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.

周细胞（Pericytes）是环绕血管的异质性壁细胞，在恶性进展中发挥关键作用。本研究鉴定出一类以血小板衍生生长因子受体β（PDGFR-β）与G蛋白偶联受体91（GPR91）的表达为特征的血管周细胞亚群，该亚群可作为透明细胞肾细胞癌（ccRCC）中癌症干细胞（CSCs）的主要甲硫氨酸来源，进而促进肿瘤发生与酪氨酸激酶抑制剂（TKIs）耐药。肿瘤细胞来源的琥珀酸可结合周细胞表面的GPR91，激活细胞自噬以合成甲硫氨酸。癌症干细胞利用甲硫氨酸在ATAD2信使RNA（ATAD2 mRNA）中诱导产生稳定性N6-甲基腺苷（m6A）修饰，由此产生的ATAD2蛋白与SRY框转录因子9（Sox9）形成复合物，进而构建超级增强子，调控癌症干细胞特征性靶基因的表达。使用特异性GPR91拮抗剂靶向PDGFR-β+GPR91+周细胞，可有效降低瘤内甲硫氨酸水平、清除癌症干细胞，并使肿瘤对酪氨酸激酶抑制剂复敏。本研究阐明了PDGFR-β+GPR91+周细胞为癌症干细胞提供支持性微环境的机制，因此该类细胞可作为治疗透明细胞肾细胞癌的潜在靶点。