Regulation of stem/progenitor cell maintenance by BMP5 in prostate homeostasis and cancer initiation

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Abstract

Tissue homeostasis relies on the fine regulation between stem and progenitor cell maintenance and lineage commitment. In the adult prostate, stem cells have been identified in both basal and luminal cell compartments. However, basal stem/progenitor cell homeostasis is still poorly understood. We show that basal stem/progenitor cell maintenance is regulated by a balance between BMP5 self-renewal signal and GATA3 dampening activity. Deleting Gata3 enhances adult prostate stem/progenitor cells self-renewal capacity in both organoid and allograft assays. This phenotype results from a local increase in BMP5 activity in basal cells as shown by the impaired self-renewal capacity of Bmp5-deficient stem/progenitor cells. Strikingly, Bmp5 gene inactivation or BMP signaling inhibition with a small molecule inhibitor are also sufficient to delay prostate and skin cancer initiation of Pten-deficient mice. Together, these results establish BMP5 as a key regulator of basal prostate stem cell homeostasis and identifies a potential therapeutic approach against Pten-deficient cancers.

Data availability

Data from this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1ABC-2C-3ABC-4AEFJ-2S1AC-4S1AB.Sequencing data have been deposited in GEO under accession codes GSE155289.

The following data sets were generated

(2020) Gata3 controls stem/progenitor maintenance potential in prostate organoids
NCBI Gene Expression Omnibus, GSE155289.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE155289

Article and author information

Author details

Mathieu Tremblay

Biochemistry, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Sophie Viala

Biochemistry, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Maxwell ER Shafer

Biochemistry, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Adda-Lee Graham-Paquin

Biochemistry, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Chloe Liu

Biochemistry, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
Maxime Bouchard

Goodman Cancer Research Centre/ Biochemistry, McGill University, Montreal, Canada

For correspondence
maxime.bouchard@mcgill.ca

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7619-9680

Funding

Canadian Institutes of Health Research (MOP-130460)

Maxime Bouchard

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures were approved by McGill University Animal Care Committee (Permit#2011-5954) according to the Canadian Council on Animal Care guidelines for use of laboratory animals in biological research.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.