The transcription factor Sox10 is an essential determinant of branching morphogenesis and involution in the mouse mammary gland

Mertelmeyer, Svenja; Weider, Matthias; Baroti, Tina; Reiprich, Simone; Fröb, Franziska; Stolt, C. Claus; Wagner, Kay Uwe; Wegner, Michael

doi:10.1038/s41598-020-74664-y

Cited by 22 publications

(15 citation statements)

References 49 publications

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“…It is first expressed in embryonic neural crest stem cells (NCSCs), where its self-reinforcing gene regulatory module facilitates multipotency and cell migration, orchestrating the embryo patterning process 25 – 28 . Once patterning is complete, SOX10 is silenced in all NCSC descendants except glial and melanocyte progenitors; and is nascently induced in ectoderm-derived epithelial progenitor cells of the salivary, lacrimal, and mammary glands 29 – 33 . In the mouse, Sox10 is an obligate requirement for mammary gland development.…”

Section: Introductionmentioning

confidence: 99%

Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer

et al. 2022

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Intratumoral heterogeneity is caused by genomic instability and phenotypic plasticity, but how these features co-evolve remains unclear. SOX10 is a neural crest stem cell (NCSC) specifier and candidate mediator of phenotypic plasticity in cancer. We investigated its relevance in breast cancer by immunophenotyping 21 normal breast and 1860 tumour samples. Nuclear SOX10 was detected in normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In tumours, nuclear SOX10 was almost exclusive to TNBC, and predicted poorer outcome amongst cross-sectional (p = 0.0015, hazard ratio 2.02, n = 224) and metaplastic (p = 0.04, n = 66) cases. To understand SOX10’s influence over the transcriptome during the transition from normal to malignant states, we performed a systems-level analysis of co-expression data, de-noising the networks with an eigen-decomposition method. This identified a core module in SOX10’s normal mammary epithelial network that becomes rewired to NCSC genes in TNBC. Crucially, this reprogramming was proportional to genome-wide promoter methylation loss, particularly at lineage-specifying CpG-island shores. We propose that the progressive, genome-wide methylation loss in TNBC simulates more primitive epigenome architecture, making cells vulnerable to SOX10-driven reprogramming. This study demonstrates potential utility for SOX10 as a prognostic biomarker in TNBC and provides new insights about developmental phenotypic mimicry—a major contributor to intratumoral heterogeneity.

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Section: Introductionmentioning

confidence: 99%

Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer

et al. 2022

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“…When carcinomas are involved, these stem-like cells are usually specified as cancer stem cells (CSCs) [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. Since members of the SOX protein family serve as versatile regulators of stem- and progenitor-cell fates [ 131 , 132 , 133 , 134 , 135 ], we next investigated the expression patterns of SOX2, SOX9, and SOX10 transcription factors in WM115 (primary) and WM266-4 (metastatic) melanoma cells via an immunofluorescence protocol employment ( Figure 4 ). SOX2 proved to be highly accumulated in all WM115 cell nuclei, while its detection could hardly be recognized in WM266-4 cells.…”

Section: Resultsmentioning

confidence: 99%

From Proteomic Mapping to Invasion-Metastasis-Cascade Systemic Biomarkering and Targeted Drugging of Mutant BRAF-Dependent Human Cutaneous Melanomagenesis

Giannopoulou

Velentzas

Anagnostopoulos

et al. 2021

Cancers

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Melanoma is classified among the most notoriously aggressive human cancers. Despite the recent progress, due to its propensity for metastasis and resistance to therapy, novel biomarkers and oncogenic molecular drivers need to be promptly identified for metastatic melanoma. Hence, by employing nano liquid chromatography-tandem mass spectrometry deep proteomics technology, advanced bioinformatics algorithms, immunofluorescence, western blotting, wound healing protocols, molecular modeling programs, and MTT assays, we comparatively examined the respective proteomic contents of WM115 primary (n = 3955 proteins) and WM266-4 metastatic (n = 6681 proteins) melanoma cells. It proved that WM115 and WM266-4 cells have engaged hybrid epithelial-to-mesenchymal transition/mesenchymal-to-epithelial transition states, with TGF-β controlling their motility in vitro. They are characterized by different signatures of SOX-dependent neural crest-like stemness and distinct architectures of the cytoskeleton network. Multiple signaling pathways have already been activated from the primary melanoma stage, whereas HIF1α, the major hypoxia-inducible factor, can be exclusively observed in metastatic melanoma cells. Invasion-metastasis cascade-specific sub-routines of activated Caspase-3-triggered apoptosis and LC3B-II-dependent constitutive autophagy were also unveiled. Importantly, WM115 and WM266-4 cells exhibited diverse drug response profiles, with epirubicin holding considerable promise as a beneficial drug for metastatic melanoma clinical management. It is the proteome navigation that enables systemic biomarkering and targeted drugging to open new therapeutic windows for advanced disease.

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“…We and others have previously shown that miR-424/503 targets genes such as IGF1R and BCL2 in the mammary epithelium and that its loss affects developmental processes (involution) and tumorigenesis (Llobet-Navas et al, 2014a;Rodriguez-Barrueco et al, 2017;Mertelmeyer et al, 2020). The newly discovered regulation of WNT signaling presents a clearer and more complete view of the function of this microRNA cluster modulating mammary epithelial fate.…”

Section: Regulation Of Mammary Epithelial Dynamics By Mir-424(322)/503mentioning

confidence: 91%

miR‐424/503 modulates Wnt/β‐catenin signaling in the mammary epithelium by targeting LRP6

et al. 2021

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During the female lifetime, the expansion of the epithelium dictated by the ovarian cycles is supported by a transient increase in the mammary epithelial stem cell population (MaSCs). Notably, activation of Wnt/b-catenin signaling is an important trigger for MaSC expansion. Here, we report that the miR-424/503 cluster is a modulator of canonical Wnt signaling in the mammary epithelium. We show that mammary tumors of miR-424(322)/503-depleted mice exhibit activated Wnt/b-catenin signaling. Importantly, we show a strong association between miR-424/503 deletion and breast cancers with high levels of Wnt/b-catenin signaling. Moreover, miR-424/503 cluster is required for Wnt-mediated MaSC expansion induced by the ovarian cycles. Lastly, we show that miR-424/503 exerts its function by targeting two binding sites at the 3'UTR of the LRP6 co-receptor and reducing its expression. These results unveil an unknown link between the miR-424/503, regulation of Wnt signaling, MaSC fate, and tumorigenesis.

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The transcription factor Sox10 is an essential determinant of branching morphogenesis and involution in the mouse mammary gland

Cited by 22 publications

References 49 publications

Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer

Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer

From Proteomic Mapping to Invasion-Metastasis-Cascade Systemic Biomarkering and Targeted Drugging of Mutant BRAF-Dependent Human Cutaneous Melanomagenesis

miR‐424/503 modulates Wnt/β‐catenin signaling in the mammary epithelium by targeting LRP6

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