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Free, publicly-accessible full text available February 6, 2025
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Abstract Breast cancer is a heterogenous disease that can be classified into multiple subtypes including the most aggressive basal-like and triple-negative subtypes. Understanding the heterogeneity within the normal mammary basal epithelial cells holds the key to inform us about basal-like cancer cell differentiation dynamics as well as potential cells of origin. Although it is known that the mammary basal compartment contains small pools of stem cells that fuel normal tissue morphogenesis and regeneration, a comprehensive yet focused analysis of the transcriptional makeup of the basal cells is lacking. We used single-cell RNA-sequencing and multiplexed RNA in-situ hybridization to characterize mammary basal cell heterogeneity. We used bioinformatic and computational pipelines to characterize the molecular features as well as predict differentiation dynamics and cell–cell communications of the newly identified basal cell states. We used genetic cell labeling to map the in vivo fates of cells in one of these states. We identified four major distinct transcriptional states within the mammary basal cells that exhibit gene expression signatures suggestive of different functional activity and metabolic preference. Our in vivo labeling and ex vivo organoid culture data suggest that one of these states, marked by Egr2 expression, represents a dynamic transcriptional state that all basal cells transit through during pubertal mammary morphogenesis. Our study provides a systematic approach to understanding the molecular heterogeneity of mammary basal cells and identifies previously unknown dynamics of basal cell transcriptional states.more » « less
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Abstract Skin epidermis constitutes the outer permeability barrier that protects the body from dehydration, heat loss, and myriad external assaults. Mechanisms that maintain barrier integrity in constantly challenged adult skin and how epidermal dysregulation shapes the local immune microenvironment and whole‐body metabolism remain poorly understood. Here, we demonstrate that inducible and simultaneous ablation of transcription factor‐encoding
Ovol1 andOvol2 in adult epidermis results in barrier dysregulation through impacting epithelial‐mesenchymal plasticity and inflammatory gene expression. We find that aberrant skin immune activation then ensues, featuring Langerhans cell mobilization and T cell responses, and leading to elevated levels of secreted inflammatory factors in circulation. Finally, we identify failure to gain body weight and accumulate body fat as long‐term consequences of epidermal‐specificOvol1/2 loss and show that these global metabolic changes along with the skin barrier/immune defects are partially rescued by immunosuppressant dexamethasone. Collectively, our study reveals key regulators of adult barrier maintenance and suggests a causal connection between epidermal dysregulation and whole‐body metabolism that is in part mediated through aberrant immune activation.