Spatiotemporal dynamics of tumor microenvironment remodelling

Lisek, K.; Theurillat, I.; Pentimalli, T. M.; Beier, S.; Leon-Perinan, D.; Antonatou, A.; Dubnov, S.; Muller, M.; Hubl, F.; Xhuri, A.; Romanowicz, H.; Smolarz, B.; Montaudon, E.; Raimundo, S.; Margineanu, A.; Schott, M.; Boltengagen, A.; Kunz, S.; Marangoni, E.; Karaiskos, N.; Nitzan, M.; Birchmeier, W.; Rajewsky, N.

doi:10.1101/2025.07.15.662972

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bioRxiv · 10.1101/2025.07.15.662972

Spatiotemporal dynamics of tumor microenvironment remodelling

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Abstract

During tumorigenesis, interactions between tumor and stromal cells progressively remodel the tumor microenvironment (TME) towards pro-tumoral functions. Understanding early TME remodeling dynamics is therefore crucial for developing interceptive therapies. However, clinical samples typically provide isolated, late tumorigenesis snapshots. To overcome this limitation, we generated triple-negative breast cancer mice that develop multifocal, asynchronous tumors along a continuous luminal-to-basal transdifferentiation trajectory. Ordering spatial transcriptomes from 100+ ducts along this trajectory reveals the spatiotemporal dynamics of TME remodeling and underlying molecular mechanisms. Cancer-associated myofibroblasts (myCAFs) emerge as key players in advanced tumors, where they orchestrate pro-invasive remodeling of the tumor-stromal interface. myCAFs are conserved in patient-derived xenograft models and steer tumor trajectories towards invasive phenotypes when co-injected with tumor cells in syngeneic mice. Our study shows that temporal ordering of spatially-resolved disease snapshots unravels some of the molecular "forces" that, starting from the cell-of-origin, propel cells/microenvironments along a disease trajectory.

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Lisek, K., Theurillat, I., Pentimalli, T. M., Beier, S., Leon-Perinan, D., Antonatou, A., Dubnov, S., Muller, M., Hubl, F., Xhuri, A., Romanowicz, H., Smolarz, B., Montaudon, E., Raimundo, S., Margineanu, A., Schott, M., Boltengagen, A., Kunz, S., Marangoni, E., Karaiskos, N., Nitzan, M., Birchmeier, W., Rajewsky, N.. 2025-07-18. Spatiotemporal dynamics of tumor microenvironment remodelling. https://doi.org/10.1101/2025.07.15.662972

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