Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Laboratory for Tissue Microenvironment, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.
Nat Cell Biol. 2024 Jun;26(6):859-867. doi: 10.1038/s41556-024-01413-y. Epub 2024 Apr 30.
Tissue regeneration and maintenance rely on coordinated stem cell behaviours. This orchestration can be impaired by oncogenic mutations leading to cancer. However, it is largely unclear how oncogenes perturb stem cells' orchestration to disrupt tissue. Here we used intravital imaging to investigate the mechanisms by which oncogenic Kras mutation causes tissue disruption in the hair follicle. Through longitudinally tracking hair follicles in live mice, we found that Kras, a mutation that can lead to squamous cell carcinoma, induces epithelial tissue deformation in a spatiotemporally specific manner, linked with abnormal cell division and migration. Using a reporter mouse capture real-time ERK signal dynamics at the single-cell level, we discovered that Kras, but not a closely related mutation Hras, converts ERK signal in stem cells from pulsatile to sustained. Finally, we demonstrated that interrupting sustained ERK signal reverts Kras-induced tissue deformation through modulating specific features of cell migration and division.
组织再生和维持依赖于协调的干细胞行为。这种协调可能会因致癌突变而受损，导致癌症。然而，目前尚不清楚癌基因如何扰乱干细胞的协调以破坏组织。在这里，我们使用活体成像来研究致癌的 Kras 突变如何导致毛囊组织破坏的机制。通过在活体小鼠中对毛囊进行纵向追踪，我们发现 Kras 突变（可导致鳞状细胞癌）以时空特异性的方式诱导上皮组织变形，与异常细胞分裂和迁移有关。利用报告小鼠，我们在单细胞水平上捕获了实时 ERK 信号动力学，发现 Kras 而不是密切相关的突变 Hras 将干细胞中的 ERK 信号从脉冲式转换为持续式。最后，我们证明通过调节细胞迁移和分裂的特定特征，中断持续的 ERK 信号可以逆转 Kras 诱导的组织变形。
