Regenerative potential of prostate luminal cells revealed by single-cell analysis

Wouter R. Karthaus; Matan Hofree; Danielle Choi; Eliot L. Linton; Mesruh Turkekul; Alborz Bejnood; Brett Carver; Anuradha Gopalan; Wassim Abida; Vincent Laudone; Moshe Biton; Ojasvi Chaudhary; Tianhao Xu; Ignas Masilionis; Katia Manova; Linas Mazutis; Dana Pe’er; Aviv Regev; Charles L. Sawyers

doi:https://doi.org/10.1126/science.aay0267

Regenerative potential of prostate luminal cells revealed by single-cell analysis

Wouter R. Karthaus, Matan Hofree, Danielle Choi, Eliot L. Linton, Mesruh Turkekul, Alborz Bejnood, Brett Carver, Anuradha Gopalan, Wassim Abida, Vincent Laudone, Moshe Biton, Ojasvi Chaudhary, Tianhao Xu, Ignas Masilionis, Katia Manova, Linas Mazutis, Dana Pe’er, Aviv Regev, Charles L. Sawyers

Research output: Contribution to journal › Article › peer-review

Abstract

Androgen deprivation is the cornerstone of prostate cancer treatment. It results in involution of the normal gland to ~90% of its original size because of the loss of luminal cells. The prostate regenerates when androgen is restored, a process postulated to involve stem cells. Using single-cel RNA sequencing, we identified a rare luminal population in the mouse prostate that expresses stemlike genes (Sca1⁺ and Psca⁺) and a large population of differentiated cells (Nkx3.1⁺, Pbsn⁺). In organoids and in mice, both populations contribute equally to prostate regeneration, partly through androgen-driven expression of growth factors (Nrg2, Rspo3) by mesenchymal cells acting in a paracrine fashion on luminal cells. Analysis of human prostate tissue revealed similar differentiated and stemlike luminal subpopulations that likewise acquire enhanced regenerative potential after androgen ablation. We propose that prostate regeneration is driven by nearly all persisting luminal cells, not just by rare stem cells.

Original language	American English
Pages (from-to)	497-505
Number of pages	9
Journal	Science
Volume	368
Issue number	6490
DOIs	https://doi.org/10.1126/science.aay0267
State	Published - 1 May 2020
Externally published	Yes

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Karthaus, W. R., Hofree, M., Choi, D., Linton, E. L., Turkekul, M., Bejnood, A., Carver, B., Gopalan, A., Abida, W., Laudone, V., Biton, M., Chaudhary, O., Xu, T., Masilionis, I., Manova, K., Mazutis, L., Pe’er, D., Regev, A., & Sawyers, C. L. (2020). Regenerative potential of prostate luminal cells revealed by single-cell analysis. Science, 368(6490), 497-505. https://doi.org/10.1126/science.aay0267

@article{0aa6b715af5a409c95340e58e05cfc47,

title = "Regenerative potential of prostate luminal cells revealed by single-cell analysis",

abstract = "Androgen deprivation is the cornerstone of prostate cancer treatment. It results in involution of the normal gland to ~90% of its original size because of the loss of luminal cells. The prostate regenerates when androgen is restored, a process postulated to involve stem cells. Using single-cel RNA sequencing, we identified a rare luminal population in the mouse prostate that expresses stemlike genes (Sca1+ and Psca+) and a large population of differentiated cells (Nkx3.1+, Pbsn+). In organoids and in mice, both populations contribute equally to prostate regeneration, partly through androgen-driven expression of growth factors (Nrg2, Rspo3) by mesenchymal cells acting in a paracrine fashion on luminal cells. Analysis of human prostate tissue revealed similar differentiated and stemlike luminal subpopulations that likewise acquire enhanced regenerative potential after androgen ablation. We propose that prostate regeneration is driven by nearly all persisting luminal cells, not just by rare stem cells.",

author = "Karthaus, {Wouter R.} and Matan Hofree and Danielle Choi and Linton, {Eliot L.} and Mesruh Turkekul and Alborz Bejnood and Brett Carver and Anuradha Gopalan and Wassim Abida and Vincent Laudone and Moshe Biton and Ojasvi Chaudhary and Tianhao Xu and Ignas Masilionis and Katia Manova and Linas Mazutis and Dana Pe{\textquoteright}er and Aviv Regev and Sawyers, {Charles L.}",

note = "Funding Information: We thank members of the Regev and Sawyers laboratories for valuable critiques and discussions; the Molecular Cytology Core Facility at MSKCC for help with confocal microscopy and IHC; and the Flow Cytometry Core Facility at MSKCC for help with FACS experiments. C.L.S. is supported by HHMI; National Institutes of Health grants CA193837, CA092629, CA224079, CA155169, and CA008748; and Starr Cancer Consortium grant I12-0007. A.R. is an HHMI Investigator and is supported by the Klarman Cell Observatory, NCI grants 1U24CA180922 and R33-CA202820, Koch Institute NCI Support (core) grant P30-CA14051, and the Ludwig Center at MIT (AR). W.R.K. is supported by a fellowship from the Dutch Cancer Foundation and a Prostate Cancer Foundation Young Investigator Award. Publisher Copyright: {\textcopyright} 2020 American Association for the Advancement of Science. All rights reserved.",

year = "2020",

month = may,

day = "1",

doi = "https://doi.org/10.1126/science.aay0267",

language = "American English",

volume = "368",

pages = "497--505",

journal = "Science",

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publisher = "American Association for the Advancement of Science",

