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bioRxiv · 10.1101/2025.08.10.669320

Breast cancer cell migration is potentiated by associated fibroblasts through a laminin-511-driven cortical localization of Arp2/3

Banerjee, M.·Mishra, S.·Vinukumar, G.·Pandhari, M.·Sarvothama, M.·Parimala, D.·Korlimarla, A.·Srinath, B.·Bhat, R.
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Abstract

Invading cancer cells are intermingled with fibroblasts that interact with them to regulate their migration, although the precise motility-driving signaling mechanisms initiated upon such interactions remain ill-understood. We constitute time-lapse-tractable 3D pathotypic cultures with breast cancer cell lines with fibroblasts enriched from invasive ductal carcinoma biopsies. Herein, cancer-associated fibroblasts (CAFs) enhanced breast cancer migration relative to non-cancerous fibroblasts (NFs), also observed through greater infiltration of orthotopically injected cancer cells within murine inguinal lymph nodes. The enhancement was also seen in cancer cells exposed to CAF-secreted medium. CAFs phenocopied laminin-rich matrix in compacting cancer cell clusters. A subsequent immunocytochemical screen identified laminins 5, -{beta}1, and -{gamma}1 to be highly expressed in enriched CAFs populations as well as in stromal areas of breast cancer sections. Depleting laminin-5, -{beta}1, and -{gamma}1 in CAFs downregulated 3D cancer cell migration. Cancer cells cultivated on Laminin-511 substrata showed increased adhesion, faster and persistent migration, enhanced shape polarization, and deformability of cancer cells relative to Laminin-211 controls. Observation of higher invadopodial F-actin dynamics on Laminin-511 led us to assay for and demonstrate anisotropically corticalized Arp 2/3 in cancer cells. An integrin antibody screen showed Integrin 6{beta}1 inhibition specifically nullified Laminin-511-driven enhancement of morphomigrational traits of cancer cells, similar to Arp2/3 inhibition. Moreover, cells on Laminin-511 showed enhanced Integrin 6 localization to their invadopodia. We propose that activated fibroblasts use Laminin-511 to localize cognate integrin receptors, and Arp2/3 of cancer cells to their invadopodia, resulting in higher Arp2/3-driven actin remodeling and enhanced cell migration.

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Banerjee, M., Mishra, S., Vinukumar, G., Pandhari, M., Sarvothama, M., Parimala, D., Korlimarla, A., Srinath, B., Bhat, R.. 2025-08-12. Breast cancer cell migration is potentiated by associated fibroblasts through a laminin-511-driven cortical localization of Arp2/3. https://doi.org/10.1101/2025.08.10.669320

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