Antiandrogen treatment induces stromal cell reprogramming to promote castration resistance in prostate cancer.
Lineage plasticity causes therapeutic resistance; however, it remains unclear how the fate conversion and phenotype switching of cancer-associated fibroblasts (CAFs) are implicated in disease relapse. Here, we show that androgen deprivation therapy (ADT)-induced SPP1+ myofibroblastic CAFs (myCAFs) are critical stromal constituents that drive the development of castration-resistant prostate cancer (CRPC). Our results reveal that SPP1+ myCAFs arise from the inflammatory CAFs in hormone-sensitive PCa; therefore, they represent two functional states of an otherwise ontogenically identical cell type. Antiandrogen treatment unleashes TGF-β signaling, resulting in SOX4-SWI/SNF-dependent CAF phenotype switching. SPP1+ myCAFs in turn render PCa refractory to ADT via an SPP1-ERK paracrine mechanism. Importantly, these sub-myCAFs are associated with inferior therapeutic outcomes, providing the rationale for inhibiting polarization or paracrine mechanisms to circumvent castration resistance. Collectively, our results highlight that therapy-induced phenotypic switching of CAFs is coupled with disease progression and that targeting this stromal component may restrain CRPC.
Pubmed ID: 37352863 RIS Download
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None foundAntibodies used in this publication
- Rabbit Anti-Cytokeratin 8 Polyclonal Antibody, Unconjugated (RRID:AB_942041)
- Androgen Receptor antibody [ER179(2)] (RRID:AB_10865716)
- RSK1 p90 (phospho S380) antibody [E239] (RRID:AB_777767)
- H3K27ac-human (RRID:AB_2118291)
- Recombinant Anti-Collagen I antibody [EPR22894-89] (RRID:AB_2922767)
- Mouse Osteopontin (OPN) Affinity Purified Polyclonal Ab (RRID:AB_2194992)
- InVivoPlus anti-mouse/human/rat/monkey/hamster/canine/bovine TGF-β (RRID:AB_1107757)
- Rabbit Anti-TGF-beta Receptor II Polyclonal Antibody, Unconjugated (RRID:AB_2240491)
- Anti-TGF-beta Receptor I Antibody, Unconjugated (RRID:AB_330933)
- ARID1A/BAF250A (D2A8U) Rabbit mAb #12354 (RRID:AB_2637010)
- SMARCC1/BAF155 (D7F8S) Rabbit mAb (RRID:AB_2797776)
- Phospho-HER3/ErbB3 (Tyr1289) (21D3) Rabbit mAb (RRID:AB_2099709)
- RSK1 p90 antibody [E4] (RRID:AB_779068)
- HER3/ErbB3 (1B2E) Rabbit mAb (RRID:AB_10691324)
- Phospho-Akt (Thr308) (244F9) Rabbit mAb (RRID:AB_331163)
- Akt (pan) (C67E7) Rabbit mAb (RRID:AB_915783)
- Phospho-Akt (Ser473) (D9E) XP® Rabbit mAb (RRID:AB_2315049)
- p44/42 MAPK (Erk1/2) Antibody (RRID:AB_330744)
- Phospho-Smad3 (Ser423/425) (C25A9) Rabbit mAb (RRID:AB_2193207)
- Phospho-SMAD2 (Ser465/Ser467) (E8F3R) Rabbit mAb (RRID:AB_2798798)
- Phospho-Smad2 (Ser465/467) Antibody (RRID:AB_331673)
- Smad3 Antibody (RRID:AB_2286450)
- Smad2 (D43B4) XP Rabbit mAb (RRID:AB_10626777)
- Mouse Anti-Human Sox-4 Monoclonal Antibody, Unconjugated (RRID:AB_2066884)
- Beta Actin antibody (RRID:AB_2687938)
- p53 (1C12) Mouse mAb (RRID:AB_331743)
- Rabbit Anti-PTEN Monoclonal Antibody, Unconjugated, Clone 138G6 (RRID:AB_390810)
- HB-EGF (H-1) (RRID:AB_10708568)
- VEGF-C (E-6) (RRID:AB_11012156)
- Podoplanin Monoclonal Antibody (eBio8.1.1 (8.1.1)), eFluor™ 660, eBioscience (RRID:AB_11150064)
- PerCP/Cyanine5.5 anti-mouse/rat CD29 (RRID:AB_2572078)
- PE/Cyanine7 anti-mouse CD90.2 (Thy1.2) (RRID:AB_10645336)
- CD90.2 (Thy-1.2) Monoclonal Antibody (53-2.1), PE, eBioscience (RRID:AB_465777)
- PE/Cyanine7 anti-mouse CD326 (Ep-CAM) (RRID:AB_1236471)
- CD31 (PECAM-1) Monoclonal Antibody (390), eFluor™ 450, eBioscience (RRID:AB_10598808)
- FITC anti-mouse CD45 (RRID:AB_312973)
- DYKDDDDK Tag (D6W5B) Rabbit mAb (Binds to same epitope as Sigma's Anti-FLAG® M2 Antibody) (RRID:AB_2572291)
- BRG1 antibody [EPNCIR111A] (RRID:AB_10861578)
- Monoclonal Anti-Actin, α-Smooth Muscle (RRID:AB_476701)
- GFP-avictoria (RRID:AB_303395)
- Androgen Receptor (RRID:AB_1563391)
- Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (D13.14.4E) XP® Rabbit mAb (RRID:AB_2315112)
- Ki-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (RRID:AB_2620142)
- TGF Beta 1 antibody (RRID:AB_2811115)
- CD140a (PDGFRA) Monoclonal Antibody (APA5), Functional Grade, eBioscience (RRID:AB_529483)
- PDGF Receptor alpha (D1E1E) XP Rabbit mAb (RRID:AB_2162345)
- COL1A1 monoclonal antibody, clone 3G3 (RRID:AB_2797597)
- Mouse Anti-OPN Monoclonal Antibody, Unconjugated, Clone LFMb-14 (RRID:AB_2194995)
- OPN (AKm2A1) (RRID:AB_2194997)
- Mouse Anti-PTN Monoclonal Antibody, Unconjugated, Clone H-6 (RRID:AB_1128556)
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This is a list of tools and resources that we have found mentioned in this publication.
