Abstract 2464: Novel models of breast cancer metastasis with different metastatic competence

Abstract

Abstract Metastasis is responsible for poor overall survival of cancer patients and a better understanding of the molecular mechanisms that drive metastasis is crucial for improving disease outcome. In mouse models, gene expression profiling of cancer cells isolated from metastases and from their matched primary tumors is an approach that has been successfully employed to identify biomarkers and drivers of metastasis. However, only few such tumor pairs have been derived from immunocompetent mouse models, limiting our ability to compare the metastatic potentials of these pairs in the context of an intact immune system. Moreover, most of the metastatic cancer cell lines currently available on the C57BL/6 background have a relatively low metastatic potential, complicating the evaluation of therapeutic interventions that may inhibit metastasis. To address these critical limitations, we developed novel cell lines from distinct spontaneous lung metastases and corresponding primary breast tumors from C57BL/6 mice. Specifically, C57BL/6 mice were orthotopically injected with copGFP-expressing E0771 breast cancer cells and the tumors were allowed to grow for 28 days. Tumor cells at different stages of the metastatic cascade - primary tumor evolution, transit through the blood circulation (circulating tumor cells), survival at secondary site, dormancy, and metastatic outgrowth, were captured by collecting and culturing copGFP-positive cancer cell lines from the primary tumor, blood circulation, and metastatic lungs at the experimental endpoint. These cells were reintroduced orthotopically (mammary fat pad injection) and intravenously (tail-vein injection) to evaluate tumor growth and metastasis in vivo. Interestingly, cell lines derived from overt metastases displayed a wide array of metastatic competences, indicating that some metastases retain that ability to further metastasize while others do not. RNA sequencing of these cell lines identified genes and pathways that are significantly upregulated in highly metastatic vs. poorly metastatic cancer cell lines. Future studies will investigate whether modulation of these pathways in the primary tumor and CTCs can be used to predict metastatic recurrence and serve as a basis for developing novel biomarker-based therapeutic approaches for the treatment of metastatic disease. We also envision that the cell lines we generated will be useful for studies of the influence of host-tumor cells interactions on metastasis on the immunocompetent C57BL/6 background. Citation Format: Akshita B. Bhatt, Ruishan Wang, Hong Jia, Myriam Labelle. Novel models of breast cancer metastasis with different metastatic competence [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 2464.