A cholesterol-dependent LRRC8A-caveolin-1 axis sustains KRAS/EGFR signaling, ribosome biogenesis and growth in pancreatic ductal adenocarcinoma.

Cellular adaptive volume regulation is essential for maintaining metabolic homeostasis and supporting survival, yet its role in desmoplastic pancreatic ductal adenocarcinoma (PDAC) remains incompletely understood. Through comprehensive bioinformatic and functional studies, we identified LRRC8A, the core subunit of volume-regulated anion channels (VRAC), as a central regulator linking volume homeostasis to PDAC progression. Beyond its established role in osmotic stress responses, genetic silencing or pharmacological inhibition of LRRC8A revealed its critical function in proliferation-associated volumetric expansion during S-phase. Functional validation through in vitro proliferation assays, in vivo xenograft models, and patient-derived pancreatic cancer organoids (PDO) demonstrated that LRRC8A critically drives PDAC progression. Mechanistically, LRRC8A coordinates plasma membrane dynamics, cortical cytoskeletal organization, membrane-delimited oncogenic signaling (KRAS/EGFR), and nucleolar ribosome biogenesis to support volumetric expansion during S phase. Co-immunoprecipitation coupled with mass spectrometry identified that LRRC8A forms complexes with Caveolin 1 (CAV1). Disruption of LRRC8A leads to decreased CAV1 protein levels, impaired activation of KRAS and EGFR oncogenic signaling, and suppressed ribosome biogenesis and global protein synthesis. Reciprocally, CAV1 knockdown or cholesterol depletion using lovastatin destabilized LRRC8A in plasma membrane, resulting in reduced cortical F-actin organization, oncogenic signaling and biosynthetic activity, indicating that LRRC8A and CAV1 are mutually stabilized and depend on cholesterol-rich membrane microdomains for proper integration and function. Furthermore, disruption of LRRC8A-CAV1 axis through LRRC8A inhibition or cholesterol depletion potently suppressed PDO growth in vitro. Collectively, our work establishes the LRRC8A-CAV1 complex as a key coordinator of biosynthetic expansion and a promising therapeutic target in pancreatic cancer.