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Karthaus, WR, Hofree, M, Choi, D, Linton, EL, Turkekul, M, Bejnood, A, Carver, B, Gopalan, A, Abida, W, Laudone, V, Biton, M, Chaudhary, O, Xu, T, Masilionis, I, Manova, K, Mazutis, L, Pe’er, D, Regev, A & Sawyers, CL 2020, 'Regenerative potential of prostate luminal cells revealed by single-cell analysis', Science, vol. 368, no. 6490, pp. 497-505. https://doi.org/10.1126/science.aay0267

TY - JOUR

T1 - Regenerative potential of prostate luminal cells revealed by single-cell analysis

AU - Karthaus, Wouter R.

AU - Hofree, Matan

AU - Choi, Danielle

AU - Linton, Eliot L.

AU - Turkekul, Mesruh

AU - Bejnood, Alborz

AU - Carver, Brett

AU - Gopalan, Anuradha

AU - Abida, Wassim

AU - Laudone, Vincent

AU - Biton, Moshe

AU - Chaudhary, Ojasvi

AU - Xu, Tianhao

AU - Masilionis, Ignas

AU - Manova, Katia

AU - Mazutis, Linas

AU - Pe’er, Dana

AU - Regev, Aviv

AU - Sawyers, Charles L.

N1 - Funding Information: We thank members of the Regev and Sawyers laboratories for valuable critiques and discussions; the Molecular Cytology Core Facility at MSKCC for help with confocal microscopy and IHC; and the Flow Cytometry Core Facility at MSKCC for help with FACS experiments. C.L.S. is supported by HHMI; National Institutes of Health grants CA193837, CA092629, CA224079, CA155169, and CA008748; and Starr Cancer Consortium grant I12-0007. A.R. is an HHMI Investigator and is supported by the Klarman Cell Observatory, NCI grants 1U24CA180922 and R33-CA202820, Koch Institute NCI Support (core) grant P30-CA14051, and the Ludwig Center at MIT (AR). W.R.K. is supported by a fellowship from the Dutch Cancer Foundation and a Prostate Cancer Foundation Young Investigator Award. Publisher Copyright: © 2020 American Association for the Advancement of Science. All rights reserved.

PY - 2020/5/1

Y1 - 2020/5/1

N2 - Androgen deprivation is the cornerstone of prostate cancer treatment. It results in involution of the normal gland to ~90% of its original size because of the loss of luminal cells. The prostate regenerates when androgen is restored, a process postulated to involve stem cells. Using single-cel RNA sequencing, we identified a rare luminal population in the mouse prostate that expresses stemlike genes (Sca1+ and Psca+) and a large population of differentiated cells (Nkx3.1+, Pbsn+). In organoids and in mice, both populations contribute equally to prostate regeneration, partly through androgen-driven expression of growth factors (Nrg2, Rspo3) by mesenchymal cells acting in a paracrine fashion on luminal cells. Analysis of human prostate tissue revealed similar differentiated and stemlike luminal subpopulations that likewise acquire enhanced regenerative potential after androgen ablation. We propose that prostate regeneration is driven by nearly all persisting luminal cells, not just by rare stem cells.

AB - Androgen deprivation is the cornerstone of prostate cancer treatment. It results in involution of the normal gland to ~90% of its original size because of the loss of luminal cells. The prostate regenerates when androgen is restored, a process postulated to involve stem cells. Using single-cel RNA sequencing, we identified a rare luminal population in the mouse prostate that expresses stemlike genes (Sca1+ and Psca+) and a large population of differentiated cells (Nkx3.1+, Pbsn+). In organoids and in mice, both populations contribute equally to prostate regeneration, partly through androgen-driven expression of growth factors (Nrg2, Rspo3) by mesenchymal cells acting in a paracrine fashion on luminal cells. Analysis of human prostate tissue revealed similar differentiated and stemlike luminal subpopulations that likewise acquire enhanced regenerative potential after androgen ablation. We propose that prostate regeneration is driven by nearly all persisting luminal cells, not just by rare stem cells.

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U2 - https://doi.org/10.1126/science.aay0267

DO - https://doi.org/10.1126/science.aay0267

M3 - Article

C2 - 32355025

SN - 0036-8075

VL - 368

SP - 497

EP - 505

JO - Science

JF - Science

IS - 6490

ER -

Regenerative potential of prostate luminal cells revealed by single-cell analysis

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