Hair follicle regeneration suppresses Ras-driven oncogenic growth

Abstract

Mutations associated with tumor development in certain tissues can be nontumorigenic in others, yet the mechanisms underlying these different outcomes remains poorly understood. To address this, we targeted an activating Hras mutation to hair follicle stem cells and discovered that Hras mutant cells outcompete wild-type neighbors yet are integrated into clinically normal skin hair follicles. In contrast, targeting the Hras mutation to the upper noncycling region of the skin epithelium leads to benign outgrowths. Follicular Hras mutant cells autonomously and nonautonomously enhance regeneration, which directs mutant cells into continuous tissue cycling to promote integration rather than aberrancy. This follicular tolerance is maintained under additional challenges that promote tumorigenesis in the epidermis, including aging, injury, and a secondary mutation. Thus, the hair follicle possesses a unique, enhanced capacity to integrate and contain Hras mutant cells within both homeostatic and perturbed tissue, demonstrating that in the skin, multiple, distinct mechanisms exist to suppress oncogenic growth.

Adult hair follicles keep oncogenic growth in check

“…Pineda et al additionally induced Hras G12V expression in the skin epithelium (6). Hras mutant cells in the skin epidermis showed hyperproliferation and outcompeted their WT neighbors, like Hras G12Vexpressing HF cells.…”

“…Pineda et al induced Hras G12V expression in Krt19 + HFSCs during the first HF regression and followed the cells over time (6). Surprisingly, the authors observed that although mutant cells proliferated more frequently than WT neighbors, they generally followed the cues of HF regeneration and regression over multiple hair cycles ( Fig.…”

“…This new transcriptional activity, associated with a reduction in lineage restriction and termed "lineage infidelity," was lost in the wound as healing progressed but advanced in tumors, providing a partial explanation as to how wounding can sometimes lead to tumors (17). In the experiments of Pineda et al, tumorigenesis in their HrasG12V +/− ; Tgfbr1 −/− model was infrequently induced by wounding and only if it was superficial (6). This interesting result suggests that mutant HFSCs, like normal HFSCs, migrate into the skin wound and induce SCCs there (see Fig.…”

“…(3)(4)(5). In this issue, Pineda et al have sought to address this complex question using a unique twophoton live imaging technique in association with elegant animal models to track cell fate after induction of oncogenic genes (6). Pineda et al (6) focused on skin and HF epithelia-highly dynamic tissues that undergo regeneration throughout the life of the individual.…”

“…In final experiments, to push HFSCs to tumorigenesis, Pineda et al induced oncogene expression in HrasG12V +/− ; Tgfbr1 −/− mice, known to promote tumorigenesis in other Ras oncogenic systems (6). Rare SCCs (one tumor per animal) were observed in regions of scratching/grooming.…”