Abstract PR02: Minor clones can drive polyclonal metastasis by affecting immune microenvironment

Most breast tumors display a high degree of intratumor heterogeneity, with many distinct subpopulations of cancer cells present. Elevated diversity within a tumor increases the chance for cellular adaptation, as individual clones may react differently to changes in the tumor microenvironment. Thus, treatment of heterogeneous tumors my lead to selection of a resistant clone, its expansion, and tumor progression. However, the fitness of cancer cells depends not only on their intrinsic properties, but could also be affected through interactions between different subpopulations. These interactions could be the reason for maintenance of minor clones along the major population. Therefore, intratumor heterogeneity may have functional relevance in tumor progression and colonization of metastatic sites. To emulate clonal interactions, we used the previously developed polyclonal breast cancer model of MDA-MB-468 cell line expressing soluble factors, IL-11 and FIGF. The IL-11 and FIGF clones, when present as minor population, support the growth of other clones in vivo. Moreover, polyclonal tumors with minor driving clone population are highly metastatic. Thus, we hypothesized that clonal interactions could not only drive tumor growth, but could also play an important role in metastasis. We have found that polyclonal tumors lead to polyclonal metastases, composed of mixture of neutral and driver clones. To investigate the mechanisms of clonal interactions driving polyclonal metastasis, we performed RNA profiling of subpopulations and stroma from polyclonal tumors. Our results suggest that this cooperation is indirect and that driver clones promote metastasis by altering the tumor microenvironment. We have also found that minor driver clones affect the immune cells within primary tumor, circulating blood, and metastatic site. These systemic changes significantly influence the metastatic progression. We are currently testing whether a treatment targeting this indirect clonal interaction mechanism could prevent polyclonal metastatic spread. Our study shows that the interaction between minor clones and other cancer cells could drive tumor growth and metastasis. Moreover, our results suggest that clonal cooperation in metastatic progression may be indirect and involve modulation of immune microenvironment of the primary tumor and distant organs. This abstract is also being presented as Poster B03. Citation Format: Michalina Janiszewska, Doris P. Tabassum, Andriy Marusyk, Muhammad B. Ekram, Zafira Castaño, Natalie L. Kingston, Yuanbo Qin, Tyler Laszewski, Minsuk Kwak, Kimiyo Nakamura, Rong Fan, Franziska Michor, Sandra S. McAllister, Kornelia Polyak. Minor clones can drive polyclonal metastasis by affecting immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr PR02.