Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts

Abstract

Even though pancreatic ductal adenocarcinoma (PDAC) is associated with fibrotic stroma, the molecular pathways regulating the formation of cancer associated fibroblasts (CAFs) are not well elucidated. An epigenomic analysis of patient-derived and de-novo generated CAFs demonstrated widespread loss of cytosine methylation that was associated with overexpression of various inflammatory transcripts including CXCR4. Co-culture of neoplastic cells with CAFs led to increased invasiveness that was abrogated by inhibition of CXCR4. Metabolite tracing revealed that lactate produced by neoplastic cells leads to increased production of alpha-ketoglutarate (aKG) within mesenchymal stem cells (MSCs). In turn, aKG mediated activation of the demethylase TET enzyme led to decreased cytosine methylation and increased hydroxymethylation during de novo differentiation of MSCs to CAF. Co-injection of neoplastic cells with TET-deficient MSCs inhibited tumor growth in vivo. Thus, in PDAC, a tumor-mediated lactate flux is associated with widespread epigenomic reprogramming that is seen during CAF formation.

Is Lactate an Oncometabolite? Evidence Supporting a Role for Lactate in the Regulation of Transcriptional Activity of Cancer-Related Genes in MCF7 Breast Cancer Cells

“…For example, Damiani et al have observed that TCA intermediates that are not used for biomass purposes can be disposed via lactate production (34). Hence, while lactate is a metabolic intermediate, it has numerous downstream effects as known to occur via cell redox changes (14), allosteric binding (47), metabolic reprograming (26), and lactylation (25). The downstream effects of lactate in cancer remain to be determined.…”

“…They also showed that lysine lactylation (Kla) levels increased in a dose-dependent fashion in response to exogenous L-lactate and that endogenous production of lactate is a key determinant of histone Kla levels (25). Furthermore, Verma's group has recently and elegantly demonstrated that tumor-mediated lactate can elicit epigenomic reprograming of cancer-associated fibroblasts from pancreatic ductal adenocarcinoma (26).…”

Epigenetics in modulating immune functions of stromal and immune cells in the tumor microenvironment

“…The fourth study described is an epigenomic analysis of patient-derived and de novo generated PDA CAFs performed by Bhagat et al, who demonstrated that a widespread loss of DNA methylation was associated with the overexpression of various inflammatory genes, including interleukins and chemokines, such as IL1A, CCL5, and CCL26 , and cellular receptors, such as CXCR4 and ICAM3 , which are all involved in critical cell signaling pathways in tumor progression. 94 Interestingly, metabolite tracing used in this study revealed that the lactate produced by PDA tumor cells led to increased MSC production of alpha-ketoglutarate (aKG), an important cofactor of the DNA demethylase TET. Conversely, aKG mediated the activation of TET enzymes, which led to decreased DNA methylation during the de novo differentiation of MSCs to CAFs.…”

The Fate of Th17 Cells is Shaped by Epigenetic Modifications and Remodeled by the Tumor Microenvironment

“…During the last decade, studies on the epigenetic interplay between immune, stromal and cancer cells in the tumor microenvironment have emerged. These publications were particularly focused on the impact of epigenetics on the formation of CAFs (cancer associated fibroblasts) and CD8 T cell exhaustion (TOX) but more data on CD4 T cell biology need to be collected [57][58][59].…”