L-2HG as a result of promiscuous activity of LDHA. This abnormally accumulated L-2HG led to H3 hypermethylation and altered gene expression, which regulated a critical balance between stemness and differentiation in pancreatic tumors. Secreted L-2HG inhibited T cell proliferation and migration, suppressing anti-tumor immunity. In a syngeneic orthotopic model of pancreatic cancer, inhibition of LDHA with GSK2837808A decreased L-2HG, induced tumor regression, and sensitized tumors to anti-PD1 therapy. In conclusion, hypoxia-mediated promiscuous activity of LDHA produces L-2HG in pancreatic tumor cells, regulating the stemness-differentiation balance and contributing to immune evasion.Targeting LDHA can be developed as a potential therapy to sensitize pancreatic tumors to checkpoint inhibitor therapy.

Identification of Clinical and Tumor Microenvironment Characteristics of Hypoxia-Related Risk Signature in Lung Adenocarcinoma

“…The hypoxia-related risk signature consists of eight hypoxia-related genes, including LDHA, DCN, PGK1, PFKP, FBP1, LOX, ENO3, and CXCR4. LDHA is an enzyme that catalyzes the mutual conversion of pyruvate and lactic acid, as well as promotes invasion, metastasis, nest loss, and apoptosis resistance in various cancers ( Cheng et al, 2021 ; Crowley et al, 2021 ; Gupta et al, 2021 ). Multiple studies have suggested that DCN can suppress lung cancer progression by blocking receptor tyrosine kinases ( Horvath et al, 2014 ).…”

Cuproptosis scoring model predicts overall survival and assists in immunotherapeutic decision making in pancreatic carcinoma

“…Previous studies report that active angiogenesis is essential for tumor growth and metastasis, thus resulting in immune function suppression; therefore, angiogenesis inhibition is a promising therapeutic option for suppressing tumor growth ( Sharma et al, 2001 ; Motz and Coukos, 2011 ; Welti et al, 2013 ). Hypoxia can suppress TME and promote PAAD progression ( Liu et al, 2019 ; Gupta et al, 2021 ; Tao et al, 2021 ). Cancer-related pathways such as P53 and VEGF were enriched in the high-CuRS group.…”

An analysis of the significance of the Tre2/Bub2/CDC 16 (TBC) domain protein family 8 in colorectal cancer

“…It has been well documented that SOX2 can promote tumor proliferation and invasion and can regulate tumor cell stemness in a hypoxic microenvironment through a variety of pathways 53 . Cell sphere formation capacity have been used as read-out for tumor stemness 54 .Previous studies have reported a less differentiated phenotype and/or an increase in stemness induced by hypoxia in Various tumors 55 – 57 . In the present study, it was shown that TBC1D8 knockdown potentiated sphere-forming capacity in CRC cells.…”