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| Item Type: | Preprint |
|---|---|
| Title: | Spatiotemporal dynamics of tumor microenvironment remodeling |
| Creators Name: | Lisek, Kamil, Theurillat, Ilan, Pentimalli, Tancredi Massimo, Beier, Svea, León-Periñán, Daniel, Antonatou, Anna, Dubnov, Serafima, Müller, Marion, Hubl, Florian, Xhuri, Artemis, Romanowicz, Hanna, Smolarz, Beata, Montaudon, Elodie, Raimundo, Sandra, Margineanu, Anca, Schott, Marie, Kunz, Séverine, Marangoni, Elisabetta, Karaiskos, Nikos, Nitzan, Mor, Birchmeier, Walter and Rajewsky, Nikolaus |
| 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. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2025.07.15.662972 |
| Date: | 18 July 2025 |
| Official Publication: | https://doi.org/10.1101/2025.07.15.662972 |
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