Abstract 885: Live-imaging reveals the correction of skin deformities within two tumor-associated mutational models

Abstract

Abstract Healthy tissues are frequently subject to oncogenic mutations that fail to produce malignancy. Such mutations can lead to aberrant cellular behaviors such as abnormal differentiation or hyperproliferation and the subsequent formation of aberrant tissue growths and cancer. However, it remains unclear how phenotypically normal tissue is capable of harboring mutations and raises the question as to how the switch from normal to malignant is initiated. One challenge to understanding the initiating events towards malignancy is the inability to follow the same cells over time in an intact mammal. Specifically, this roadblock hinders the ability to understand both the role of specific cells and how their location contributes to their growth, whether that growth be normal or cancerous. To overcome this, we have established a novel live imaging approach to perform in vivo lineage tracing of the same mutant cells over time within two distinct mutational systems in the skin epithelium. To begin, we turned to the pro-differentiation pathway Wnt/β-catenin, which when mutated is known to drive benign growths in the skin, and activated this mutant form in skin stem cells. We show that the resulting growths that deform the skin tissue architecture spontaneously regress, irrespective of their size. Endogenous behaviors such as differentiation and apoptosis as well as ectopic cell extrusions are employed to eliminate mutant cells from the tissue and dismantle the aberrant structures. Following regression, the remaining structures are either completely eliminated or converted into functional skin appendages in a niche-dependent manner. While these results demonstrate the remarkable capacity to reverse aberrant phenotypes, the question remained whether this phenomenon was Wnt/β-catenin specific. To address this, we next turned to mutant Hras, which is well established to cause a hyperproliferative, pro-growth advantage and frequently found mutated in malignant skin tumors such as cutaneous Squamous Cell Carcinoma. Activation of mutant Hras in the skin epithelium produced a range of phenotypes from hyperthickening to follicular structural deformities to macroscopic skin growths, all of which demonstrated the capacity to correct. Currently, we are utilizing a combination of extensive biochemical characterization together with targeted cellular ablations to investigate the mechanisms at play both within the mutant pool and the surrounding normal tissue that leads to the reversibility and integration observed within the Hras model. Altogether, this study reveals an unanticipated plasticity of adult skin epithelium when faced with mutational insult and elucidates the dynamic cellular behaviors employed for its return to a homeostatic state. Citation Format: Cristiana Pineda, Samara Brown, Valentina Greco. Live-imaging reveals the correction of skin deformities within two tumor-associated mutational models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 885. doi:10.1158/1538-7445.AM2017-885