Single-cell transcriptomics identifies a distinct luminal progenitor cell type in distal prostate invagination tips

Guo, Wangxin; Li, Lin; He, Jinzhi; Liu, Zhuang; Han, Ming; Li, Fēi; Xia, Xinyi; Zhang, Xiaoyu; Zhu, Yao; Yu, Wei; Li, Yunguang; Aji, Rebiguli; Dai, Hao; Wei, Hui; Li, Chunfeng; Yu, Chen; Chen, Luonan

doi:10.1038/s41588-020-0642-1

Cited by 85 publications

(185 citation statements)

References 57 publications

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“…We demonstrate that these RUNX1 + PLCs exhibit a greater organoid forming potential compared to the remaining luminal fraction, consistent with previous reports isolating similar proximal populations using different markers such as SCA-1, TROP2 or CD26 (Crowley et al, 2020;Goldstein et al, 2008;Guo et al, 2020;Karthaus et al, 2020;Kwon et al, 2016).…”

Section: Discussionsupporting

confidence: 92%

“…Here, we identified a subset of RUNX1 + luminal cells located in the proximal region of the developing and adult prostate, referred to as RUNX1 + PLCs, and corresponding to the Lum-D cluster identified in our adult scRNA-seq dataset. Of note, this subset appears to be the equivalent of the 'L2' (Karthaus et al, 2020) or 'LumP' (Crowley et al, 2020), or 'Lum-C' (Guo et al, 2020) clusters identified in recent studies. In light of the extensive contribution of RUNX transcription factors to developmental processes (Mevel et al, 2019), our study suggests that Runx1, but also Runx2, may be involved in the development and maintenance of specific subpopulations of the prostate epithelium.…”

Section: Discussionmentioning

confidence: 61%

“…In particular, our adult scRNA-seq dataset highlighted an extensive degree of cellular heterogeneity, in particular within the luminal epithelia. Several studies recently made similar observations either focusing on the AP (Karthaus et al, 2020), the intact prostate (Crowley et al, 2020;Joseph et al, 2020), or both the intact and castrated prostates (Guo et al, 2020). Integration of these multiple datasets will provide a more global view of the transcriptional landscape of the prostate epithelium.…”

Section: Discussionmentioning

confidence: 80%

“…Finally, our study suggests that the emerging C2/Lum-D population retains a more embryonic-like program, which may relate to their intrinsic castration-resistant potential and have broader relevance to cancer treatment. Along these lines, recent work by Guo and colleagues indicates that Pten loss induced in Psca expressing cells of the proximal prostate can initiate prostatic intraepithelial neoplasia (Guo et al, 2020). These results warrant future investigation of this luminal subset in the context of cancer development, tumor aggressiveness and treatment responses.…”

Section: Discussionmentioning

confidence: 90%

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RUNX1 marks a luminal castration resistant lineage established at the onset of prostate development

Mével

Steiner

Mason

et al. 2020

Preprint

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22The development of castration-resistant prostate cancer is a major complication of androgen-23 deprivation therapy. However, the origin and identity of these resistant cells remains controversial. 24Here, we report that the transcription factor RUNX1 marks a specific subpopulation of proximal luminal 25 cells (PLCs), enriched in the periurethral region of the developing and adult mouse prostate, and distinct 26 from the previously identified NKX3.1 + luminal castration resistant cells. Using scRNA-seq profiling and 27 genetic lineage tracing, we show that RUNX1 + PLCs are unaffected by androgen deprivation, and do not 28 contribute to the regeneration of the distal luminal compartments. Furthermore, we demonstrate that a 29 transcriptionally similar RUNX1 + population emerges at the onset of embryonic prostate specification to 30 populate the proximal region of the ducts. Collectively, our results reveal that RUNX1 + PLCs is an intrinsic 31 castration-resistant and self-sustained lineage that emerges early during prostate development and 32 provide new insights into the lineage relationships of the prostate epithelium.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 90%

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RUNX1 marks a luminal castration resistant lineage established at the onset of prostate development

Mével

Steiner

Mason

et al. 2020

Preprint

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“…In particular, several studies have suggested increased progenitor potential in the proximal region of the prostate (nearest to the urethra) (Burger et al, 2005;Goto et al, 2006;Tsujimura et al, 2002), particularly for proximal luminal cells (Guo et al, 2020;Karthaus et al, 2020;Kwon et al, 2016;Wei et al, 2019;Zhang et al, 2018). However, the nature and distribution of these epithelial populations have been poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors

Crowley

Cambuli

Aparicio

et al. 2020

eLife

159

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Understanding the cellular constituents of the prostate is essential for identifying the cell of origin for prostate adenocarcinoma. Here we describe a comprehensive single-cell atlas of the adult mouse prostate epithelium, which displays extensive heterogeneity. We observe distal lobe-specific luminal epithelial populations (LumA, LumD, LumL, and LumV), a proximally-enriched luminal population (LumP) that is not lobe-specific, and a periurethral population (PrU) that shares both basal and luminal features. Functional analyses suggest that LumP and PrU cells have multipotent progenitor activity in organoid formation and tissue reconstitution assays. Furthermore, we show that mouse distal and proximal luminal cells are most similar to human acinar and ductal populations, that a PrU-like population is conserved between species, and that the mouse lateral prostate is most similar to the human peripheral zone. Our findings elucidate new prostate epithelial progenitors, and help resolve long-standing questions about anatomical relationships between the mouse and human prostate.

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Single‐Cell RNA‐seq Reveals a Developmental Hierarchy Super‐Imposed Over Subclonal Evolution in the Cellular Ecosystem of Prostate Cancer

Han

Zhang

et al. 2022

Advanced Science

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Prostate cancer (PCa) is a complex disease. An ongoing accumulation of mutations results in increased genetic diversity, with the tumor acquiring distinct subclones. However, non-genetic intra-tumoral heterogeneity, the cellular differentiation state and the interplay between subclonal evolution and transcriptional heterogeneity are poorly understood. Here, the authors perform single-cell RNA sequencing from 14 untreated PCa patients. They create an extensive cell atlas of the PCa patients and mapped developmental states onto tumor subclonal evolution. They identify distinct subclones across PCa patients and then stratify tumor cells into four transcriptional subtypes, EMT-like (subtype 0), luminal A-like (subtype 1), luminal B/C-like (subtype 2), and basal-like (subtype 3). These subtypes are hierarchically organized into stem cell-like and differentiated status. Strikingly, multiple subclones within a single primary tumor present with distinct combinations of preferential subtypes. In addition, subclones show different communication strengths with other cell types within the tumor ecosystem, which may modulate the distinct transcriptional subtypes of the subclones. Notably, by integrating TCGA data, they discover that both tumor cell transcriptional heterogeneity and cellular ecosystem diversity correlate with features of a poor prognosis. Collectively, their study provides the analysis of subclonal and transcriptional heterogeneity and its implication for patient prognosis.

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Single-cell transcriptomics identifies a distinct luminal progenitor cell type in distal prostate invagination tips

Cited by 85 publications

References 57 publications

RUNX1 marks a luminal castration resistant lineage established at the onset of prostate development

RUNX1 marks a luminal castration resistant lineage established at the onset of prostate development

A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors

Single‐Cell RNA‐seq Reveals a Developmental Hierarchy Super‐Imposed Over Subclonal Evolution in the Cellular Ecosystem of Prostate Cancer

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