Abstract 2388: Role of the primary cilium in the crosstalk between obesity and cancer
Authors: Bustamante-Marin Ximena , Merlino Jenna L. , Grindstaff Emma J. , Coleman Michael F. , Rezeli Erika , Camp Kristina K. , Smith Laura , Hursting Stephen D. 
Published: June 2022

Background: Defects in primary cilium can lead to a group of disorders termed ciliopathies, with links to both obesity and cancer. Obesity causes inflammation and downregulates anti-tumor immunity generating a protumor microenvironment and increases the risk of breast cancer (BC) development and metastasis. Also, obesity affects cilium length, which could disrupt the essential role of the cilium in detecting extracellular cues, coordinating cell signaling responses, and regulating cell fate and mitochondrial function. However, there is a gap in understanding the effects of obesity on ciliogenesis in cancer cells and in regard to the impact of cilium length and localization on mitochondrial function of tumor cells. We therefore sought to elucidate the impact of obesity on the presence, localization, and function of primary cilium, using murine models of triple-negative breast cancer (TNBC).

Methods: We generated mammary tumors by orthotopic transplantation of murine metM-Wntlung or E0771 TNBC cells, and evaluated the impact of obesity on ciliary specific gene sets in tumors using GSEA analysis. We also tested the abundance of cilium in tumor sections using immunofluorescence. Additionally, we developed metM-Wntlung and E0771 expressing the ciliary transmembrane protein Smo fluorescently tagged to pHluorin. Using these cells, we performed in vitro studies to investigate the length and cellular localization of the cilium in cancer cells in 3 compartments; intracellular (in), intermediate, or extracellular (out).

Results: Our GSEA analysis results indicated significant upregulation of 18/19 ciliary gene sets in metM-Wntlung mammary tumors from obese mice and 19/19 ciliary gene sets in E0771 mammary tumors from obese mice compared to the corresponding tumors developed in non-obese mice. Ongoing leading-edge analysis will determine the genes driving the enrichment of ciliary-related gene sets in tumors of obese mice. Immunofluorescence analysis showed a significant number of ciliated cells in tumor sections of obese mice and in cultured cells expressing pHluorin-Smo. Ongoing studies will reveal the specific cellular localization of the cilium on cancer cells and the effects on mitochondrial function. Our research is establishing a proof-of-concept that mammary cancer cells express cilium and will elucidate key mechanistic details related to the role of the primary cilium in the crosstalk between obesity and cancer metabolism. This research is supported by R35CA197627 (SDH), AICR Marylin Gentry Fellowship (XBM).

Citation Format: Ximena Bustamante-Marin, Jenna L. Merlino, Emma J. Grindstaff, Michael F. Coleman, Erika Rezeli, Kristina K. Camp, Laura Smith, Stephen D. Hursting. Role of the primary cilium in the crosstalk between obesity and cancer [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 2388.