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CALB2 is a mechanoresistance gene in metastatic prostate cancer

ABSTRACT: Metastatic progression hinges on the ability of circulating tumor cells (CTCs) to withstand the extreme mechanical forces of the bloodstream, yet the mechanisms that enable this survival remain poorly defined. Understanding how prostate cancer (PCa) cells adapt to fluid shear stress (FSS) is essential for identifying vulnerabilities that could be leveraged to prevent metastatic spread. Here, we generate “mechanoresistant” (MR) LNCaP and PC3 PCa cell lines by repeatedly exposing cells to high‑intensity (HI) FSS (3950 dyn/cm²), modeling the forces encountered by CTCs in circulation. LNCaP MR cells acquire marked resistance to HI FSS, exhibiting significantly reduced apoptosis compared to controls, while PC3 cells demonstrate a more innate resistance. Morphologically, PC3 MR cells adopt an amoeboid phenotype, whereas LNCaP MR cells retain parental characteristics. Both MR populations show significantly increased Piezo1 expression. Bulk RNA‑sequencing reveals that LNCaP and PC3 MR cells developed distinct molecular programs. Notably, CALB2 (calretinin) emerges as a mechanoresistance gene selectively upregulated in PC3 MR cells, and CALB2 knockout significantly reduces viability upon re‑exposure to HI FSS. Analysis of CALB2‑high PCa cases capture patient‑level molecular heterogeneity, with reproducible co‑expression correlated with EPB41L3 and DGKI, suggesting a mechanoadaptive state rather than a uniform aggressiveness-driven tumor phenotype. This is consistent with the absence of correlation between CALB2 levels and Gleason Scores. In an orthotopic PCa mouse model, the PC3 MR condition displays the most aggressive early tumor growth and the largest endpoint tumor volumes, consistent with enhanced proliferation observed in vitro. Together, these findings demonstrate that PCa cells acquire discrete mechanoadaptive phenotypes under extreme shear stress, revealing targetable pathways that may ultimately be exploited to limit metastatic competence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE337264 | GEO | 2026/07/20

REPOSITORIES: GEO

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Project description:Tissue Factor Pathway Inhibitor-2 is Induced by Fluid Shear Stress in Vascular Smooth Muscle Cells and Affects Cell Proliferation and Survival Introduction: Vascular smooth muscle cells (SMCs) are exposed to fluid shear stress (FSS) after interventional procedures such as balloon-angioplasty. Whereas the effects of hemodynamic forces on endothelial cells are explored in detail, the influence of FSS on smooth muscle cell function is poorly characterized. Here, we investigated the effect of FSS on SMC gene expression and function. Methods: Laminar FSS of arterial level (14 dynes/cm2) was applied to SMC cultures for 24 h in a parallel-plate flow chamber. The effect of FSS on gene expression was first screened with microarray technology and the results further verified by real time (RT) PCR and immunoblotting. Protein expression was also studied in the rat carotid artery after balloon-injury and DNA synthesis and apoptosis was examined in SMCs in vitro. Results: Microarrays identified tissue-pathway inhibitor-2 (TFPI-2) as the most differentially expressed gene by FSS in cultured SMCs. The regulatory effect of FSS on the expression of TFPI-2 was confirmed by RT-PCR and immunobloting demonstrating a more than 400-fold increase in TFPI-2 expression in SMCs exposed to FSS compared to static controls and a consistent upregulation at the protein level. Functionally, SMC proliferation was decreased by FSS and recombinant TFPI-2 was found to inhibit SMC proliferation and induce SMC apoptosis as indicated by activation of caspase-3. In vivo, TFPI-2 expression was found to be up-regulated 5, 10 and 20 h after rat carotid balloon-injury and immunohistochemistry demonstrated TFPI-2 protein in luminal SMCs exposed to FSS in rat carotid intimal hyperplasia 10 days after balloon-injury. Conclusion: FSS strongly influence gene expression in cultured SMCs and induce TFPI-2 expression, which is also expressed after rat carotid balloon injury in luminal SMCs exposed to FSS. Functionally, TFPI-2 may play an important role in vessel wall repair by regulating SMC proliferation and survival. Further studies are needed to elucidate the mechanisms by which TFPI-2 control SMC function. 3 x 2 samples from a paired fluid shear stress experiment on smooth muscle cells.

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CALB2 is a mechanoresistance gene in metastatic prostate cancer

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