Wounds That Never Heal? Stem Cell Lineage Infidelity at the Crossroads of Wound-Repair and Cancer

Tissue stem cells govern tissue regeneration and wound-repair. Tumors often hijack these normal cellular programs and exploit them for malignancy. Here, we identify such a phenomenon in skin, where stem cells of the epidermis and hair follicle remain faithfully restricted to fueling their own tissue during homeostasis. They lose lineage fidelity during tumorigenesis. Moreover, breakdown of stem cell lineage confinement – granting privileges associated with both fates – is not only a hallmark, but also obligatory for malignancy. Intriguingly, we find that lineage plasticity is also critical in wound-repair, where it functions transiently to redirect fates. Probing mechanism, we show that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers are activated and override the normal 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. Open chromatin regions bound by TFs typically exhibit higher accessibility than otherwise closed regions. Since ATAC-seq technology can be applied on small numbers of SCs, we could use this approach to delineate open chromatin states across homeostatic, wound-induced and tumorigenic SC populations in vivo. Importantly, by complementing these data with transcriptional profiling, we could predict the TF binding sites that are functional for each cellular state