ArticleJournal of the National Cancer Institute2019
The Role of Castration-Resistant Bmi1+Sox2+ Cells in Driving Recurrence in Prostate Cancer.
Article in Journal of the National Cancer Institute, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed, 36 citations in OpenAlex.
- The interplay of DNA damage, epigenetics and tumour heterogeneity in driving cancer cell fitness.Nature communications · 2025Review
- Progress and prospects of the combination of BMI1-targeted therapy and immunotherapy in cervical cancer.American journal of cancer research · 2025Review
- Prostate cancer microenvironment: multidimensional regulation of immune cells, vascular system, stromal cells, and microbiota.Molecular cancer · 2024Review
- Asparagine Dependency Is a Targetable Metabolic Vulnerability in TP53-Altered Castration-Resistant Prostate Cancer.Cancer research · 2024Article
- Human intermediate prostate cancer stem cells contribute to the initiation and development of prostate adenocarcinoma.Stem cell research & therapy · 2024Article
- Ubiquitination Process Mediates Prostate Cancer Development and Metastasis through Multiple Mechanisms.Cell biochemistry and biophysics · 2024Review
- Immune mechanisms shape the clonal landscape during early progression of prostate cancer.Developmental cell · 2023Article
- Article
- SOX2 inhibits LLGL2 polarity protein in esophageal squamous cell carcinoma via miRNA-142-3p.Cancer biology & therapy · 2022Article
- The driver role of JAK-STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy- and castration-resistant prostate cancer.Clinical and translational medicine · 2022Article
- The Crucial Roles of Bmi-1 in Cancer: Implications in Pathogenesis, Metastasis, Drug Resistance, and Targeted Therapies.International journal of molecular sciences · 2022Review
- Expansion of mouse castration-resistant intermediate prostate stem cells in vitro.Stem cell research & therapy · 2022Article
- Understanding and targeting prostate cancer cell heterogeneity and plasticity.Seminars in cancer biology · 2022Review
- Prostate luminal progenitor cells: from mouse to human, from health to disease.Nature reviews. Urology · 2022Review
- Article
- Tumor Microenvironment in Prostate Cancer: Toward Identification of Novel Molecular Biomarkers for Diagnosis, Prognosis, and Therapy Development.Frontiers in genetics · 2021Review
- The role of Trop2 in prostate cancer: an oncogene, biomarker, and therapeutic target.American journal of clinical and experimental urology · 2021Article
- LIN28B promotes the development of neuroendocrine prostate cancer.The Journal of clinical investigation · 2020Article
- Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer.Nature communications · 2020Article
- Cellular rewiring in lethal prostate cancer: the architect of drug resistance.Nature reviews. Urology · 2020Review
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6 authors at 1 institution in 1 country.
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Abstract
backgroundRecurrence following androgen-deprivation therapy is associated with adverse clinical outcomes in prostate cancer, but the cellular origins and molecular mechanisms underlying this process are poorly defined. We previously identified a population of castration-resistant luminal progenitor cells expressing Bmi1 in the normal mouse prostate that can serve as a cancer cell-of-origin. Here, we investigate the potential of Bmi1-expressing tumor cells that survive castration to initiate recurrence in vivo.
methodsWe employed lineage retracing in Bmi1-CreER; R26R-confetti; Ptenf/f transgenic mice to mark and follow the fate of emerging recurrent tumor clones after castration. A tissue recombination strategy was used to rescue transgenic mouse prostates by regeneration as grafts in immunodeficient hosts. We also used a small molecule Bmi1 inhibitor, PTC-209, to directly test the role of Bmi1 in recurrence.
resultsTransgenic prostate tumors (n = 17) regressed upon castration but uniformly recurred within 3 months. Residual regressed tumor lesions exhibited a transient luminal-to-basal phenotypic switch and marked cellular heterogeneity. Additionally, in these lesions, a subpopulation of Bmi1-expressing castration-resistant tumor cells overexpressed the stem cell reprogramming factor Sox2 (mean [SD] = 41.1 [3.8]%, n = 10, P < .001). Bmi1+Sox2+ cells were quiescent (BrdU+Bmi1+Sox2+ at 3.4 [1.5]% vs BrdU+Bmi1+Sox2- at 18.8 [3.4]%, n = 10, P = .009), consistent with a cancer stem cell phenotype. By lineage retracing, we established that recurrence emerges from the Bmi1+ tumor cells in regressed tumors. Furthermore, treatment with the small molecule Bmi1 inhibitor PTC-209 reduced Bmi1+Sox2+ cells (6.1 [1.4]% PTC-209 vs 38.8 [2.3]% vehicle, n = 10, P < .001) and potently suppressed recurrence (retraced clone size = 2.6 [0.5] PTC-209 vs 15.7 [5.9] vehicle, n = 12, P = .04).
conclusionsThese results illustrate the utility of lineage retracing to define the cellular origins of recurrent prostate cancer and identify Bmi1+Sox2+ cells as a source of recurrence that could be targeted therapeutically.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.