Abstract 1863: Mouse strain variations in drug-induced lung stromal responses

Abstract Chemotherapy has significantly improved the survival of cancer patients. However, the vast variation in treatment responses remains a major issue in the clinic. It is imperative to understand the molecular mechanisms underlying treatment failure in specific populations of patients. Genetic diversity has been recognized to mainly account for the differences in drug responses among patients. Yet, it is not feasible to map the responsible genetic variants within millions of single-nucleotide polymorphisms in the human genome in clinical settings with a limited number of subjects and insufficient genomic information. Genetically diverse mice are an ideal tool to overcome the limitations in clinical studies and model drug responses in hosts that require genetic susceptibility and resistance factors. Recent studies have also implicated a critical role for host cells (i.e., the tissue microenvironment) in building a protective “niche” for tumor cells enabling their escape from chemotherapeutic treatments. Notably, the host regenerative response upon chemotherapy “injury,” which is regarded as an intrinsic host mechanism to repair damaged tissues, may be exploited by tumor cells for their local recurrence or distant metastases. In this study, using a lung injury model, we determined how drug-induced lung stromal wound healing responses differed among eight inbred mouse strains (BALB/cJ, NSG, C57BL/6J, CH3/HeJ, CBA/J, SJL/J, A/J, and NOD/ShiLtJ). Upon either cisplatin or doxorubicin stimulation, the wound healing-associated genes Il-6, Spp1, Cxcl1, and Ccl2 were all found upregulated in lung stromal cells but showed a great variation across different strains. Furthermore, we performed single-cell RNA sequencing on the lung stromal cells and immune cells isolated from three selected mouse strains (BALB/cJ, C57BL/6J, and NOD/ShiLtJ) without and with doxorubicin treatment in vivo. The transcriptomic analyses revealed strain-specific and non-specific therapy-elicited gene signatures in different types of lung tissue cells. Collectively, our results signify an association between genetic backgrounds and drug-induced host responses in mice. The next steps of the study aim to understand how genetic diversity would functionally impact drug-induced lung tissue regeneration, lung inflammation, and post-therapy tumor relapse or metastasis in the lung. Citation Format: Carlos M. Leon, Zheng Gong, Qing Li, Jiayuan Shi, Wulin Zuo, Muneer G. Hasham, Lenny Shultz, Sheng Li, Guangwen Ren. Mouse strain variations in drug-induced lung stromal responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1863.