Methionine secreted by tumor-associated pericytes supports cancer stem cells in clear cell renal carcinoma.
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.
Pubmed ID: 38378000 RIS Download
Research resources used in this publication
- C57BL/6-Gt(ROSA)26Sortm1(HBEGF)Awai/J (RRID:IMSR_JAX:007900) (organism)
- HEK293T/17 (RRID:CVCL_1926) (cell line)
- GPR91 Polyclonal Antibody (RRID:AB_2812793) (antibody)
- GPR91 Polyclonal Antibody (RRID:AB_2812793) (antibody)
- PDGF Receptor beta (28E1) Rabbit mAb (RRID:AB_2162497) (antibody)
- Recombinant Anti-Rb antibody [EPR17512] (RRID:AB_2848193) (antibody)
- PDGF Receptor beta (28E1) Rabbit mAb (RRID:AB_2162497) (antibody)
- Recombinant Anti-Rb antibody [EPR17512] (RRID:AB_2848193) (antibody)
- TP53-human (RRID:AB_628082) (antibody)
- TP53-human (RRID:AB_628082) (antibody)
- Recombinant Anti-Ki67 antibody [SP6] (RRID:AB_302459) (antibody)
- Recombinant Anti-Ki67 antibody [SP6] (RRID:AB_302459) (antibody)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- HRP AffiniPure Goat Anti-Rabbit IgG(H+L) (RRID:AB_2572420)
- alpha Tubulin antibody [DM1A] - Loading Control (RRID:AB_2241126)
- N Cadherin antibody [EPR1791-4] (RRID:AB_1310479)
- Anti-pan Cytokeratin antibody [PAN-CK (Cocktail)] (RRID:AB_2922672)
- Recombinant Anti-NG2 antibody [EPR23976-145] (RRID:AB_2922401)
- CD146 antibody [EPR3208] (RRID:AB_2143375)
- Desmin antibody [Y266] (RRID:AB_731901)
- Recombinant Anti-SQSTM1 / p62 antibody [EPR4844] - Autophagosome Marker (RRID:AB_2810880)
- Rabbit Anti-LC3B Polyclonal Antibody, Unconjugated, Clone G40 (RRID:AB_2137703)
- Histone H3 (tri methyl K27) antibody [mAbcam 6002] - ChIP Grade (RRID:AB_305237)
- H3K9me3-human,H3K9me3-mouse (RRID:AB_306848)
- Anti-Histone H3 (tri methyl K4) antibody - ChIP Grade (RRID:AB_306649)
- MED26 (D4B1X) Rabbit mAb (RRID:AB_2798656)
- MED17 Polyclonal Antibody (RRID:AB_2576978)
- CRSP2 / MED14 antibody [2214C1a] (RRID:AB_869273)
- PBRM1/BAF180 (E9X2Z) Rabbit mAb (RRID:AB_2936366)
- ARID1A/BAF250A (D2A8U) Rabbit mAb #12354 (RRID:AB_2637010)
- SMARCC2/BAF170 (D8O9V) Rabbit mAb (RRID:AB_2798017)
- Brg1 (E9O6E) Mouse mAb (RRID:AB_2799410)
- HDAC1 antibody [EPR460(2)] (RRID:AB_10861012)
- Anti-Sox9 (RRID:AB_2239761)
- NaPi2b/SLC34A2 (D6W2G) Rabbit mAb (RRID:AB_2799218)
- Bcl-2 (D17C4) Rabbit mAb (Mouse Preferred) (RRID:AB_1903907)
- Atg7 Antibody (RRID:AB_2227783)
- Atg14 (RRID:AB_2737056)
- PI 3 Kinase Class 3 antibody [EPR5301] (RRID:AB_10975462)
- Recombinant Anti-Beclin 1 antibody [EPR19662] (RRID:AB_2692326)
- Rabbit Anti-HA tag Polyclonal Antibody, Unconjugated (RRID:AB_307019)
- Recombinant Anti-LC3B antibody [EPR18709] - Autophagosome Marker (RRID:AB_2827794)
- ALDH1A1 antibody [EP1933Y] (RRID:AB_867566)
- Recombinant Anti-CXCR4 antibody [EPUMBR3] (RRID:AB_2910168)
- PE anti-mouse CD31 (RRID:AB_312903)
- HRP, Goat Anti-Mouse IgG(H+L) (RRID:AB_2890177)
- Recombinant Anti-CD31 antibody [EPR17260-263] (RRID:AB_2905525)
- Rabbit Anti-Collagen IV Polyclonal Antibody, Unconjugated (RRID:AB_305584)
- Endomucin antibody [V.7C7.1] (RRID:AB_10859306)
- CD105 antibody [MEM-226] (RRID:AB_303134)
- Mouse Anti-Cytokeratin, pan Monoclonal Antibody, Unconjugated, Clone C-11 (RRID:AB_306047)
- GPR91 Polyclonal Antibody (RRID:AB_2812793)
- PDGF Receptor beta (28E1) Rabbit mAb (RRID:AB_2162497)
- Recombinant Anti-Rb antibody [EPR17512] (RRID:AB_2848193)
- TP53-human (RRID:AB_628082)
- Recombinant Anti-Ki67 antibody [SP6] (RRID:AB_302459)
Associated grants
NonePublication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This is a list of tools and resources that we have found mentioned in this publication.
