CALB2 is a Mechanoresistance Gene in Metastatic Prostate Cancer.

It remains unclear how circulating tumor cells (CTCs) adapt to and survive mechanical forces in the bloodstream, including fluid shear stress (FSS), making it critical to define the mechanisms that enable their survival and promote metastasis. To model these forces, we generated "mechanoresistant" (MR) LNCaP and PC3 prostate cancer (PCa) cell lines by repeatedly exposing cells to high‑intensity (HI) FSS (3950 dyn/cm2). LNCaP MR cells acquired marked resistance to HI FSS, exhibiting significantly reduced apoptosis, while PC3 cells demonstrated innate resistance. Bulk RNA‑sequencing revealed that LNCaP and PC3 MR cells developed distinct molecular programs. CALB2 (calretinin) emerged as a mechanoresistance gene selectively upregulated in PC3 MR cells, and CALB2 knockout significantly reduced viability upon re‑exposure to HI FSS. Analysis of CALB2‑high PCa cases captured patient‑level molecular heterogeneity, suggesting a mechanoadaptive state rather than a uniform aggressiveness-driven tumor phenotype. This was consistent with the absence of correlation between CALB2 levels and Gleason Scores. In an orthotopic PCa mouse model, the PC3 MR condition displayed the most aggressive early tumor growth and the largest endpoint tumor volumes, consistent with enhanced proliferation. Together, these findings demonstrate that PCa cells acquire discrete mechanoadaptive phenotypes under extreme FSS, revealing targetable pathways to limit metastatic competence.