A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumours

Lucila Sackmann Sala, Florence Boutillon, Giulia Menara, Andréa De Goyon-Pélard, Mylène Leprévost, Julie Codzamanian, Natalie Lister, Jan Pencik, Ashlee Clark, Nicolas Cagnard, Christine Bole-Feysot, Richard Moriggl, Gail P. Risbridger, Renea A. Taylor, Lukas Kenner, Jacques Emmanuel Guidotti, Vincent Goffin

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen deprivation remain poorly described, despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild-type (WT) mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin-/Sca-1+/CD49fmed). Here, we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumourigenesis (Pb-PRL, Ptenpc-/-, and Hi-Myc mice). LSCmed prevalence is low (∼8%, similar to WT) in Hi-Myc mice, where prostatic androgen receptor signalling is unaltered, but is significantly higher in the two other models, where androgen receptor signalling is decreased, rising up to more than 80% in Ptenpc-/- prostates. LSCmed tolerate androgen deprivation and persist or are enriched 2-3 weeks after castration. The tumour-initiating properties of LSCmed from Ptenpc-/- mice were demonstrated by regeneration of tumours in vivo. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signalling is markedly decreased, explaining why LSCmed tolerate androgen deprivation. This also illuminates why Ptenpc-/- tumours are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, there was significant proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. Taken together, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.

Original languageEnglish
Pages (from-to)51-64
Number of pages14
JournalJournal of Pathology
Volume243
Issue number1
DOIs
Publication statusPublished - Sep 2017

Keywords

  • Androgen signalling
  • Castration resistance
  • CK4
  • Epithelial cells
  • Progenitor cell
  • Prostate cancer

Cite this

Sackmann Sala, L., Boutillon, F., Menara, G., De Goyon-Pélard, A., Leprévost, M., Codzamanian, J., ... Goffin, V. (2017). A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumours. Journal of Pathology, 243(1), 51-64. https://doi.org/10.1002/path.4924
Sackmann Sala, Lucila ; Boutillon, Florence ; Menara, Giulia ; De Goyon-Pélard, Andréa ; Leprévost, Mylène ; Codzamanian, Julie ; Lister, Natalie ; Pencik, Jan ; Clark, Ashlee ; Cagnard, Nicolas ; Bole-Feysot, Christine ; Moriggl, Richard ; Risbridger, Gail P. ; Taylor, Renea A. ; Kenner, Lukas ; Guidotti, Jacques Emmanuel ; Goffin, Vincent. / A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumours. In: Journal of Pathology. 2017 ; Vol. 243, No. 1. pp. 51-64.
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abstract = "Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen deprivation remain poorly described, despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild-type (WT) mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin-/Sca-1+/CD49fmed). Here, we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumourigenesis (Pb-PRL, Ptenpc-/-, and Hi-Myc mice). LSCmed prevalence is low (∼8{\%}, similar to WT) in Hi-Myc mice, where prostatic androgen receptor signalling is unaltered, but is significantly higher in the two other models, where androgen receptor signalling is decreased, rising up to more than 80{\%} in Ptenpc-/- prostates. LSCmed tolerate androgen deprivation and persist or are enriched 2-3 weeks after castration. The tumour-initiating properties of LSCmed from Ptenpc-/- mice were demonstrated by regeneration of tumours in vivo. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signalling is markedly decreased, explaining why LSCmed tolerate androgen deprivation. This also illuminates why Ptenpc-/- tumours are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, there was significant proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. Taken together, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.",
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Sackmann Sala, L, Boutillon, F, Menara, G, De Goyon-Pélard, A, Leprévost, M, Codzamanian, J, Lister, N, Pencik, J, Clark, A, Cagnard, N, Bole-Feysot, C, Moriggl, R, Risbridger, GP, Taylor, RA, Kenner, L, Guidotti, JE & Goffin, V 2017, 'A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumours', Journal of Pathology, vol. 243, no. 1, pp. 51-64. https://doi.org/10.1002/path.4924

A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumours. / Sackmann Sala, Lucila; Boutillon, Florence; Menara, Giulia; De Goyon-Pélard, Andréa; Leprévost, Mylène; Codzamanian, Julie; Lister, Natalie; Pencik, Jan; Clark, Ashlee; Cagnard, Nicolas; Bole-Feysot, Christine; Moriggl, Richard; Risbridger, Gail P.; Taylor, Renea A.; Kenner, Lukas; Guidotti, Jacques Emmanuel; Goffin, Vincent.

In: Journal of Pathology, Vol. 243, No. 1, 09.2017, p. 51-64.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumours

AU - Sackmann Sala, Lucila

AU - Boutillon, Florence

AU - Menara, Giulia

AU - De Goyon-Pélard, Andréa

AU - Leprévost, Mylène

AU - Codzamanian, Julie

AU - Lister, Natalie

AU - Pencik, Jan

AU - Clark, Ashlee

AU - Cagnard, Nicolas

AU - Bole-Feysot, Christine

AU - Moriggl, Richard

AU - Risbridger, Gail P.

AU - Taylor, Renea A.

AU - Kenner, Lukas

AU - Guidotti, Jacques Emmanuel

AU - Goffin, Vincent

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N2 - Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen deprivation remain poorly described, despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild-type (WT) mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin-/Sca-1+/CD49fmed). Here, we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumourigenesis (Pb-PRL, Ptenpc-/-, and Hi-Myc mice). LSCmed prevalence is low (∼8%, similar to WT) in Hi-Myc mice, where prostatic androgen receptor signalling is unaltered, but is significantly higher in the two other models, where androgen receptor signalling is decreased, rising up to more than 80% in Ptenpc-/- prostates. LSCmed tolerate androgen deprivation and persist or are enriched 2-3 weeks after castration. The tumour-initiating properties of LSCmed from Ptenpc-/- mice were demonstrated by regeneration of tumours in vivo. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signalling is markedly decreased, explaining why LSCmed tolerate androgen deprivation. This also illuminates why Ptenpc-/- tumours are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, there was significant proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. Taken together, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.

AB - Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen deprivation remain poorly described, despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild-type (WT) mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin-/Sca-1+/CD49fmed). Here, we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumourigenesis (Pb-PRL, Ptenpc-/-, and Hi-Myc mice). LSCmed prevalence is low (∼8%, similar to WT) in Hi-Myc mice, where prostatic androgen receptor signalling is unaltered, but is significantly higher in the two other models, where androgen receptor signalling is decreased, rising up to more than 80% in Ptenpc-/- prostates. LSCmed tolerate androgen deprivation and persist or are enriched 2-3 weeks after castration. The tumour-initiating properties of LSCmed from Ptenpc-/- mice were demonstrated by regeneration of tumours in vivo. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signalling is markedly decreased, explaining why LSCmed tolerate androgen deprivation. This also illuminates why Ptenpc-/- tumours are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, there was significant proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. Taken together, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.

KW - Androgen signalling

KW - Castration resistance

KW - CK4

KW - Epithelial cells

KW - Progenitor cell

KW - Prostate cancer

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Sackmann Sala L, Boutillon F, Menara G, De Goyon-Pélard A, Leprévost M, Codzamanian J et al. A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumours. Journal of Pathology. 2017 Sep;243(1):51-64. https://doi.org/10.1002/path.4924