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.