Mechano-signaling of prostate tumor initiating cells facilitates their tropism to stiff metastatic niche

Chen, L.; Zhao, G.; De Menna, M.; Coppola, S.; Groenewoud, A.; Landman, N.; Schieven, S.; Thalmann, G. N.; Schmidt, T.; de Vrie, J.; Kruithof-de Julio, M.; Snaar, E. B.

doi:10.1101/2023.08.28.553410

bioRxiv · 10.1101/2023.08.28.553410

Mechano-signaling of prostate tumor initiating cells facilitates their tropism to stiff metastatic niche

Chen, L.·Zhao, G.·De Menna, M.·Coppola, S.·Groenewoud, A.·Landman, N.·Schieven, S.·Thalmann, G. N.·Schmidt, T.·de Vrie, J.·Kruithof-de Julio, M.·Snaar, E. B.

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Abstract

Analysis of clinical datasets indicate that cancer stem-like cells/tumor-initiating cells (CSCs/TICs) derived from prostate cancer (PCa) patients display an elevated expression of genes for cell-matrix interactions, cell adhesion proteins and of the putative mechanotransducer TAZ. Here we combined measurements on the cellular mechano-responses to matrix stiffness, including cell-generated forces, zebrafish and PDX-derived organoid models, to show that mechanotransduction serves as a key determinant for PCa CSC maintenance during metastatic onset. The {beta}1-integrin-ILK-CDC42-N-Wasp dependent cytoskeletal tension and TAZ nucleus-translocation mediate this mechano-signaling axis. As a result, expression of the stemness genes NANOG and OCT4 are induced, leading to metastatic tumor initiation. It is further demonstrated that pharmaceutical perturbation of this mechano-signaling using a novel YAP/TAZ inhibitor K975 constrains PCa metastasis in zebrafish, and development of PDX-derived organoids. Our data highlights the essential role of mechanotransduction in PCa aggressiveness, thereby underlying this pathway as a therapeutic target for future studies.

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Chen, L., Zhao, G., De Menna, M., Coppola, S., Groenewoud, A., Landman, N., Schieven, S., Thalmann, G. N., Schmidt, T., de Vrie, J., Kruithof-de Julio, M., Snaar, E. B.. 2023-08-29. Mechano-signaling of prostate tumor initiating cells facilitates their tropism to stiff metastatic niche. https://doi.org/10.1101/2023.08.28.553410

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