We have established that the spiny mouse possesses remarkable regenerative capacity that extends beyond typical wound healing to include cancer resistance. When exposed to genotoxic agents and carcinogens, spiny mice activate a coordinated tissue replacement program we term Damaged Tissue Removal by Widespread Turnover (DTRWT). Through synchronized apoptosis and proliferation, DTRWT fully replaces carcinogen-exposed tissue regions, conferring significant resistance to tumor development even under chronic treatment. Laboratory mice, by contrast, develop extensive tumors within weeks under identical conditions. Our preliminary data indicate that these divergent outcomes stem from active coordinated turnover in spiny mice rather than differential carcinogen sensitivity, as both species show equivalent DNA damage levels following genotoxic exposure.

This proposal will establish a comprehensive mechanistic understanding of DTRWT through parallel in vivo and organoid model systems that compare spiny mice to non-regenerative laboratory mice. In the first aim, we will determine whether DTRWT extends across diverse genotoxic agents by testing UVB radiation, benzo[a]pyrene, and cisplatin on spiny mouse skin. We will use deep sequencing and whole-exome approaches to demonstrate that DTRWT eliminates mutated cells before clonal expansion can occur. The mechanistic necessity of apoptotic cell death will be tested by treating spiny mice with caspase inhibitors during carcinogen exposure, with extended monitoring for mutation retention and tumor formation over 1.5 years. Spatial transcriptomics with single-cell resolution will map proximity-based communication networks between epidermis, dermal fibroblasts, and macrophage subpopulations during DTRWT. In the second aim, we will develop an organoid platform designed to partition epithelial-intrinsic from epithelial-extrinsic contributions to DTRWT. After establishing baseline epithelial-intrinsic responses and validating endogenous carcinogen metabolic activation, we will systematically reconstitute microenvironmental components through co-culture with fibroblasts and macrophages in different activation states. Cross-species co-culture experiments will test whether spiny mouse stromal cells can confer enhanced damage responses to laboratory mouse organoids. Most importantly, we will identify targetable pathways for inducing DTRWT-like responses in laboratory mouse organoids, directly addressing therapeutic translation potential. Together, these complementary approaches will provide fundamental insights into coordinated tissue turnover mechanisms and establish proof-of-concept for transferring regenerative damage responses to non-regenerating species, with profound implications for skin rejuvenation and elimination of cells with cancerous potential in humans.