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FGD3 mediates lytic cell death, enhancing efficacy and immunogenicity of chemotherapy agents in breast cancer

Junyao Zhu,Xinyi Dai,Santanu Ghosh,Elaine Wei,C. Mao,Qianjin Jiang,Abigail J. Spaulding,Michael P. Mulligan,R. Romero,Y. Han,Matthew W. Boudreau,Olufunmilayo Olopade,P. Hergenrother,D. Shapiro

Published 2025 in Journal of experimental & clinical cancer research : CR

ABSTRACT

Although anticancer therapies inducing necrosis, necroptosis and pyroptosis trigger cell swelling, plasma membrane rupture (PMR) and release of damage-associated molecular patterns (DAMPs), potentially facilitating antitumor immunity, little was known of proteins and mechanisms controlling the life-death decision of whether swollen and stressed cancer cells enter PMR and undergo lytic cell death. We conducted a genome-wide CRISPR screen with selection against a lytic cell death inducer, complemented by studies using breast cancer cells in 2D culture, patient-derived organoids and orthotopic mouse xenografts. The effect of FGD3 on immunogenicity was explored by immunoblotting, immunofluorescence staining and NK-cell mediated cytotoxicity assays. The correlation between the level of FGD3 expression and patient prognosis and response to chemotherapy was assessed by analysis of patient databases. We identified FGD3 as a key mediator, coupling cell swelling to PMR and lytic cell death induced by emerging and current breast cancer therapies, including ErSO, aprepitant, doxorubicin and epirubicin. FGD3 coupled cell swelling to PMR across the spectrum of immunogenic lytic cell death pathways, including necrosis, necroptosis and pyroptosis. Mechanistically, FGD3 facilitated PMR by controlling actin reorganization via the Cdc42-ARP2/3 axis. Notably, elevated FGD3 increased release of DAMPs, strongly enhanced exposure of immunogenic cell surface calreticulin and increased sensitivity of cancer cells to NK cell-mediated lysis. Supporting clinical relevance, high FGD3 expression strongly correlated with improved relapse-free survival in breast cancer patients after chemotherapy and this correlation was stronger than was seen for NINJ1 and other proteins associated with lytic cell death. FGD3 is a key mediator of chemotherapy-induced plasma membrane rupture and lytic cell death. It is also a useful biomarker for identifying breast cancer patients most likely to benefit from lytic cell death-inducing immunogenic anticancer therapies.

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