Mechanoresistant cancer cells reveal survival strategies in high-stress environments

Cancer cells that metastasize must endure a threat most cells cannot tolerate: repeated, high mechanical forces as they circulate through blood vessels and the heart. In this newly reported study, Rice University bioengineers show that prostate cancer cells can be trained to survive these extreme shear-stress pulses. The work reframes metastasis as a mechanically driven adaptation problem, not only a biochemical one.

Lead author Abigail Fabiano and colleagues used a shear-stress protocol designed to mimic the physical stresses circulating tumor cells experience in vivo. They began with two prostate cancer models: LNCaP cells, representing earlier-stage disease and sensitive to androgen deprivation, and PC3 cells, representing advanced, androgen-resistant cancer. Under cyclic high-shear exposure, the researchers repeatedly selected survivors and expanded them through multiple training rounds over roughly six months.

After training, most cells from both lines became mechanoresistant, meaning they could withstand periodic bursts of force that previously triggered widespread damage. Importantly, the resistant and non-resistant populations often appeared similar under standard observation, suggesting that resistance is encoded more subtly in cellular programs than in overt phenotype.

To uncover the underlying cause, the team sequenced genomes from the mechanoresistant populations. Despite comparable appearances, both resistant groups showed increased expression of a gene called CALB2. The researchers further observed that CALB2 is elevated in cancer cells obtained from metastatic prostate cancer patients, indicating that the adaptation observed in the lab may reflect an existing pathway in human disease.

To test whether CALB2 was causal, the researchers used gene editing to reduce CALB2 expression in mechanoresistant cells and then re-ran the shear-stress challenge. Cells with diminished CALB2 once again showed vulnerability and failed during the stress pulses, while cells retaining high CALB2 expression continued to survive. This cause-and-effect result positions CALB2 as a key contributor to mechanoresistance.

The study argues that mechanoresistance models can reveal previously overlooked metastasis predictors. King’s group emphasizes that distant spread in prostate cancer remains difficult to treat and is associated with poor prognosis, so new mechanical risk factors and drug targets could improve how clinicians anticipate and counter metastatic capability.

By combining mechanical selection, whole-genome profiling, and targeted gene perturbation, the research establishes a framework for identifying metastasis-relevant vulnerabilities tied to a cell’s ability to endure circulation. The findings also suggest that additional genetic drivers—beyond CALB2—likely contribute to the full resistance phenotype, and these are now under investigation in the lab.

Finally, the work was supported by major research funding from the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, and a National Science Foundation Graduate Research Fellowship, underscoring the broader push to connect physical microenvironments to cancer evolution.