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.

组织干细胞（Tissue stem cells）调控组织再生与伤口修复。肿瘤通常会劫持这些正常细胞程序，并利用其驱动恶性表型的形成。本研究在皮肤组织中发现了这一现象：在稳态（homeostasis）条件下，表皮（epidermis）与毛囊（hair follicle）的干细胞始终严格受限，仅为自身组织的维持提供支持。而在肿瘤发生（tumorigenesis）过程中，这些干细胞会丧失谱系保真度（lineage fidelity）。此外，干细胞谱系限制（lineage confinement）的打破——使其获得了兼具两种细胞命运的特性——不仅是恶性表型的标志性特征，更是恶性增殖发生的必要条件。有趣的是，本研究发现谱系可塑性（lineage plasticity）在伤口修复中同样至关重要：它会短暂发挥作用，以重定向细胞命运。在机制探究中，我们证实无论细胞起源如何，当应激响应增强子（stress-responsive enhancers）被激活并取代调控谱系特异性（lineage-specificity）的正常增强子时，伤口修复过程中便会出现谱系保真度丧失的现象。在癌症中，应激响应转录因子（stress-responsive transcription factor）的表达水平升高，导致谱系调控因子过量积累。当谱系调控因子与应激因子协同作用时，二者会激活全新的致癌增强子（oncogenic enhancers），这也是癌症与伤口修复的区别所在。