Sian, T. C. C. L. K. | Search bioRxiv

bioRxiv2026

The way less obvious: PIEZO1 supports apoptotic cell extrusion by optimizing tissue mechanical tension for homeostasis.

Apical cell extrusion is a mechanical process that allows epithelia to eliminate apoptotic cells and prevent inflammation. Mechanosensitive ion channels are often invoked for their capacity to mediate rapid mechanical responses in dynamic morphogenetic processes. Here we report an unexpected strategy for PIEZO1 to support apoptotic extrusion. PIEZO1 inhibition blocks extrusion in cultured cells and zebrafish larvae. However, although PIEZO1 mediates calcium signals during the extrusion process, we show that extrusion is instead antagonized by increase in the preexisting mechanical tension of the epithelium when PIEZO1 is disrupted. Correcting enhanced pre-stress in PIEZO1-disrupted epithelia is sufficient to rescue apoptotic extrusion, even though it does not restore dynamic calcium signals. PIEZO1 supports mechanical homeostasis through a calcium/calcineurin-dependent pathway that protects MYPT1/myosin phosphatase from degradation to limit Myosin II activation. Therefore, PIEZO1 support the morphogenetic process of apoptotic extrusion through mechanical homeostasis.

cell biology↗

bioRxiv2023

Comprehensive multi-platform tyrosine kinase profiling reveals novel actionable FGFR aberrations across pediatric and AYA sarcomas

No targeted agents are approved for pediatric sarcomas. Tyrosine kinase (TK) inhibitors represent attractive therapeutic candidates, however, beyond rare TK-activating fusions or mutations, predictive biomarkers are lacking. RNA overexpression of TKs is more commonly observed in pediatric sarcomas, however, an unresolved question is when upregulated TK expression is associated with kinase activation and signaling dependence. We explored the TK molecular landscape of 107 sarcoma patients from the ZERO Childhood Cancer precision medicine program using whole genomic and transcriptomic sequencing. Phosphoproteomic analyses of tyrosine phosphorylation (pY) and functional in vitro and in vivo assays were also performed in cell lines and patient-derived xenografts (PDXs). Our integrated analysis shows that although novel genomic driver lesions are rare, they are present and therapeutically actionable in selected patients as exemplified by a novel LSM1-FGFR1 fusion identified in an osteosarcoma patient. We further show that in certain contexts, TK expression data can be used to indicate TK pathway activity and predict TK-inhibitor sensitivity. We exemplify the utility of FGFR-inhibitors in PAX3-FOXO1 fusion-positive rhabdomyosarcomas (FP-RMS) mediated by high FGFR4 and FGF8 RNA expression levels, and overt activation of FGFR4 (FGFR4_pY). We demonstrate marked tumor growth inhibition in all FP-RMS PDXs treated with single agent FGF401 (FGFR4-specific inhibitor) and single agent lenvatinib (multi-kinase FGFR-inhibitor). Clinical benefit of lenvatinib in a relapsed metastatic FP-RMS patient further exemplifies that FGFR-inhibitors deserve additional investigation in FP-RMS patients. Statement of significanceOur multi-omic interrogation of sarcomas in the ZERO Childhood Cancer program illustrates how an RNA-expression biomarker signature (FGFR4+/FGF8+) in association with FGFR4 activation identifies that PAX3-FOXO1-positive rhabdomyosarcoma patients could benefit from FGFR-inhibitors.

cancer biology↗