RUNX1 Marks a Luminal Castration-resistant Lineage Established at the Onset of Prostate Development

Overview

Journal Elife

Specialty Biology

Date 2020 Oct 7

PMID 33025905

Citations 23

Authors

Renaud Mevel

Ivana Steiner

Susan Mason

Laura Ca Galbraith

Rahima Patel

Muhammad Zh Fadlullah

Imran Ahmad

Hing Y Leung

Pedro Oliveira

Karen Blyth

Esther Baena

Georges Lacaud

Affiliations

Soon will be listed here.

Abstract

The characterization of prostate epithelial hierarchy and lineage heterogeneity is critical to understand its regenerative properties and malignancies. Here, we report that the transcription factor RUNX1 marks a specific subpopulation of proximal luminal cells (PLCs), enriched in the periurethral region of the developing and adult mouse prostate, and distinct from the previously identified NKX3.1 luminal castration-resistant cells. Using scRNA-seq profiling and genetic lineage tracing, we show that RUNX1 PLCs are unaffected by androgen deprivation, and do not contribute to the regeneration of the distal luminal compartments. Furthermore, we demonstrate that a transcriptionally similar RUNX1 population emerges at the onset of embryonic prostate specification to populate the proximal region of the ducts. Collectively, our results reveal that RUNX1 PLCs is an intrinsic castration-resistant and self-sustained lineage that emerges early during prostate development and provide new insights into the lineage relationships of the prostate epithelium.

Citing Articles

Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer.

Pitzen S, Rudenick A, Qiu Y, Zhang W, Munro S, McCluskey B Proc Natl Acad Sci U S A. 2025; 122(6):e2415308122.

PMID: 39913208 PMC: 11831193. DOI: 10.1073/pnas.2415308122.

Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer.

Aparicio L, Crowley L, Christin J, Laplaca C, Hibshoosh H, Rabadan R Genome Med. 2025; 17(1):5.

PMID: 39825401 PMC: 11740708. DOI: 10.1186/s13073-025-01432-w.

Rarγ-Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer.

De Felice D, Alaimo A, Bressan D, Genovesi S, Marmocchi E, Annesi N EMBO Rep. 2024; 26(2):443-469.

PMID: 39633177 PMC: 11772605. DOI: 10.1038/s44319-024-00335-y.

Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells.

Kirk J, Wang J, Long M, Rosario S, Tracz A, Ji Y Cell Stem Cell. 2024; 31(8):1203-1221.e7.

PMID: 38878775 PMC: 11297676. DOI: 10.1016/j.stem.2024.05.008.

Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia.

Fei X, Liu J, Xu J, Jing H, Cai Z, Yan J J Transl Med. 2024; 22(1):380.

PMID: 38654277 PMC: 11036735. DOI: 10.1186/s12967-024-05212-9.

References

Mevel R, Draper J, Lie-A-Ling M, Kouskoff V, Lacaud G . RUNX transcription factors: orchestrators of development. Development. 2019; 146(17). DOI: 10.1242/dev.148296. View

Scheitz C, Lee T, McDermitt D, Tumbar T . Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. EMBO J. 2012; 31(21):4124-39. PMC: 3492731. DOI: 10.1038/emboj.2012.270. View

Luche H, Weber O, Rao T, Blum C, Fehling H . Faithful activation of an extra-bright red fluorescent protein in "knock-in" Cre-reporter mice ideally suited for lineage tracing studies. Eur J Immunol. 2006; 37(1):43-53. DOI: 10.1002/eji.200636745. View

Burger P, Xiong X, Coetzee S, Salm S, Moscatelli D, Goto K . Sca-1 expression identifies stem cells in the proximal region of prostatic ducts with high capacity to reconstitute prostatic tissue. Proc Natl Acad Sci U S A. 2005; 102(20):7180-5. PMC: 1129148. DOI: 10.1073/pnas.0502761102. View

McGinnis C, Patterson D, Winkler J, Conrad D, Hein M, Srivastava V . MULTI-seq: sample multiplexing for single-cell RNA sequencing using lipid-tagged indices. Nat Methods. 2019; 16(7):619-626. PMC: 6837808. DOI: 10.1038/s41592-019-0433-8. View

