Mutant KRAS Reprograms Luminal Progenitor Differentiation to Establish a Novel Transformation-Competent Mammary Epithelial Cell State
- 1Department of Oncology and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA
- 2National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Abstract
Background/Objectives: Previous studies reported that basal-like breast cancers may originate from luminal progenitors, suggesting that a classification of this malignancy is not strictly indicative of its cellular origin. Reinforcing this notion, we recently provided experimental evidence in genetically engineered models that basal-like and claudin-low mammary tumors, the two most common triple-negative breast cancer (TNBC) types, can evolve from transformed luminal epithelial cells. The primary objective of this study was to define, at the single-cell level, the earliest molecular changes associated with neoplastic transformation prior to the formation of mammary cancer. Methods: We isolated green fluorescent protein (GFP)-labeled mammary epithelial cells from MMTV-Flp FSF-KrasG12D Rosa26FSF-GFP mice and controls without mutant KRAS by fluorescence-activated cell sorting (FACS) and performed particle-templated instant partition sequencing (PIP-seq). Following hierarchical clustering of the single-cell transcriptomes, as well as differential gene expression and gene ontology analyses, we used Slingshot, TSCAN, and Monocle3 to infer developmental trajectories of luminal epithelial cell states. Results: Based on their single-cell transcriptomes, GFP-expressing mammary epithelial cells were predominantly luminal-type and resolved into 11 transcriptionally distinct cellular states organized into six functional groups. Most notably, mutant KRAS induced a novel oncogenic-permissive state with unique molecular features, including cancer-associated metabolic reprogramming, oncogenic pathway activation, and epithelial-to-mesenchymal cell plasticity. Trajectory inference positioned this KRAS-associated state along an alveolar progenitor differentiation path. Conclusions: The collective results provide new insights into the epithelial states associated with early neoplastic transformation and identify signaling and metabolic programs that may present candidate targets for cancer prevention.
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BibTeX
@article{wicker2026mutant,
title = {{Mutant KRAS Reprograms Luminal Progenitor Differentiation to Establish a Novel Transformation-Competent Mammary Epithelial Cell State}},
author = {Madison N. Wicker and Hye Kyung Lee and Kerry Vistisen and Kay-Uwe Wagner},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18213483},
url = {https://www.mdpi.com/2072-6694/18/21/3483},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mutant KRAS Reprograms Luminal Progenitor Differentiation to Establish a Novel Transformation-Competent Mammary Epithelial Cell State
AU - Madison N. Wicker
AU - Hye Kyung Lee
AU - Kerry Vistisen
AU - Kay-Uwe Wagner
PY - 2026
DA - 2026/10/28
JO - Cancers
DO - 10.3390/cancers18213483
UR - https://www.mdpi.com/2072-6694/18/21/3483
AB - Background/Objectives: Previous studies reported that basal-like breast cancers may originate from luminal progenitors, suggesting that a classification of this malignancy is not strictly indicative of its cellular origin. Reinforcing this notion, we recently provided experimental evidence in genetically engineered models that basal-like and claudin-low mammary tumors, the two most common triple-negative breast cancer (TNBC) types, can evolve from transformed luminal epithelial cells. The primary objective of this study was to define, at the single-cell level, the earliest molecular changes associated with neoplastic transformation prior to the formation of mammary cancer. Methods: We isolated green fluorescent protein (GFP)-labeled mammary epithelial cells from MMTV-Flp FSF-KrasG12D Rosa26FSF-GFP mice and controls without mutant KRAS by fluorescence-activated cell sorting (FACS) and performed particle-templated instant partition sequencing (PIP-seq). Following hierarchical clustering of the single-cell transcriptomes, as well as differential gene expression and gene ontology analyses, we used Slingshot, TSCAN, and Monocle3 to infer developmental trajectories of luminal epithelial cell states. Results: Based on their single-cell transcriptomes, GFP-expressing mammary epithelial cells were predominantly luminal-type and resolved into 11 transcriptionally distinct cellular states organized into six functional groups. Most notably, mutant KRAS induced a novel oncogenic-permissive state with unique molecular features, including cancer-associated metabolic reprogramming, oncogenic pathway activation, and epithelial-to-mesenchymal cell plasticity. Trajectory inference positioned this KRAS-associated state along an alveolar progenitor differentiation path. Conclusions: The collective results provide new insights into the epithelial states associated with early neoplastic transformation and identify signaling and metabolic programs that may present candidate targets for cancer prevention.
SN - 2072-6694
ER -