Abstract 2265: Insulin-like growth factor 1 inhibition promotes a pro-metastatic tumor microenvironment and reduces cell adhesion in breast cancer

Abstract

Historically, IGF-1R has been considered a target for inhibition to treat breast cancer patients. We recently identified low levels of IGF-1R are associated with worse overall patient survival and basal-like, triple-negative breast cancer. Our findings present a frame-shift for the function of IGF-1R in breast cancer. To elucidate how loss of IGF-1R function impacts aggressive breast cancers, we have integrated the use of human patient data with mouse models where IGF-1R has been deleted or dysregulated. Single cell RNA-sequencing (scRNAseq) analyses from mouse mammary tumors with decreased IGF-1R has revealed expansion of macrophage populations within the tumor consistent with our previous data identifying IGF-1R attenuation promotes an immune evasive tumor microenvironment. Further analysis of the epithelial cell populations identified expansion of the basal and luminal progenitor cells in tumors with reduced IGF-1R. Gene expression alterations in these populations includes enrichment of pathways necessary for cell invasion, adhesion, and metastasis. We have further defined how reduced tumor epithelial IGF-1R promotes metastasis by utilizing tail vein injection (TVI). Micrometastatic lesion numbers were similar in animals injected with tumor epithelial cells from control and tumor models with decreased IGF-1R. In contrast to primary tumor-induced metastases, IGF-1R attenuation in dissociated tumor cells decreased metastatic cell proliferation in TVI lungs. Moreover, we observed alterations in expression of several cadherins in tumors with decreased IGF-1R; E-cadherin gene and protein levels are decreased, while P-cadherin gene and protein levels are increased. In vitro cell adhesion assays revealed epithelial cells from tumors with attenuated IGF-1R had reduced adherence to matrix and cell-cell contacts. We have aligned the scRNAseq data from mouse mammary tumors with attenuated IGF-1R with human data gene profiles from patient tumors with low IGF-1R and identified common pathways necessary for promoting tumor metastasis including EMT, cell adhesion, cell cycle, and immune evasion. Correlation with the human patient data suggests the mouse models with attenuated IGF-1R reflect similar biology to patient tumors with low IGF-1R expression. Furthermore, we have uncovered a function for IGF-1R in maintaining proper cell-cell adhesion in the primary tumor supporting the conclusion that dysregulated IGF-1R favors metastatic extravasation of tumor epithelial cells. Citation Format: Alison E. Obr, Alexander Lemenze, Krystopher Maingrette, Yun-juan Chang, Virginia Ciliento, Joseph J. Bulatowicz, Teresa L. Wood. Insulin-like growth factor 1 inhibition promotes a pro-metastatic tumor microenvironment and reduces cell adhesion in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2265.