Increasing Cancer Stemness Drives Prostate Cancer Progression, Plasticity, Therapy Resistance and Poor Patient Survival
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Le résumé fourni par la source
Abstract Background Cancer progression is often accompanied by dedifferentiation and acquisition of stem cell-like properties (stemness). In prostate cancer (PCa), lineage plasticity and therapy resistance remain major clinical challenges, yet a unified quantitative transcriptomic framework connecting stemness, androgen receptor (AR) signaling, castration resistance, and disease progression across the PCa continuum is lacking. Methods We integrated 87,339 transcriptomic profiles from 33 preclinical and clinical datasets spanning the PCa continuum from normal prostate and treatment-naïve primary PCa (Pri-PCa) to PCa treated with neoadjuvant ADT (nADT) and metastatic castration-resistant PCa (mCRPC), with single-cell RNA-seq analyses encompassing 115,197 cells. Cancer stemness was quantified using a transcriptome-derived mRNA-based Stemness Index (mRNAsi; hereafter Stemness), and a 12-gene PCa-Stem signature was developed to capture PCa-specific stemness. Stemness, PCa-Stem, canonical AR activity (c_AR-A), castration-reprogrammed AR activity (cr_AR-A), RB1 -loss, PTEN -loss, and MYC activity signatures were quantified across cohorts. Functional validation included MYC inhibition and representative PCa-Stem signature gene depletion in PCa models. Clinical prognostic significance was evaluated in independent patient cohorts. Results The Stemness score and c_AR-A increased concordantly during early prostate tumorigenesis but diverged with PCa progression: as Gleason grade increased, c_AR-A declined while Stemness continually increased. mCRPC exhibited the highest Stemness and lowest c_AR-A, a pattern recapitulated in Pten / Rb1 / Trp53 -deficient mouse models. Global Stemness increased progressively across the PCa continuum, was enriched in aggressive PAM50-LumB and PCS1 subtypes, associated with proliferative and lineage plasticity programs, and predicted poor patient survival. The newly derived 12-gene PCa-Stem signature provided a PCa-specific molecular representation of Stemness and tracked disease progression and poor patient survival. Network analyses identified a coordinated mitotic regulatory program linking MYC activity, RB1 -loss, cr_AR-A, and the PCa-Stem signature. Spatial and single-cell transcriptomic analyses localized the PCa-Stem program to lineage plasticity-related epithelial cells and demonstrated progressive expansion of PCa-Stem⁺ epithelial cells during PCa progression. Functional perturbation of representative PCa-Stem signature genes, as well as genetic and pharmacological MYC inhibition, consistently suppressed Stemness-associated phenotypes in diverse PCa models. Conclusions Cancer Stemness quantitatively captures PCa aggressiveness, lineage plasticity, treatment resistance, disease progression, and poor patient survival. cr_AR-A, RB1 loss, and MYC activation cooperate to reinforce the high-Stemness state and therapy resistance in mCRPC. Collectively, our work establishes a trajectory-integrated transcriptomic framework defining cancer Stemness as a quantifiable molecular and clinical determinant of PCa aggressiveness, lineage plasticity, disease progression, therapy resistance and patient survival.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Increasing Cancer Stemness Drives Prostate Cancer Progression, Plasticity, Therapy Resistance and Poor Patient Survival
- Date Crossref
- 30/04/2025
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Roswell Park Comprehensive Cancer Center Experimental Therapeutics Graduate Program pays non établi dans la noticeStructure de recherche
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University at Buffalo Department of Biostatistics pays non établi dans la noticeUniversité ou école supérieure
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Veracyte (United States) pays non établi dans la noticeEntreprise
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The University of Texas at Austin Department of Biomedical Engineering pays non établi dans la noticeUniversité ou école supérieure
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University of California Department of Radiation Oncology pays non établi dans la noticeUniversité ou école supérieure
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Michigan Medicine pays non établi dans la noticeÉtablissement de santé
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University Hospitals Seidman Cancer Center pays non établi dans la noticeÉtablissement de santé
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Case Western Reserve University pays non établi dans la noticeUniversité ou école supérieure
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Centre for Cancer Biology pays non établi dans la noticeStructure de recherche
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Hunan University pays non établi dans la noticeUniversité ou école supérieure
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The University of Texas MD Anderson Cancer Center pays non établi dans la noticeÉtablissement de santé
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Department of Pharmacology and Therapeutics pays non établi dans la noticeInstitution
Experimental Therapeutics Graduate Program — Roswell Park Comprehensive Cancer Center, Department of Biostatistics — University at Buffalo et Veracyte (United States), avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.