Abstract Barrier epithelial tissues such as the skin, lung and gut are the first line of defense between our body and the outside world. As such, their stem cells must continually generate and rejuvenate their tissue, but also self-renew to maintain the reservoir of stem cells. When the barrier has been breached, for example by wounding, the stem cells must not only repair the damaged tissue but also call to the immune system to help guard against pathogen entry. All the while the stem cells must protect themselves from a variety of assaults, including not only injury but also mechanical stress, pathogens and allergens that stimulate an inflammatory response. How do epithelial stem cells equip themselves to respond to these different stresses? My laboratory studies the crosstalk that tissue stem cells have with their niche microenvironment and how they protect themselves when upended from their niche in wound repair. We’ve discovered that when stem cells acquire an oncogenic mutation in Ras that sets them on a path to cancer, they hijack these natural mechanisms of immune suppression and tissue regeneration, while bypassing their negative feedback controls. Additionally, they embark upon a miscommunication with their microenvironment that becomes increasingly aberrant during tumor progression. Using high throughput, genetic and biochemical approaches in mice, we’ve dissected the molecular nature of this crosstalk that leads to malignant behavior. Many of the steps in this aberrant epigenetic dialogue are mutated in metastatic cancers with high mutational burden. The ultimate goal is to devise strategies to target cancerous stem cells without affecting their normal tissue counterparts. Citation Format: Elaine Fuchs. Cancer: A tango of miscommunication between oncogenic stem cells and their microenvironment abstract. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31 (23Suppl): Abstract nr IA004.
Elaine Fuchs (Wed,) studied this question.