Abstract 132: The molecular basis of an evolutionary arms race between cancer cells and their host

Abstract Genetic and nongenetic changes can drive abnormal characteristics of cancer cells, including resistance to tumor growth. Through selective breeding of animals with the slowest growing tumor at 11 days following implantation over ten generations, we evolved resistance to tumor growth in two contrasting strains of mice: severe combined immunodeficiency disease (SCID) and immuno-competent C57BL/6. We found that the two strains evolved different strategies of resistance to the cancer. In the immunocompromised mice, skin fibroblasts infiltrated into and around the tumor to impede growth, while an enhanced immune response to tumor antigens, slowed tumor growth in the immunocompetent mice. However, when the experiment was extended beyond 11 days, tumor growth rapidly increased so that, at 28 days, it was comparable in size to the control animals. We investigated the molecular-level mechanisms underlying these resistance traits in SCID mice. We identified transcriptomic changes using RNA-Seq in both skin and tumor samples to compare the evolved mice (EV) with the original strain (WT) at 11 days and 28 days. We used DESeq2 and two-way ANOVAs on the normalized data to identify significant differences in gene expression. We adjusted p-values for multiple testing with the Benjamini-Hochberg false discovery correction and used a q value of less than 0.1 (and/or a greater than two-fold change) to determine the significance for differential expression levels. Comparing transcriptomic data from skin fibroblasts from evolved (EV) and non-evolved (WT) SCID mice at day 11 following implantation (i.e., the point of maximal tumor suppression) revealed 98 differentially expressed genes (DEGs). EV SCID fibroblasts showed increased expression of MicroRNAs, including MiR-7 and Mir5125, and acid metabolic pathways, such as Carbonic anhydrase III. A comparison of the tumor cells from day 11 and day 28 demonstrated substantial epigenetic evolution with 1353 DEGs. The tumor cells at day 28 adapted to the host response by increasing expression of genes for extracellular matrix (ECM) remodeling, mainly the metalloproteases gene family. Here we used selective breeding to allow evolution to reveal potential host strategies to suppress tumor growth. However, we find that, over time, tumor cells can evolve successful counter strategies to overcome host resistance. Our results provide novel insights into key dynamics of somatic evolution during carcinogenesis and highlight the critical roles of epigenetic modification and inheritance in these somatic eco-evolutionary dynamics. Citation Format: Arig A. Ibrahim-Hashim, Robert A. Gatenby, Christina L. Richards, Joel S. Brown. The molecular basis of an evolutionary arms race between cancer cells and their host [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 132.