Researchers have identified CALB2 as a gene associated with the ability of metastatic prostate cancer cells to survive the mechanical forces encountered in the bloodstream. Published in Advanced Science, the study suggests that CALB2 may serve as a marker of tumor cells that have adapted to survive circulation during metastasis, offering a potential avenue for future biomarker and therapeutic research.
For metastasis to occur, circulating tumor cells (CTCs) must survive extreme fluid shear stress as they travel through the vasculature. To investigate this process, researchers repeatedly exposed two prostate cancer cell lines – LNCaP, representing androgen-sensitive disease, and PC3, representing advanced, androgen-independent disease – to high-intensity fluid shear stress, selecting the cells that survived each cycle. Over several months, the surviving populations developed "mechanoresistant" characteristics that resembled adaptations needed to withstand circulation.
Gene expression analysis showed that the two cell lines adapted differently. In the more aggressive PC3 cells, CALB2, which encodes the calcium-binding protein calretinin, was markedly upregulated. When researchers knocked out CALB2 in these mechanoresistant PC3 cells, their ability to survive subsequent shear stress was substantially reduced, suggesting the gene contributes to this adaptive phenotype.
The investigators also examined CALB2 expression in patient tissue samples and public prostate cancer datasets. Calretinin expression was higher in prostate adenocarcinoma and metastatic tissue than in adjacent normal tissue. However, CALB2 expression did not correlate with Gleason score, indicating that the marker may reflect a tumor's ability to adapt to mechanical stress rather than overall histologic aggressiveness.
In an orthotopic mouse model, tumors derived from the mechanoresistant PC3 cells showed greater early growth and larger final tumor volumes than control tumors, while retaining elevated calretinin expression.
According to corresponding author Michael R. King in the press release, the experimental model enabled the team to study a stage of metastasis that is difficult to examine directly in patients. "By inducing mechanoresistance in the lab and then characterizing it, we are able to find entirely new predictors of metastasis and new drug targets. For instance, this study identified a gene called CALB2 that is strongly correlated with mechanoresistance."
Lead researcher Abigail R. Fabiano said the findings emerged only after developing the laboratory model. "We may never have looked into CALB2 if we hadn't developed this mechanoresistance model. It isn't a gene that's been studied much in the context of cancer – prior to this, there's been little indication it plays any role in cancer progression."
Although the findings are preclinical, they highlight CALB2 as a candidate biomarker for studying CTC biology and metastatic adaptation. The researchers noted that further work is needed to determine whether CALB2 or related mechanoadaptive pathways could support future diagnostic or therapeutic strategies in prostate cancer.
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