Sox2 Expression Marks Castration-Resistant Progenitor Cells in the Adult Murine Prostate

Abstract

Identification of defined epithelial cell populations with progenitor properties is critical for understanding prostatic development and disease. Here, we demonstrate that Sox2 expression is enriched in the epithelial cells of the proximal prostate adjacent to the urethra. We use lineage tracing of Sox2-positive cells during prostatic development, homeostasis, and regeneration to show that the Sox2 lineage is capable of self-renewal and contributes to prostatic regeneration. Persisting luminal cells express Sox2 after castration, highlighting a potential role for Sox2 in cell survival and castration-resistance. In addition to revealing a novel progenitor population in the prostate, these data implicate Sox2 as a regulatory factor of adult prostate epithelial stem cells.

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

“…RUNX1-expressing cells often co-expressed TROP2 ( Figure 2E ), known to be widely expressed in castrated prostate epithelium ( Goldstein et al, 2008 ; Wang et al, 2007 ). Several castration-resistant luminal populations have been identified in mice ( Barros-Silva et al, 2018 ; Kwon et al, 2016 ; McAuley et al, 2019 ; Tsujimura et al, 2002 ; Wang et al, 2015 ; Wang et al, 2009 ; Yoo et al, 2016 ), including rare castration-resistant Nkx3-1 -expressing cells (CARNs). Accordingly, we observed low, but detectable, levels of NKX3.1 in some luminal cells, but only occasional RUNX1 + NKX3.1 + luminal cells in the distal regions of the castrated prostate ( Figure 2D ; Figure 2—figure supplement 1B,C ).…”

“…Despite being mostly quiescent under homeostatic conditions, the prostate gland encompasses incredible plasticity. In mice, surgical castration-induced prostate involution has proven an invaluable tool to identify progenitor castration-resistant cell populations, characterized by their ability to survive in the absence of androgens, and to fully regenerate an intact adult prostate after re-administration of testosterone ( Barros-Silva et al, 2018 ; Kwon et al, 2016 ; McAuley et al, 2019 ; Tsujimura et al, 2002 ; Wang et al, 2015 ; Wang et al, 2009 ; Yoo et al, 2016 ). Such plasticity has also been shown in defined experimental conditions to stimulate regenerative properties of epithelial subpopulations, including transplantations ( Barros-Silva et al, 2018 ; Burger et al, 2005 ; Lawson et al, 2007 ; Lukacs et al, 2010 ; Richardson et al, 2004 ; Wang et al, 2009 ; Xin et al, 2005 ; Yoo et al, 2016 ), injury repair ( Centonze et al, 2020 ; Horton et al, 2019 ; Kwon et al, 2014 ; Toivanen et al, 2016 ), and organoid assays ( Chua et al, 2014 ; Höfner et al, 2015 ; Karthaus et al, 2014 ).…”

The Sca-1+ and Sca-1− mouse prostatic luminal cell lineages are independently sustained

“…Previously, we and others have identified a Sca-1 + Nkx3.1 − luminal cell population that resides at the mouse proximal prostatic ducts adjacent to the urethra. [18][19][20][21] We showed that these cells are not only phenotypically different from the Sca-1 − Nkx3.1 + luminal cells in the other anatomic regions in the mouse prostate but are also functionally distinct in that they possess a higher bipotent differentiation capacity. In this study, we examine their hierarchical relationships using a lineage tracing approach and determine the role of Sox2 in the maintenance and stem cell potential of the Sca-1 + luminal cells.…”

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

“…RUNX1 expressing cells often co-expressed TROP2 (Figure 2E), known to be widely expressed in castrated prostate epithelium (Goldstein et al, 2008;X.-D. Wang et al, 2007). Several castration-resistant luminal populations have been identified in mice (Barros-Silva et al, 2018;Kwon et al, 2016;McAuley et al, 2019;Tsujimura et al, 2002;B. Wang et al, 2015;X.…”

“…Despite being mostly quiescent under homeostatic conditions, the prostate gland encompasses incredible plasticity. In mice, surgical castration-induced prostate involution has proven an invaluable tool to identify progenitor castration-resistant cell populations, characterized by their ability to survive in the absence of androgens, and to fully regenerate an intact adult prostate after re-administration of testosterone (Barros-Silva et al, 2018;Kwon et al, 2016;McAuley et al, 2019;Tsujimura et al, 2002;B. Wang et al, 2015;X.…”