HRP AffiniPure Goat Anti-Rabbit IgG(H+L) (antibody)
RRID:AB_2572420
This unknown targets IgG(H+L)
View all literature mentionsalpha Tubulin antibody [DM1A] - Loading Control (antibody)
RRID:AB_2241126
This monoclonal targets alpha Tubulin antibody [DM1A] - Loading Control
View all literature mentionsN Cadherin antibody [EPR1791-4] (antibody)
RRID:AB_1310479
This monoclonal targets N Cadherin antibody [EPR1791-4]
View all literature mentionsAnti-pan Cytokeratin antibody [PAN-CK (Cocktail)] (antibody)
RRID:AB_2922672
This monoclonal targets pan Cytokeratin
View all literature mentionsRecombinant Anti-NG2 antibody [EPR23976-145] (antibody)
RRID:AB_2922401
This recombinant monoclonal targets NG2
View all literature mentionsCD146 antibody [EPR3208] (antibody)
RRID:AB_2143375
This monoclonal targets MCAM
View all literature mentionsDesmin antibody [Y266] (antibody)
RRID:AB_731901
This monoclonal targets Desmin antibody [Y266]
View all literature mentionsRecombinant Anti-SQSTM1 / p62 antibody [EPR4844] - Autophagosome Marker (antibody)
RRID:AB_2810880
This recombinant targets SQSTM1 / p62
View all literature mentionsRabbit Anti-LC3B Polyclonal Antibody, Unconjugated, Clone G40 (antibody)
RRID:AB_2137703
This polyclonal targets LC3B
View all literature mentionsHistone H3 (tri methyl K27) antibody [mAbcam 6002] - ChIP Grade (antibody)
RRID:AB_305237
This monoclonal targets Histone H3 (tri methyl K27) antibody [mAbcam 6002] - ChIP Grade
View all literature mentionsH3K9me3-human,H3K9me3-mouse (antibody)
RRID:AB_306848
This polyclonal targets H3K9me3
View all literature mentionsAnti-Histone H3 (tri methyl K4) antibody - ChIP Grade (antibody)
RRID:AB_306649
This polyclonal targets Histone H3 (tri methyl K4)
View all literature mentionsMED26 (D4B1X) Rabbit mAb (antibody)
RRID:AB_2798656
This monoclonal targets MED26
View all literature mentionsMED17 Polyclonal Antibody (antibody)
RRID:AB_2576978
This unknown targets MED17
View all literature mentionsCRSP2 / MED14 antibody [2214C1a] (antibody)
RRID:AB_869273
This monoclonal targets Human CRSP2 / MED14
View all literature mentionsPBRM1/BAF180 (E9X2Z) Rabbit mAb (antibody)
RRID:AB_2936366
This monoclonal targets PBRM1/BAF180
View all literature mentionsARID1A/BAF250A (D2A8U) Rabbit mAb #12354 (antibody)
RRID:AB_2637010
This monoclonal targets ARID1A/BAF250A
View all literature mentionsSMARCC2/BAF170 (D8O9V) Rabbit mAb (antibody)
RRID:AB_2798017
This monoclonal targets SMARCC2
View all literature mentionsBrg1 (E9O6E) Mouse mAb (antibody)
RRID:AB_2799410
This monoclonal targets SMARCA4
View all literature mentionsHDAC1 antibody [EPR460(2)] (antibody)
RRID:AB_10861012
This monoclonal targets HDAC1 antibody [EPR460(2)]
View all literature mentionsNaPi2b/SLC34A2 (D6W2G) Rabbit mAb (antibody)
RRID:AB_2799218
This monoclonal targets SLC34A2
View all literature mentionsBcl-2 (D17C4) Rabbit mAb (Mouse Preferred) (antibody)
RRID:AB_1903907
This monoclonal targets Bcl-2 (D17C4) Rabbit mAb (Mouse Preferred)
View all literature mentionsPI 3 Kinase Class 3 antibody [EPR5301] (antibody)
RRID:AB_10975462
This monoclonal targets PI 3 Kinase Class 3 antibody [EPR5301]
View all literature mentionsRecombinant Anti-Beclin 1 antibody [EPR19662] (antibody)
RRID:AB_2692326
This recombinant monoclonal targets Beclin 1
