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    • Previously we showed that the

    2018-10-20

    Previously, we showed that the transcription factor SLUG is an important regulator of mammary epithelial lineage commitment and differentiation (Proia et al., 2011). Recent studies have also shown that SLUG is necessary for the mammary stem cell state (Guo et al., 2012). However, SLUG-deficient mice develop mammary glands, and transplantation of tissue fragments from these mice were able to fully regenerate functional mammary glands; this suggests that SLUG might be dispensable for stem cell activity (Nassour et al., 2012). Thus, the precise role of SLUG in mammary stem and progenitor cell dynamics remains unclear. The ability to study stem cell-state transitions and progenitor cell dynamics in vivo is challenging; even when cell-state markers are available, most transitions are short-lived and difficult to capture. We sought to gain insights into how SLUG controls stem cell activity in normal disease-free mammary epithelial Quinacrine Dihydrochloride by using a recently developed and validated quantitative model to predict cell-state transition rates in vitro (Gupta et al., 2011). Using this approach, we were able to (1) infer differences in cell-state transition probabilities between wild-type (WT) and SLUG-deficient mammary epithelial cell populations, (2) accurately predict the in vivo phenotype associated with SLUG deficiency, and (3) provide insights into how SLUG inhibition influences progenitor cell dynamics to ultimately disrupt cellular differentiation as well as tissue homeostasis, regeneration, and tumor initiation.
    Results
    Discussion In this study, we uncover the complex connection between cellular differentiation and cellular plasticity regulated by SLUG, thus revealing how it impacts stem cell activity during tissue homeostasis, function, regeneration, and even the genesis of cancer. Our findings support a model in which the transcription factor, SLUG, plays a dual role in regulating MEC lineage identity; on the one hand, it represses luminal epithelial differentiation, but on the other it promotes stem cell-state transitions necessary for transplantation and tumorigenesis. As a transcriptional repressor of luminal differentiation, we showed that SLUG interacts with LSD1 and recruits it to specific luminal gene promoters where it demethylates H3K4 (Figure 5E). In the absence of SLUG, LSD1 is no longer recruited to these genes to modify chromatin; this results in the expression of otherwise-repressed genes. Consistent with this, our in vivo and in vitro observations showed that loss of SLUG resulted in aberrant EPCAM expression in basal/ME cells. As a regulator of progenitor cell dynamics, we found that SLUG also actively influences stem cell transitions. In the absence of SLUG, cellular transitions from and into the basal and stem cell states were compromised. This was supported in vivo, where SLUG-deficient MECs were unable to regenerate a mammary gland following transplantation and were unable to form oncogene induced mammary tumors; both processes require the transition of basal progenitor cells into primitive stem-like states not normally present during development (van Amerongen et al., 2012; Van Keymeulen et al., 2011). Future studies will be needed to determine whether LSD1 is also necessary for repressing SLUG target genes that regulate stem cell activity. The observations that transplantation of Snai2LacZ/LacZ mouse tissue fragments, rather than dissociated cells, results in mature, highly branched mammary ductal trees that infiltrate the entire fat pad (Nassour et al., 2012) and that Snai2LacZ/LacZ mice exhibit normal embryonic and pubertal mammary stem cell activity suggest that SLUG is dispensable for normal mammary stem cell activity. However, our findings and those of others clearly show that SLUG is necessary for mammary stem cell activity during transplantation of dissociated cells (Figure 4A) (Guo et al., 2012). These conflicting observations can be reconciled by the differences in stem cell activity required during tissue regeneration following transplantation of dissociated cells from those used during ductal elongation of already-established structures. Mammary tissues are regenerated by unipotent lineage-restricted progenitor cells that can expand to give rise to mature luminal or basal/ME cells (Keller et al., 2011; van Amerongen et al., 2012; Van Keymeulen et al., 2011). Therefore, dissociated cells must adopt a bipotent fate upon transplantation, unlocking a regenerative potential that is not normally used during development (van Amerongen et al., 2012; Van Keymeulen et al., 2011). Thus, our findings suggest that the cell-state transitions necessary for this process require SLUG.