Abstract B24: Stem cell lineage infidelity drives wound repair and cancer

Human adult tissues harbor resident stem cells (SCs) responsible for homeostasis and wound repair. Tumorigenesis arises when normal SCs accumulate mutations that cause them to derail, shifting their homeostatic balance to favor tissue growth at the expense of differentiation. In contrast to wound repair, where the growth:differentiation imbalance is transient, cancers are refractory to tissue restoration cues, seemingly hijacking these normal cellular programs to fuel their molecular thirst for uncontrolled growth. The notion that a “cancer is a wound that never heals” has origins dating back to Rudolf Virchow in the 1800s. Since then, intimate connections between wounds and tumors have also been drawn at the molecular level. Although intriguing, it remains unclear which of the normal SC remodeling pathways are exploited by tumor SCs and how cancers rewire preinstalled regulatory networks to support malignancy. Here, we investigate such a phenomenon in the skin, where during homeostasis, stem cells of epidermis and hair follicle fuel their respective tissues. We find that breakdown of stem cell lineage confinement--granting privileges associated with both fates--is not only a hallmark but also functional in cancer development. We show that lineage plasticity is critical in wound repair, where it operates transiently to redirect fates. Probing the mechanism, we discover that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers become activated and override homeostatic enhancers that govern lineage specificity. In cancer, stress-responsive transcription factor levels rise, causing lineage commanders to reach excess. When lineage and stress factors collaborate, they activate new oncogenic enhancers that distinguish cancers from wounds. Citation Format: Yejing Ge, Elaine Fuchs. Stem cell lineage infidelity drives wound repair and cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B24.