Abstract A16: Understanding the principles of tissue repair that accelerate tumor initiation

Abstract

Abstract Cancer development depends on the capacity of malignant cells to boost growth-promoting signals and restrain growth-inhibiting mechanisms, thus resulting in unbalanced homeostasis. Among growth-promoting mechanisms, sustained proliferation has been described as a fundamental trait of cancer cells. Hyperproliferative behavior is usually acquired in cancer by the constitutive activation of oncogenes such as H-Ras (G12V activating mutation). Previous work showed that H-Ras-G12V promotes epithelial cell hyperproliferation, a feature required but not sufficient to trigger cancer formation. Interestingly, injury has been linked to skin cancer emergence across several mutations. Yet it remains elusive how wound-triggered behaviors lead to cancer. Wound repair process increases cell proliferation, a key event to re-establish epithelial integrity. This observation suggests a possible cooperation between wound-induced and H-Ras-driven proliferation to reach the homeostatic breaking point that promotes cancer. To understand if enhanced proliferation during wound repair could contribute to cancer emergence, I tested the sufficiency of this behavior in promoting tumor in H-RasG12V-model in comparison to other hyperproliferative models, loss of function of the cell cycle inhibitor p21 (p21-/-) and loss of function of Tgf-beta Receptor I (Tgf-beta-RI-/-). Interestingly, in both Tgf-beta-RI-/- and p21-/- models, despite wound-increased cell proliferation, the tissue repairs normally without emergence of tumor. Surprisingly, in H-RasG12V-model wound repair does not increase significantly proliferation, yet tumors consistently develop in the wounded area after two weeks, in line with previous studies. These results indicate that wound-induced proliferation is insufficient to promote tumor initiation. To determine how differences in H-RasG12V cell numbers affect the wound repair outcome, I have activated H-RasG12V mutation in a mosaic fashion, conditions under which H-Ras cells outcompete wild-type neighboring cells via hyperproliferation during homeostatic conditions (Pineda and Greco, in revision). Unexpectedly, the repaired epithelium does not develop tumor after two weeks. Analyses of cellular behaviors show that wild-type cells display an hyperproliferative behaviors in response to the wound settings and they appear to outcompete the H-Ras cells, reversing the relationship established in homeostatic conditions. These data show that wound-induced proliferation seems to provide homeostatic protection against tumor formation. Wild-type cells force Hras-mutant cells to follow physiologic wound repair process suppressing their tumorigenic potential. In conclusion, my discoveries suggest that hyperproliferation is dispensable for tumor initiation. Furthermore, enhanced proliferation of the wild-type population through wounding may help eliminate oncogenic mutant cells that would otherwise integrate and expand into the tissue. Citation Format: Sara Gallini, Valentina Greco. Understanding the principles of tissue repair that accelerate tumor initiation [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A16.