Rabbit Anti-Cytokeratin 8 Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_942041
This polyclonal targets Cytokeratin 8
View all literature mentionsAndrogen Receptor antibody [ER179(2)] (antibody)
RRID:AB_10865716
This monoclonal targets Androgen Receptor antibody [ER179(2)]
View all literature mentionsRSK1 p90 (phospho S380) antibody [E239] (antibody)
RRID:AB_777767
This monoclonal targets RSK1 p90 (phospho S380)
View all literature mentionsH3K27ac-human (antibody)
RRID:AB_2118291
This polyclonal targets H3K27ac
View all literature mentionsRecombinant Anti-Collagen I antibody [EPR22894-89] (antibody)
RRID:AB_2922767
This recombinant monoclonal targets Collagen I
View all literature mentionsMouse Osteopontin (OPN) Affinity Purified Polyclonal Ab (antibody)
RRID:AB_2194992
This polyclonal targets Mouse Osteopontin (OPN) Affinity Purified Ab
View all literature mentionsInVivoPlus anti-mouse/human/rat/monkey/hamster/canine/bovine TGF-β (antibody)
RRID:AB_1107757
This monoclonal targets TGF-β
View all literature mentionsRabbit Anti-TGF-beta Receptor II Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_2240491
This polyclonal targets TGFBR2
View all literature mentionsAnti-TGF-beta Receptor I Antibody, Unconjugated (antibody)
RRID:AB_330933
This unknown targets TGF-beta Receptor I
View all literature mentionsARID1A/BAF250A (D2A8U) Rabbit mAb #12354 (antibody)
RRID:AB_2637010
This monoclonal targets ARID1A/BAF250A
View all literature mentionsSMARCC1/BAF155 (D7F8S) Rabbit mAb (antibody)
RRID:AB_2797776
This monoclonal targets SMARCC1
View all literature mentionsPhospho-HER3/ErbB3 (Tyr1289) (21D3) Rabbit mAb (antibody)
RRID:AB_2099709
This monoclonal targets ERBB3
View all literature mentionsRSK1 p90 antibody [E4] (antibody)
RRID:AB_779068
This monoclonal targets RSK1 p90
View all literature mentionsHER3/ErbB3 (1B2E) Rabbit mAb (antibody)
RRID:AB_10691324
This monoclonal targets Erbb3
View all literature mentionsPhospho-Akt (Thr308) (244F9) Rabbit mAb (antibody)
RRID:AB_331163
This monoclonal targets Phospho-Akt (Thr308) (244F9) Rabbit mAb
View all literature mentionsAkt (pan) (C67E7) Rabbit mAb (antibody)
RRID:AB_915783
This monoclonal targets Akt (pan) (C67E7) Rabbit mAb
View all literature mentionsPhospho-Akt (Ser473) (D9E) XP® Rabbit mAb (antibody)
RRID:AB_2315049
This monoclonal targets Phospho-Akt (Ser473)
View all literature mentionsp44/42 MAPK (Erk1/2) Antibody (antibody)
RRID:AB_330744
This polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsPhospho-Smad3 (Ser423/425) (C25A9) Rabbit mAb (antibody)
RRID:AB_2193207
This monoclonal targets Phospho-Smad3 (Ser423/425) (C25A9) Rabbit mAb
View all literature mentionsPhospho-SMAD2 (Ser465/Ser467) (E8F3R) Rabbit mAb (antibody)
RRID:AB_2798798
This monoclonal targets SMAD2
View all literature mentionsPhospho-Smad2 (Ser465/467) Antibody (antibody)
RRID:AB_331673
This polyclonal targets Phospho-Smad2 (Ser465/467)
View all literature mentionsSmad3 Antibody (antibody)
RRID:AB_2286450
This polyclonal targets Smad3
View all literature mentionsSmad2 (D43B4) XP Rabbit mAb (antibody)
RRID:AB_10626777
This monoclonal targets Smad2 (D43B4) XP Rabbit mAb
View all literature mentionsMouse Anti-Human Sox-4 Monoclonal Antibody, Unconjugated (antibody)
RRID:AB_2066884
This monoclonal targets C4A
View all literature mentionsBeta Actin antibody (antibody)
RRID:AB_2687938
This monoclonal targets Beta Actin
View all literature mentionsp53 (1C12) Mouse mAb (antibody)
RRID:AB_331743
This monoclonal targets p53 (1C12) Mouse mAb
