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Pandhari, M.

Publications and source records attributed to Pandhari, M..

2 recordsLinked to original sources
bioRxiv2025

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

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.

cancer biology↗
bioRxiv2025

A PKM2-YAP reciprocal repartitioning modulates invasion of breast cancer cells

Invasive cancer cells exhibit distinct morphomigrational and metabolic traits when confronted with biophysically variant matrix microenvironments enroute metastasis. Whether dynamical shifts in such traits are interlinked through a common molecular program remains ill-understood. Using triple negative breast cancer cell lines on Collagen I substrata coated hydrogels recapitulating stiffness values of non-cancerous breast tissue and the desmoplasia of tumors, we observed greater cell shape polarization and migration in the latter. Associated lower lactate and pyruvate levels in such conditions motivated us to examine their pyruvate kinase M2 expression, which showed nuclear and cytoplasmic localization in softer and stiffer environments respectively. Pharmacologically impairing PKM2 activity in stiffer substrata decreased migration and shape polarization of cancer cells while increasing lactate and pyruvate levels. In contrast, increasing its activity on softer substrata attenuated cancer cell migration and elongation. We assayed for localization of the mechanosensory protein YAP upon PKM2 activity modulation: PKM2 activation increased nuclear YAP localization on soft substrata. Pharmacologically inhibiting YAP on stiff substrata not just decreased migration but also increased nuclear localization of PKM2 and lactate and pyruvate levels. We propose that a reciprocal repartitioning of PKM2-YAP interlinks the cognate metabolic and migrational states of cancer cells; targeting such positive feedback may hold the key to future therapeutic strategies.

cancer biology↗