View all literature mentionsRabbit Anti-HA tag Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_307019
This polyclonal targets HA tag - ChIP Grade
View all literature mentionsRecombinant Anti-LC3B antibody [EPR18709] - Autophagosome Marker (antibody)
RRID:AB_2827794
This monoclonal targets LC3B
View all literature mentionsALDH1A1 antibody [EP1933Y] (antibody)
RRID:AB_867566
This monoclonal targets ALDH1A1
View all literature mentionsRecombinant Anti-CXCR4 antibody [EPUMBR3] (antibody)
RRID:AB_2910168
This recombinant monoclonal targets CXCR4
View all literature mentionsPE anti-mouse CD31 (antibody)
RRID:AB_312903
This monoclonal targets CD31
View all literature mentionsHRP, Goat Anti-Mouse IgG(H+L) (antibody)
RRID:AB_2890177
This polyclonal targets IgG (H+L)
View all literature mentionsRecombinant Anti-CD31 antibody [EPR17260-263] (antibody)
RRID:AB_2905525
This recombinant monoclonal targets CD31
View all literature mentionsRabbit Anti-Collagen IV Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_305584
This polyclonal targets Collagen IV
View all literature mentionsEndomucin antibody [V.7C7.1] (antibody)
RRID:AB_10859306
This monoclonal targets Endomucin antibody [V.7C7.1]
View all literature mentionsCD105 antibody [MEM-226] (antibody)
RRID:AB_303134
This monoclonal targets CD105
View all literature mentionsMouse Anti-Cytokeratin, pan Monoclonal Antibody, Unconjugated, Clone C-11 (antibody)
RRID:AB_306047
This monoclonal targets pan Cytokeratin
View all literature mentionsGPR91 Polyclonal Antibody (antibody)
RRID:AB_2812793
This unknown targets GPR91
View all literature mentionsPDGF Receptor beta (28E1) Rabbit mAb (antibody)
RRID:AB_2162497
This recombinant monoclonal targets PDGFRB
View all literature mentionsRecombinant Anti-Rb antibody [EPR17512] (antibody)
RRID:AB_2848193
This recombinant targets RB1
View all literature mentionsRecombinant Anti-Ki67 antibody [SP6] (antibody)
RRID:AB_302459
This recombinant monoclonal targets Ki67
View all literature mentionsC57BL/6-Gt(ROSA)26Sortm1(HBEGF)Awai/J (organism)
RRID:IMSR_JAX:007900
Mus musculus with name C57BL/6-Gt(ROSA)26Sortm1(HBEGF)Awai/J from IMSR.
View all literature mentionsHEK293T/17 (cell line)
RRID:CVCL_1926
Cell line HEK293T/17 is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsGPR91 Polyclonal Antibody (antibody)
RRID:AB_2812793
This unknown targets GPR91
View all literature mentionsGPR91 Polyclonal Antibody (antibody)
RRID:AB_2812793
This unknown targets GPR91
View all literature mentionsPDGF Receptor beta (28E1) Rabbit mAb (antibody)
RRID:AB_2162497
This recombinant monoclonal targets PDGFRB
View all literature mentionsRecombinant Anti-Rb antibody [EPR17512] (antibody)
RRID:AB_2848193
This recombinant targets RB1
View all literature mentionsPDGF Receptor beta (28E1) Rabbit mAb (antibody)
RRID:AB_2162497
This recombinant monoclonal targets PDGFRB
View all literature mentionsRecombinant Anti-Rb antibody [EPR17512] (antibody)
RRID:AB_2848193
This recombinant targets RB1
View all literature mentionsRecombinant Anti-Ki67 antibody [SP6] (antibody)
RRID:AB_302459
This recombinant monoclonal targets Ki67
View all literature mentionsRecombinant Anti-Ki67 antibody [SP6] (antibody)
RRID:AB_302459
This recombinant monoclonal targets Ki67
View all literature mentions
