Methionine secreted by tumor-associated pericytes supports cancer stem cells in clear cell renal carcinoma

Cell Metab. 2024 Apr 2;36(4):778-792.e10. doi: 10.1016/j.cmet.2024.01.018. Epub 2024 Feb 19.

Abstract

Here, we identify a subset of vascular pericytes, defined by expression of platelet-derived growth factor receptor beta (PDGFR-β) and G-protein-coupled receptor 91 (GPR91), that promote tumorigenesis and tyrosine kinase inhibitors (TKIs) resistance by functioning as the primary methionine source for cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC). Tumor-cell-derived succinate binds to GPR91 on pericyte to activate autophagy for methionine production. CSCs use methionine to create stabilizing N6-methyladenosine in ATPase-family-AAA-domain-containing 2 (ATAD2) mRNA, and the resulting ATAD2 protein complexes with SRY-box transcription factor 9 to assemble super enhancers and thereby dictate its target genes that feature prominently in CSCs. Targeting PDGFR-β+GPR91+ pericytes with specific GRP91 antagonists reduce intratumoral methionine level, eliminate CSCs, and enhance TKIs sensitivity. These results unraveled the mechanisms by which PDGFR-β+GPR91+ pericytes provide supportive niche for CSCs and could be used to develop targets for treating ccRCC.

Keywords: GPR91; autophagy; cancer stem cell; clear cell renal cell carcinoma; methionine; pericytes.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Carcinoma, Renal Cell* / pathology
  • DNA-Binding Proteins / metabolism
  • Humans
  • Kidney Neoplasms* / pathology
  • Methionine / metabolism
  • Neoplastic Stem Cells / metabolism
  • Pericytes / metabolism
  • Racemethionine / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / metabolism

Substances

  • Methionine
  • Racemethionine
  • Receptor, Platelet-Derived Growth Factor beta
  • ATAD2 protein, human
  • ATPases Associated with Diverse Cellular Activities
  • DNA-Binding Proteins