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Preprint WatchMildAugust 28th, 2026

Piezo1 balances focal and reticular adhesions to enable EGFR clathrin-mediated endocytosis

Bagudanch O, Zoroa O, Ayala V, Midyan R, Bagley DC, Moparthi SB, Hakanpää L, Lenaerts A, Almeida-Souza L, Muñoz FJ, Valverde MA, Vassilopoulos S, Rosenblatt J, Pardo-Pastor C.

Piezo1-dependent calcium influx activates Fyn and VAV2 to balance focal and reticular adhesions, and that balance sets the rate of clathrin-mediated EGFR endocytosis.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

Degrader and antibody-drug conjugate approaches to EGFR depend on receptor internalisation, and this preprint places that internalisation downstream of a mechanically gated ion channel rather than of ligand availability alone. Claidex holds one EGFR failure, [[bg-60366-egfr-cdac-nsclc-strategic-shutdown]], a strategic shutdown of an EGFR chimeric degrader in EGFR-mutant non-small cell lung carcinoma. If adhesion state governs endocytic flux, then internalisation-dependent EGFR modalities carry a source of variance that expression and mutation status do not capture. The flag is mild because the single matching failure was a sponsor decision and because the preprint work is in cell models rather than tumour tissue.

Abstract excerpt

Cells attach to the extracellular matrix through distinct integrin-mediated adhesive structures, including force-transmitting focal adhesions (FAs) and clathrin-enriched reticular adhesions (RAs). FAs enable mesenchymal cell migration and disassemble at mitotic entry, whereas RAs impede migration, persist during mitosis, and contribute to clathrin-mediated endocytosis (CME) as they disassemble. FAs grow with RhoA contractility, whereas RAs shrink, but the mechanisms coordinating these opposing responses remain unclear. Here, we identify the mechanically activated ion channel Piezo1 as a master regulator of FA/RA balance. Piezo1-dependent calcium influx activates the Src family kinase Fyn, which activates two actin polymerization pathways: FA and stress fiber growth via VAV2-RhoA and RA disassembly via N-WASP-Arp2/3. Inhibition or knockdown of Piezo1, Fyn, or VAV2 decreases FA size and increases RA coverage. Critically, cells lacking Piezo1 fail to internalize ligand-activated EGFR on stiff substrates despite normal CME on soft substrates, establishing an essential role for Piezo1 in EGFR CME mechanoadaption. Our findings reveal Piezo1 as the mechanosensor linking membrane tension to coordinated actin polymerization pathways that co-regulate cell-matrix adhesion and endocytosis. Given that CME contributes to viral entry into host cells and cancer resistance to anti-EGFR antibody therapy, targeting the Piezo1-RA-CME axis may offer novel therapeutic opportunities.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.