A clear cell renal cancer stem cell niche supported by autophagic methionine secretion from PDGFR-β+GPR91+ tumor-associated pericytes

Pericytes are heterogeneous mural cells surrounding blood vessels that are critically involved in malignant progression. Here we identify a subset of vascular pericytes, defined by expression of PDGFR-β and 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 the pericyte surface to activate autophagy for methionine production. CSCs use methionine to create stabilizing N6-methyladenosine (m6A) in ATAD2 mRNA, and the resulting ATAD2 protein complexes with SRY-box transcription factor 9 (Sox9) to establish super enhancers and thereby dictate its target genes that feature prominently in CSCs. Targeting PDGFR-β+GPR91+ pericytes with specific GRP91 antagonists effectively reduced intratumoral methionine level, eliminated CSCs and sensitized tumors to TKIs. Our results describe how PDGFR-β+GPR91+ pericytes provide supportive niche for CSCs and therefore could be potential targets for treating ccRCC.