Biomaterials, Biodegradables and Biomimetics Research Group

Comunication - Oral

Tumor-associated protrusion fluctuations govern cancer invasiveness


Cancer metastasis is a multi-step process where tumor cells disseminate from the primary tumor to a different site in the body. In part, the elongation of invasive protrusions mediates the initial steps in tumor dissemination. These protrusions change their phenotype to maximize the invasion efficiency of cancer cells [1]. The formation of invasive protrusions during cancer dissemination is well understood, however, less is known about how the morphodynamics of these protrusions correlate with the metastatic potential of tumors [2]. In this work, we analyzed the role of tumor-associated protrusion fluctuations using non-metastatic and more metastatic tumor u-spheroids as a model of cancer cell culture. We identified novel biophysical indicators, which were characteristic of tumor invasiveness. In particular, we found that tumor-associated protrusions displayed distinct morphodynamics, which depended on the tumor metastatic potential. In particular, we observed that non-metastatic A549 lung tumor u-spheroids showed a lower frequency of probing (nu_p) and a larger stabilization lifetime (tau_s) compared to more-metastatic MCF7 breast cancer cells. The addition of doxorubicin, an anti-cancerous drug, perturbed protrusion fluctuations, increasing (decreasing) nu_p (tau_s) in both tumor types. Surprisingly, we found that low drug concentrations also enhanced tumor invasiveness. Interestingly, we noted a linear correlation between both parameters, which was in agreement with the invasive potential of tumor cells. We also observed that the inhibition of the Rho pathway modulated nu_p and tau_s, and abolished the invasive capacity of tumors. We further used a tumor-on-a-chip model integrating our tumor u-spheroids and endothelial cells to investigate the crosstalk between both cell types in a native-like environment. The obtained results showed that the endothelial cells modulated protrusion morphodynamics and their orientation. All these observations were encoded into a phase diagram, which provided a novel landscape to determine the invasiveness potential of tumors based on their fluctuations. Overall, the obtained results illustrate that protrusion fluctuations are key players in the physicochemical mechanism of tumor invasion, and are governed mainly by their frequency of probing and their stabilization lifetime.

Acknowledgements: This work is financially supported by European Union Framework Programme for Research and Innovation HORIZON 2020 under grant agreement nº 668983 – FoReCaST and Portuguese FCT (PTDC/BTM-ORG/28070/2017 – 2MATCH) funded by the Programa Operacional Regional do Norte supported by European Regional Development Funds (ERDF).

[1] Friedl P et al. J Cell Biol, 2010. 188(1):11-19
[2] Caballero D et al. Biophys J. 2014; 107:34-42

2nd FoReCaST workshop
Cancer, nanotechnology, translation, tumor models
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