Physical immune escape: Weakened mechanical communication leads to escape of metastatic colorectal carcinoma cells from macrophages

What is it about?

This study developed a quasi-3D in vitro co-culture model based on type I collagen hydrogel to deeply investigate the tracking response of macrophages to two colorectal carcinoma (CRC) cell lines with different metastatic potentials. By using the collagen-based in vitro co-culture model, the study found significant differences in the attraction of macrophages to CRC cells with different metastatic potentials: the low-metastatic potential SW480 cells had a higher attraction effect on macrophages, whereas the highly metastatic SW620 cells had the opposite effect. On a solid Petri dish, however, both CRC cell lines exhibited the same, relatively low level of attraction. To explore how the collagen ECM influences the attraction effect of CRC cells, the research team observed the collagen structure surrounding the CRC cells and found that SW480 cells had a significantly stronger ability to remodel collagen, with the collagen network around them showing noticeable rearrangement. Using traction force microscopy (TFM) based on particle image velocimetry (PIV), the team further quantitatively characterized the extent of ECM remodeling by the two CRC cell lines. Based on the correlation between the remodeling ability of the CRC cells and their attraction effect, the research team preliminarily hypothesized that the tracking response of macrophages to cancer cells is related to the extent of ECM remodeling and the corresponding tensile-force signals. To verify this hypothesis, the team used a micromanipulation system to simulate the remodeling behavior of cancer cells on the matrix. The results demonstrated that stronger ECM mechanical signals (i.e., the extent of remodeling) could significantly enhance the corresponding response behavior of macrophages, revealing the mechanical response mechanism in macrophage-targeted tracking behavior. To further validate the role of ECM-mediated mechanical signals in CRC cell immune evasion, the team used small interfering RNA (siRNA) to reduce the expression of E-cadherin in SW480 cells to increase their metastatic potential. The results showed that compared to the negative control group, SW480 cells with low E-cadherin expression significantly reduced their extent of collagen ECM remodeling (as the expression of integrin α1β1 in siEcad-SW480 was also correspondingly reduced), accompanied by a significant inhibition of the attraction effect.

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Why is it important?

The metastasis of cancer cells is closely related to their ability to evade attacks from immune cells and degrade the extracellular matrix (ECM). Although the importance of the tumor immune microenvironment in influencing cancer cell immune evasion and metastasis has been well established, past research has primarily focused on biochemical aspects. The role of physical factors within the microenvironment remains largely unexplored, especially regarding whether and how the mechanical interactions mediated by the ECM between cancer cells and immune cells affect cancer cell immune evasion. The findings of this project indicate that the traction forces exerted by CRC cells significantly influence the targeting efficiency of macrophages. Weakened mechanical communication allows CRC cells with higher metastatic potential to evade macrophages, thereby enhancing immune evasion. This discovery provides valuable new insights into the immune response against cancer cells and offers important references for future cancer immunotherapy strategies.