Abstract P6-06-03: Mechanobiology of cancer cells and tumour microenvironment jointly regulates cancer cell invasion and onset of metastasis

Mechanical properties of cancer cells and their microenvironment play a critical role in cancer progression and metastatic dissemination. We have established an in vitro assay using native human basement membrane (BM) to study interactions with normal epithelial cells in terms of BM composition, architecture and stiffness. We showed that these are required to act jointly in order to achieve apico-basal polarity, tissue barrier formation and specific stiffness to maintain healthy epithelial tissues. In contrast, in cancer the onset of metastasis occurs when cancer cells invade and breach the BM. For example, it is well known that cancer cells can perforate BM using proteolysis. However, recently we have demonstrated that in presence of carcinoma-associated fibroblasts (CAFs) isolated from cancer patients, moderately invasive cancer cells were able to invade into surrounding stromal matrix in a metalloproteinase-independent manner. In fact cell invasion was associated with decrease in stiffness and correlated to changes in cell and BM morphology. Using live imaging and atomic force microscopy (AFM), we could visualise CAFs actively pulling, stretching and softening the BM, forming gaps through which cancer cells can migrate. By exerting contractile forces, CAFs altered the organisation and physical properties of native BM, making it permissive for cancer cell invasion. Also recently we showed that from the epithelial side, structural centrosome aberrations known to accompany breast cancer progression can create local stiffness heterogeneity that triggers the escape of soft cells undergoing mitosis. In particular, we demonstrated that structural centrosome aberrations can trigger cell dissemination through a non-cell-autonomous mechanism, raising the prospect that centrosome aberrations might facilitate dissemination of soft metastatic cells. In summary, physical interactions between cancer cells and the extracellular matrix (ECM) components contribute to softening of specific cancer cells, physical activation of stromal cells such as CAFs to facilitate cancer invasion and metastases. By extending these findings to a routine clinical setting we measured nanomechanical profiles of biopises from breast cancer patients in a physiological tissue protective solution thus preserving tissue viability and allowing for further pathohistological analysis of the same specimens. Conclusively, we demonstrated how detecting highly deformable cancer cells in patient tissues can serve as a unique marker of cancer aggressiveness thus potentially enabling treatment optimization and development of novel treatment strategies. Citation Format: Marija Plodinec, Philipp Oertle, Alexandre Glentis, Danijela Vignjevic, Olivier Ganier, Eric Nigg, Tobias Appenzeller, Ahmed Jizawi, Flora Scott, Cristian Raez, Marko Loparic, Zlatko Marusic, Ellen C. Obermann, Rosemarie Burian, Roderick Y.H. Lim. Mechanobiology of cancer cells and tumour microenvironment jointly regulates cancer cell invasion and onset of metastasis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-06-03.