Abstract 2376: Clonal evolution of skin carcinomas during tumor progression and metastasis

Abstract

Abstract Tumor heterogeneity and the ongoing evolution of tumor subpopulations have presented considerable challenges to the success of cancer therapies, highlighting a critical need for greater understanding of these phenomena. We used a K5CreER-Confetti reporter mouse in combination with the DMBA (dimethylbenzanthracene)/TPA (12-O-tetradecanoylphorbol-13-acetate) skin carcinogenesis model to study the genetics, clonality, and evolutionary behavior of tumor subpopulations from tumor initiation to metastasis. Treating the skin of K5CreER-Confetti mice with tamoxifen results in widespread labeling of the epidermis and hair follicles, which persists for at least 18 months. Papillomas that develop from Confetti-activated skin are of clonal origin, evidenced by each tumor being distinctly dominated by a single Confetti color (RFP, YFP, GFP, or CFP; or uncolored). Twelve weeks after initiation, the majority of tumors remain single-colored, with only 22% (36 of 133) showing any evidence of a secondary color population present. By 20 weeks after initiation, however, nearly all tumors (78%, 42 of 54) have incorporated one or more secondary populations, readily identifiable as streaks of a distinct color. FACS separation and sequencing of these different colored populations reveals these populations are genetically distinct: in preliminary analysis, the primary color population typically carries the expected driver Hras Q61L mutation while the secondary populations do not. The tumor thus appears to be incorporating pseudo-normal tissue from its microenvironment during early growth. Activation of the Confetti reporter in tumors post-initiation in papillomas results in labeling of single cells with all 4 Confetti colors, allowing subpopulations and their evolution to be studied at later stages. These highly multi-color papillomas subsequently give rise to single-color carcinomas and metastases, suggesting that the conversion from a benign to malignant tumor is clonally driven. The Confetti mouse is a valuable tool for studying the clonality and genetics of subpopulations present in tumors, which need to be better understood in order to improve the treatment of heterogeneous human tumors. Citation Format: Melissa Q. McCreery, Allan Balmain. Clonal evolution of skin carcinomas during tumor progression and metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2376.