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Microenvironmental signals combine to induce non-additive molecular and phenotypic responses in mammary epithelial cells

ABSTRACT: The local microenvironment plays a critical role in determining cellular phenotype. While responses to many individual ligands have been well characterized, the integration of multiple extracellular signals into a cohesive molecular and phenotypic response remains largely unexplored. Here, we systematically investigate the combinatorial effects of Oncostatin M, Transforming Growth Factor Beta 1, and Epidermal Growth Factor on MCF10A mammary epithelial cells. Live-cell imaging revealed that ligand combinations produce emergent phenotypic responses distinct from single-ligand treatments, suggesting induction of new molecular programs. RNA sequencing showed synergistic upregulation of genes involved in migration and chemotaxis, including CXCL3 and CXCL5. Partial least squares regression identified transcriptional signatures associated with cellular phenotypes quantified from image data, which we validated in independent datasets. Finally, functional analysis revealed that synergistic upregulation of CXCR2 signaling, mediated by CREB activation, contributes to increased cell motility. This study provides a framework for understanding how complex ligand interactions shape phenotypic and molecular landscapes.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Laura M. Heiser

PROVIDER: MSV000098762 | MassIVE | Thu Aug 07 14:12:00 BST 2025

SECONDARY ACCESSION(S): PXD067098

REPOSITORIES: MassIVE

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