Sox11 regulates mammary tumour-initiating and metastatic capacity in <i>Brca1</i>-deficient mouse mammary tumour cells

Tsang, Siu Man; Kim, Hyojin; Oliemuller, Erik; Newman, Richard; Boateng, Naa-Anyima; Guppy, Naomi; Howard, Beatrice A.

doi:10.1242/dmm.046037

Cited by 3 publications

(2 citation statements)

References 20 publications

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“…Indeed, Sox11 is expressed in MECs only during the early stages of MG embryonic development—when MG epithelial cells are largely quiescent—and is no longer detected by E16.5, consistent with our results. Of interest, Sox11 has been recently involved in cell fate regulation in the embryonic MG (Tsang et al, 2021 ). Genes involved in epithelial stratification, such as Lgals7, Dsc3 , and Krtdap , are switched on only in luminal-like cells at E15.5 (Pattern 6).…”

Section: Resultsmentioning

confidence: 99%

Spatially distinct epithelial and mesenchymal cell subsets along progressive lineage restriction in the branching embryonic mammary gland

Carabaña,

Sun,

Veludo Ramos

et al. 2024

EMBO J

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How cells coordinate morphogenetic cues and fate specification during development remains a fundamental question in organogenesis. The mammary gland arises from multipotent stem cells (MaSCs), which are progressively replaced by unipotent progenitors by birth. However, the lack of specific markers for early fate specification has prevented the delineation of the features and spatial localization of MaSC-derived lineage-committed progenitors. Here, using single-cell RNA sequencing from E13.5 to birth, we produced an atlas of matched mouse mammary epithelium and mesenchyme and reconstructed the differentiation trajectories of MaSCs toward basal and luminal fate. We show that murine MaSCs exhibit lineage commitment just prior to the first sprouting events of mammary branching morphogenesis at E15.5. We identify early molecular markers for committed and multipotent MaSCs and define their spatial distribution within the developing tissue. Furthermore, we show that the mammary embryonic mesenchyme is composed of two spatially restricted cell populations, and that dermal mesenchyme-produced FGF10 is essential for embryonic mammary branching morphogenesis. Altogether, our data elucidate the spatiotemporal signals underlying lineage specification of multipotent MaSCs, and uncover the signals from mesenchymal cells that guide mammary branching morphogenesis.

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Section: Resultsmentioning

confidence: 99%

Spatially distinct epithelial and mesenchymal cell subsets along progressive lineage restriction in the branching embryonic mammary gland

Carabaña,

Sun,

Veludo Ramos

et al. 2024

EMBO J

View full text Add to dashboard Cite

show abstract

“…Indeed, Sox11 is expressed in MECs only during the early stages of MG embryonic development – when MG epithelial cells are largely quiescent – and is no longer detected by E16.5, consistent with our results. Of interest, Sox11 has been recently involved in cell fate regulation in the embryonic MG (Tsang et al, 2021). Genes involved in epithelial stratification, such as Lgals7, Dsc3 and Krtdap , are switched on only in luminal-like cells present at E15.5 (Pattern 6).…”

Section: Resultsmentioning

confidence: 99%

Positional cues underlie cell fate specification during branching morphogenesis of the embryonic mammary epithelium

Carabaña

Sun

Perkins

et al. 2022

Preprint

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How cells coordinate morphogenetic cues and fate specification during development is a fundamental question at the basis of tissue formation. Lineage tracing studies have demonstrated that many stratified epithelia, including the mammary gland, first arise from multipotent stem cells, which are progressively replaced by distinct pools of unipotent progenitors that maintain tissue homeostasis postnatally. The lack of specific markers for early fate specification in the mammary gland has prevented the delineation of the features and spatial localization of lineage-committed progenitors that co-exist with multipotent stem cells (MaSCs) during tissue development. Here, using single-cell RNA-sequencing across 4 stages of embryonic development, we reconstructed the differentiation trajectories of multipotent mammary stem cells towards basal and luminal fate. Our data revealed that MaSCs can already be resolved into distinct populations exhibiting lineage commitment at the time coinciding with the first sprouting events of mammary branching morphogenesis (E15.5). By visualizing gene expression across our developmental atlas, we provide novel molecular markers for committed and multipotent MaSCs, and define their spatial distribution within the developing tissue. Furthermore, we show that the mammary embryonic mesenchyme is composed of two spatially-restricted cell populations, representing the sub-epithelial and dermal mesenchyme. Mechanistically, we explored the communication between different subsets of mesenchymal and epithelial cells, using time-lapse analysis of mammary embryonic explant cultures, and reveal that mesenchymal-produced FGF10 accelerates embryonic mammary branching morphogenesis without affecting cell proliferation. Altogether, our data elucidate the spatiotemporal signals underlying lineage specification of multipotent mammary stem cells and uncover the paracrine interactions between epithelial and mesenchymal cells that guide mammary branching morphogenesis.

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Gpr125 is a unifying hallmark of multiple mammary progenitors coupled to tumor latency

et al. 2022

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Gpr125 is an orphan G-protein coupled receptor, with homology to cell adhesion and axonal guidance factors, that is implicated in planar polarity and control of cell movements. By lineage tracing we demonstrate that Gpr125 is a highly specific marker of bipotent mammary stem cells in the embryo and of multiple long-lived unipotent basal mammary progenitors in perinatal and postnatal glands. Nipple-proximal Gpr125+ cells express a transcriptomic profile indicative of chemo-repulsion and cell movement, whereas Gpr125+ cells concentrated at invasive ductal tips display a hybrid epithelial-mesenchymal phenotype and are equipped to bind chemokine and growth factors and secrete a promigratory matrix. Gpr125 progenitors acquire bipotency in the context of transplantation and cancer and are greatly expanded and massed at the pushing margins of short latency MMTV-Wnt1 tumors. High Gpr125 expression identifies patients with particularly poor outcome within the basal breast cancer subtype highlighting its potential utility as a factor to stratify risk.

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Sox11 regulates mammary tumour-initiating and metastatic capacity in Brca1-deficient mouse mammary tumour cells

Cited by 3 publications

References 20 publications

Spatially distinct epithelial and mesenchymal cell subsets along progressive lineage restriction in the branching embryonic mammary gland

Spatially distinct epithelial and mesenchymal cell subsets along progressive lineage restriction in the branching embryonic mammary gland

Positional cues underlie cell fate specification during branching morphogenesis of the embryonic mammary epithelium

Gpr125 is a unifying hallmark of multiple mammary progenitors coupled to tumor latency

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