A compromise between Tgfβ and Egfr signaling programs confers the ability to lead heterogeneous collective invasion

• Published in: bioRxiv
• Main Authors: Nasir, Apsra, Camacho, Sharon, Mcintosh, Alec T, Graham, Garrett T, Rahhal, Raneen, Huysman, Molly E, Riegel, Anna T, Pearson, Gray W
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 11.05.2022
• Subjects: Autocrine signalling; Breast cancer; E-cadherin; Epidermal growth factor; Epidermal growth factor receptors; Explants; Extracellular signal-regulated kinase; Fra1 protein; Genetic engineering; Keratin; Mesenchyme; Metastasis; Organoids; Tumors; Vimentin
• DOI: 10.1101/2020.11.14.383232

Phenotypic heterogeneity promotes tumor evolution and confounds treatment. Minority subpopula-tions of trailblazer cells enhance the heterogeneity of invading populations by creating paths in ex-tracellular matrix (ECM) that permit the invasion of phenotypically diverse siblings. The regulatory programs that induce a trailblazer state are poorly understood. Here, we define a new Tgfβ induced trailblazer population that is more aggressive than previously characterized Keratin 14 expressing trailblazer cells. Rather than triggering a binary switch to a single trailblazer state, Tgfβ induced multiple unique states that were distinguished by their expression of regulatory transcription fac-tors, genes involved in ECM reorganization and capacity to initiate collective invasion. The integra-tion of a parallel Egfr signaling program was necessary to induce pro-motility genes and could be targeted with clinically approved drugs to prevent trailblazer invasion. Surprisingly, Egfr pathway activity also had the collateral consequence of antagonizing the expression of a cohort of Tgfβ in-duced ECM remodeling genes, potentially limiting features of trailblazer invasion. Together, our results reveal a new compromise mode of signal integration that promotes a trailblazer state and can be therapeutically targeted to prevent collective invasion. Competing Interest Statement The authors have declared no competing interest. Footnotes * Expanded scope of investigation within new data and text