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Luminal Stem Cell Determinant SOX9 Controls Lineage Plasticity and Progression in Basal-Like Breast Cancer (Sox9-KO)

ABSTRACT: Lineage plasticity plays an important role in the development of basal-like breast cancer (BLBC), an aggressive cancer subtype. Although studies suggest BLBC is likely to originate from luminal progenitor cells, it acquires substantial basal cell features and contains a heterogenous collection of cells exhibiting basal, luminal and bipotent phenotypes. Why luminal progenitors are prone to BLBC transformation and what drives luminal-to-basal/bipotent reprogramming remains unclear. Here we show that the transcription factor SOX9 acts as a determinant for ER– luminal stem/progenitor cells (LSPCs). SOX9 controls LSPC activity in part by activating both canonical and non-canonical NF-B signaling. Inactivation of p53 and Rb in a BLBC mouse tumor model leads to upregulation of SOX9, which drives luminal-to-bipotent reprogramming in vivo. SOX9 deletion inhibits the progression of benign, neoplastic lesions to invasive carcinoma. Furthermore, SOX9 is overexpressed and correlated with shorter relapse-free survival in human BLBC. These data show that ER– LSPC determinant SOX9 acts as a lineage-specific driver for BLBC transformation.

ORGANISM(S): Mus musculus

PROVIDER: GSE135891 | GEO | 2020/06/09

REPOSITORIES: GEO

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Project description:Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular ageing. Sox9 (SRY-Box Transcription Factor 9) is a master regulator of chondrogenesis, also expressed in the vasculature, that has been implicated in vascular smooth muscle cell (VSMC) osteo-chondrogenic conversion. Here, we investigated the relationship between vascular ageing, calcification and Sox9-driven ECM regulation in VSMCs. Immunohistochemistry in human aortic samples showed that Sox9 was not spatially associated with vascular calcification but correlated with the senescence marker p16. Analysis of Sox9 expression in vitro showed it was mechanosensitive with increased expression and nuclear translocation in senescent cells and on stiff matrices. Manipulation of Sox9 via overexpression and depletion, combined with atomic force microscopy (AFM) and proteomics, revealed that Sox9 regulates ECM stiffness and organisation by orchestrating changes in collagen expression and reducing VSMC contractility, leading to the formation of an ECM that mirrored that of senescent cells. These ECM changes promoted phenotypic modulation of VSMCs whereby senescent cells plated onto ECM synthesized from cells depleted of Sox9 returned to a proliferative state, while proliferating cells on a matrix produced by Sox9 expressing cells showed reduced proliferation and increased DNA damage, reiterating features of senescent cells. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (LH3) was identified as a Sox9 target, and key regulator of ECM stiffness. LH3 is packaged into extracellular vesicles (EVs) and Sox9 promoted EV secretion, leading to increased LH3 deposition within the ECM. These findings identify cellular senescence and Sox9 as a key regulators of ECM stiffness during VSMC ageing and highlight a crucial role for ECM structure and composition in regulating VSMC phenotype. We identify a positive feedback cycle whereby cellular senescence and increased ECM stiffening promote Sox9 expression which drives further ECM modifications that act to accelerate vascular stiffening and cellular senescence.

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Luminal Stem Cell Determinant SOX9 Controls Lineage Plasticity and Progression in Basal-Like Breast Cancer (Sox9-KO)

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