Tsujimura A, Koikawa Y, Salm S, Takao T, Coetzee S, Moscatelli D . Proximal location of mouse prostate epithelial stem cells: a model of prostatic homeostasis. J Cell Biol. 2002; 157(7):1257-65. PMC: 2173539. DOI: 10.1083/jcb.200202067. View

Ferrari N, Mohammed Z, Nixon C, Mason S, Mallon E, McMillan D . Expression of RUNX1 correlates with poor patient prognosis in triple negative breast cancer. PLoS One. 2014; 9(6):e100759. PMC: 4072705. DOI: 10.1371/journal.pone.0100759. View

Wang B, Wang X, Long J, Eastham-Anderson J, Firestein R, Junttila M . Castration-resistant Lgr5(+) cells are long-lived stem cells required for prostatic regeneration. Stem Cell Reports. 2015; 4(5):768-79. PMC: 4437474. DOI: 10.1016/j.stemcr.2015.04.003. View

Satija R, Farrell J, Gennert D, Schier A, Regev A . Spatial reconstruction of single-cell gene expression data. Nat Biotechnol. 2015; 33(5):495-502. PMC: 4430369. DOI: 10.1038/nbt.3192. View

10.

Zhang D, Zhao S, Li X, Kirk J, Tang D . Prostate Luminal Progenitor Cells in Development and Cancer. Trends Cancer. 2018; 4(11):769-783. PMC: 6212301. DOI: 10.1016/j.trecan.2018.09.003. View

11.

Choi N, Zhang B, Zhang L, Ittmann M, Xin L . Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell. 2012; 21(2):253-65. PMC: 3285423. DOI: 10.1016/j.ccr.2012.01.005. View

12.

Lukacs R, Goldstein A, Lawson D, Cheng D, Witte O . Isolation, cultivation and characterization of adult murine prostate stem cells. Nat Protoc. 2010; 5(4):702-13. PMC: 2943378. DOI: 10.1038/nprot.2010.11. View

13.

Thambyrajah R, Mazan M, Patel R, Moignard V, Stefanska M, Marinopoulou E . GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD1. Nat Cell Biol. 2015; 18(1):21-32. DOI: 10.1038/ncb3276. View

14.

Kruithof-de Julio M, Shibata M, Desai N, Reynon M, Halili M, Hu Y . Canonical Wnt signaling regulates Nkx3.1 expression and luminal epithelial differentiation during prostate organogenesis. Dev Dyn. 2013; 242(10):1160-71. PMC: 3788082. DOI: 10.1002/dvdy.24008. View

15.

Berman D, Desai N, Wang X, Karhadkar S, Reynon M, Abate-Shen C . Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis. Dev Biol. 2004; 267(2):387-98. DOI: 10.1016/j.ydbio.2003.11.018. View

16.

Chimge N, Little G, Baniwal S, Adisetiyo H, Xie Y, Zhang T . RUNX1 prevents oestrogen-mediated AXIN1 suppression and β-catenin activation in ER-positive breast cancer. Nat Commun. 2016; 7:10751. PMC: 4773428. DOI: 10.1038/ncomms10751. View

17.

Yokomizo T, Yamada-Inagawa T, Yzaguirre A, Chen M, Speck N, Dzierzak E . Whole-mount three-dimensional imaging of internally localized immunostained cells within mouse embryos. Nat Protoc. 2012; 7(3):421-31. PMC: 3629302. DOI: 10.1038/nprot.2011.441. View

18.

Draper J, Sroczynska P, Fadlullah M, Patel R, Newton G, Breitwieser W . A novel prospective isolation of murine fetal liver progenitors to study in utero hematopoietic defects. PLoS Genet. 2018; 14(1):e1007127. PMC: 5754050. DOI: 10.1371/journal.pgen.1007127. View

19.

Guo W, Li L, He J, Liu Z, Han M, Li F . Single-cell transcriptomics identifies a distinct luminal progenitor cell type in distal prostate invagination tips. Nat Genet. 2020; 52(9):908-918. PMC: 8383310. DOI: 10.1038/s41588-020-0642-1. View

20.

Barros-Silva J, Linn D, Steiner I, Guo G, Ali A, Pakula H . Single-Cell Analysis Identifies LY6D as a Marker Linking Castration-Resistant Prostate Luminal Cells to Prostate Progenitors and Cancer. Cell Rep. 2018; 25(12):3504-3518.e6. PMC: 6315111. DOI: 10.1016/j.celrep.2018.11.069. View