View all literature mentionsRabbit Anti-PTEN Monoclonal Antibody, Unconjugated, Clone 138G6 (antibody)
RRID:AB_390810
This monoclonal targets PTEN
View all literature mentionsHB-EGF (H-1) (antibody)
RRID:AB_10708568
This monoclonal targets HB-EGF (H-1)
View all literature mentionsVEGF-C (E-6) (antibody)
RRID:AB_11012156
This monoclonal targets VEGF-C (E-6)
View all literature mentionsPodoplanin Monoclonal Antibody (eBio8.1.1 (8.1.1)), eFluor™ 660, eBioscience (antibody)
RRID:AB_11150064
This monoclonal targets Podoplanin
View all literature mentionsPerCP/Cyanine5.5 anti-mouse/rat CD29 (antibody)
RRID:AB_2572078
This monoclonal targets CD29
View all literature mentionsPE/Cyanine7 anti-mouse CD90.2 (Thy1.2) (antibody)
RRID:AB_10645336
This monoclonal targets CD90.2
View all literature mentionsCD90.2 (Thy-1.2) Monoclonal Antibody (53-2.1), PE, eBioscience (antibody)
RRID:AB_465777
This monoclonal targets CD90.2 (Thy-1.2)
View all literature mentionsPE/Cyanine7 anti-mouse CD326 (Ep-CAM) (antibody)
RRID:AB_1236471
This monoclonal targets CD326
View all literature mentionsCD31 (PECAM-1) Monoclonal Antibody (390), eFluor™ 450, eBioscience (antibody)
RRID:AB_10598808
This monoclonal targets CD31 (PECAM-1)
View all literature mentionsFITC anti-mouse CD45 (antibody)
RRID:AB_312973
This monoclonal targets CD45
View all literature mentionsDYKDDDDK Tag (D6W5B) Rabbit mAb (Binds to same epitope as Sigma's Anti-FLAG® M2 Antibody) (antibody)
RRID:AB_2572291
This monoclonal targets DYKDDDDK Tag
View all literature mentionsBRG1 antibody [EPNCIR111A] (antibody)
RRID:AB_10861578
This monoclonal targets BRG1 antibody [EPNCIR111A]
View all literature mentionsMonoclonal Anti-Actin, α-Smooth Muscle (antibody)
RRID:AB_476701
This monoclonal targets Actin, α-Smooth Muscle
View all literature mentionsPhospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (D13.14.4E) XP® Rabbit mAb (antibody)
RRID:AB_2315112
This monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204)
View all literature mentionsKi-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (antibody)
RRID:AB_2620142
This monoclonal targets Ki-67
View all literature mentionsTGF Beta 1 antibody (antibody)
RRID:AB_2811115
This polyclonal targets TGF Beta 1
View all literature mentionsCD140a (PDGFRA) Monoclonal Antibody (APA5), Functional Grade, eBioscience (antibody)
RRID:AB_529483
This monoclonal targets CD140a (PDGFRA)
View all literature mentionsPDGF Receptor alpha (D1E1E) XP Rabbit mAb (antibody)
RRID:AB_2162345
This monoclonal targets PDGF Receptor alpha
View all literature mentionsCOL1A1 monoclonal antibody, clone 3G3 (antibody)
RRID:AB_2797597
This monoclonal targets COL1A1
View all literature mentionsMouse Anti-OPN Monoclonal Antibody, Unconjugated, Clone LFMb-14 (antibody)
RRID:AB_2194995
This monoclonal targets Spp1
View all literature mentionsOPN (AKm2A1) (antibody)
RRID:AB_2194997
This monoclonal targets OPN (AKm2A1)
View all literature mentionsMouse Anti-PTN Monoclonal Antibody, Unconjugated, Clone H-6 (antibody)
RRID:AB_1128556
This monoclonal targets PTN
View all literature mentionsMyc-CaP (cell line)
RRID:CVCL_J703
Cell line Myc-CaP is a Cancer cell line with a species of origin Mus musculus
View all literature mentionsLNCaP C4-2 (cell line)
RRID:CVCL_4782
Cell line LNCaP C4-2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsLAPC-4 (cell line)
RRID:CVCL_4744
Cell line LAPC-4 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsPC-3 (cell line)
RRID:CVCL_0035
Cell line PC-3 is a Cancer cell line with a species of origin Homo sapiens (Human)
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 mentions
