Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation from Pten null Sca-1+ prostate luminal cells

Kwon, Oh-Joon; Zhang, Li; Jia, Dongyu; Li, Xin

doi:10.1038/s41388-020-01526-2

Cited by 25 publications

(21 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While we cannot exclude that these lineages arise from early activation and/or leakiness of Pbsn-Cre, notably with respect to EMT-Gfp, there is compelling evidence through lineage tracing using luminal Nkx3.1-Cre and Krt8-Cre mice, and our spatial IF showing PANCK and SYP staining that transformed luminal cells readily transdifferentiate into NEPC (23). Specifically, and consistent with our data, L2 (SCA-1+) cells have an increased propensity to transdifferentiate to neuroendocrine cells upon androgen ablation compared with L1 (SCA-1-) (24).…”

Section: Main Textsupporting

confidence: 89%

Multilineage plasticity in prostate cancer through expansion of stem–like luminal epithelial cells with elevated inflammatory signaling

Zaidi

Zhao

Chan

et al. 2021

Preprint

View full text Add to dashboard Cite

Lineage plasticity is a well–established mechanism of resistance to targeted therapies in lung and prostate cancer, where tumors transition from adenocarcinoma to small–cell or neuroendocrine carcinoma. Through single–cell analysis of a cohort of heavily–treated castration–resistant human prostate cancers (CRPC), we report a greater degree of plasticity than previously appreciated, with multiple distinct neuroendocrine (NEPC), mesenchymal (EMT–like), and other subpopulations detected within single biopsies. To explore the steps leading to this plasticity, we turned to two genetically engineered mouse models of prostate cancer that recapitulate progression from adenocarcinoma to neuroendocrine disease. Time course studies reveal expansion of stem–like luminal epithelial cells (Sca1+, Psca+, called L2) that, based on trajectories, gave rise to at least 4 distinct subpopulations, NEPC (Ascl1+), POU2F3 (Pou2f3+), TFF3 (Tff3+) and EMT–like (Vim+, Ncam1+)––these populations are also seen in human prostate and small cell lung cancers. Transformed L2–like cells express stem–like and gastrointestinal endoderm–like transcriptional programs, indicative of reemerging developmental plasticity programs, as well as elevated Jak/Stat and interferon pathway signaling. In sum, while the magnitude of multilineage heterogeneity, both within and across patients, raises considerable treatment challenges, the identification of highly plastic luminal cells as the likely source of this heterogeneity provides a target for more focused therapeutic intervention.One Sentence SummaryMultilineage plasticity results from expansion of stem–like luminal cells with JAK/STAT activation, serving as a therapeutic target.

show abstract

Section: Main Textsupporting

confidence: 89%

Multilineage plasticity in prostate cancer through expansion of stem–like luminal epithelial cells with elevated inflammatory signaling

Zaidi

Zhao

Chan

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Patterns of gene expression in the prostate have been shown to associate with anatomical and histological structure 18,28–30 . We and others demonstrated that several Wnt ligands were expressed at a higher level in the periurethral prostatic ducts (i.e., proximal ducts) than other ductal locations (distal ducts) 18,31 .…”

Section: Resultsmentioning

confidence: 96%

Paracrine Wnt signaling is necessary for prostate epithelial proliferation

et al. 2022

Self Cite

View full text Add to dashboard Cite

Introduction The Wnt proteins play key roles in the development, homeostasis, and disease progression of many organs including the prostate. However, the spatiotemporal expression patterns of Wnt proteins in prostate cell lineages at different developmental stages and in prostate cancer remain inadequately characterized. Methods We isolated the epithelial and stromal cells in the developing and mature mouse prostate by flow cytometry and determined the expression levels of Wnt ligands. We used Visium spatial gene expression analysis to determine the spatial distribution of Wnt ligands in the mouse prostatic glands. Using laser‐capture microscopy in combination with gene expression analysis, we also determined the expression patterns of Wnt signaling components in stromal and cancer cells in advanced human prostate cancer specimens. To investigate how the stroma‐derived Wnt ligands affect prostate development and homeostasis, we used a Col1a2‐CreERT2 mouse model to disrupt the Wnt transporter Wntless specifically in prostate stromal cells. Results We showed that the prostate stromal cells are a major source of several Wnt ligands. Visium spatial gene expression analysis revealed a distinct spatial distribution of Wnt ligands in the prostatic glands. We also showed that Wnt signaling components are highly expressed in the stromal compartment of primary and advanced human prostate cancer. Blocking stromal Wnt secretion attenuated prostate epithelial proliferation and regeneration but did not affect cell survival and lineage maintenance. Discussion Our study demonstrates a critical role of stroma‐derived Wnt ligands in prostate development and homeostasis.

show abstract

“…In the normal prostate, SOX2 expression is restricted to basal epithelial cells. It is repressed by canonical AR signaling [35][36][37] and conversely upregulated by AR signaling inhibitors [38] . SOX2 upregulation in prostate cancer has been associated with a poorly-differentiated stem-cell-like phenotype [35] and is necessary for castration-induced neuroendocrine differentiation in both PTEN null [39] and RB1/TP3 null [23] models of prostate cancer.…”

Section: Transcriptional Profile Of T-scncmentioning

confidence: 99%

Genomic characterization of treatment-associated small cell neuroendocrine carcinoma of the prostate

Kouchkovsky¹,

Quigley²,

Small³

et al. 2021

jtgg

View full text Add to dashboard Cite

Treatment-associated small cell neuroendocrine carcinoma of the prostate (t-SCNC) is an aggressive prostate cancer variant with rising incidence. Although morphologically similar to de novo small cell prostate cancer, t-SCNC is thought to emerge from metastatic castration-resistant prostate cancer (mCRPC) under the selective pressure of prolonged AR-targeted therapies. t-SCNC is associated with a distinct transcriptional landscape, characterized by the upregulation of stem cell-associated and neuronal programs (e.g., SOX2, N-MYC, FOXA2) and decreased canonical AR signaling. In addition, as with other neuroendocrine carcinomas, RB1 loss and inactivating TP53 mutations are key genomic hallmarks of t-SCNC. Nevertheless, despite their histologic, molecular, and clinical differences, there is a striking degree of genomic overlap between t-SCNC and its adenocarcinoma counterpart. This finding underscores the clonal evolution of t-SCNC from mCRPC, as well as the importance of epigenetic mechanisms in regulating tumor phenotype. In this review, we summarize the key genomic, transcriptional, and epigenetic features of t-SCNC and discuss how recent advances in our understanding of molecular drivers of t-SCNC have contributed to improving the diagnosis and treatment of this aggressive disease.

show abstract

Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation from Pten null Sca-1+ prostate luminal cells

Cited by 25 publications

References 45 publications

Multilineage plasticity in prostate cancer through expansion of stem–like luminal epithelial cells with elevated inflammatory signaling

Multilineage plasticity in prostate cancer through expansion of stem–like luminal epithelial cells with elevated inflammatory signaling

Paracrine Wnt signaling is necessary for prostate epithelial proliferation

Genomic characterization of treatment-associated small cell neuroendocrine carcinoma of the prostate

Contact Info

Product

Resources

About