Role of the Primary Cilium in the Crosstalk Between Obesity and Cancer

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  • April 27, 2022
Creator
  • Merlino, Jenna
    • Gillings School of Global Public Health, Department of Nutrition
Abstract
  • Background: Defects in primary cilium cause ciliopathies, with links to both obesity and cancer. Obesity contributes to inflammation and downregulates anti-tumor immunity, generating a pro-tumor microenvironment and increasing 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, the effect of obesity on ciliogenesis in cancer cells and the impact of cilium length and localization on the mitochondrial function of tumor cells are unclear. We 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: The presence of primary cilium in murine models of TNBC, including M28, M6, M6C, metM-Wnt-lung and E0771 cell lines was quantified by immunofluorescence analysis. To investigate the localization of the cilium, we developed metM-Wnt-lung cells expressing the ciliary protein Smo tagged to pH-luorin and utilized a two-color immunofluorescence assay. To analyze the impact of obesity on tumor ciliation we generated mammary tumors by orthotopic transplantation of murine metM-Wnt-lung or E0771 cells into the mammary fat pad of obese female mice. In mammary tumors, the enrichment of ciliary genes was evaluated using gene set enrichment analysis (GSEA) and the abundance of cilium using immunofluorescence. Results: In M28 (weakly tumorigenic) cell cultures, 33% of the cells were ciliated, while in invasive (M6) and metastatic models (M6C, metM-Wnt-lung and E0771) the ciliation fluctuated between 5% and 20%. The presence and length of primary cilium was unaffected by serum deprivation. In vivo, obesity resulted in upregulation of 13/18 and 9/18 ciliary gene sets in metM-Wnt-lung and E0771 mammary tumors, respectively, compared to tumors developed in non-obese mice. The enrichment of these ciliary associated gene sets was contributed to by 389 genes in metM-Wnt-lung mammary tumors and 195 genes in E0771 mammary tumors, 168 of which were commonly enriched in both tumor types. Immunofluorescence analysis showed a significant increase in the number of cilia per area of the tumor in obese mice compared to non-obese mice. Conclusion: We established a proof-of-concept that murine mammary cancer cells express primary cilium and the presence of primary cilium is upregulated by obesity. The importance of primary cilium in cancer is emerging. Ongoing studies will reveal the localization of the cilium in cancer cells and its effects on mitochondrial function. We will elucidate mechanistic details of the role of primary cilium in the crosstalk between obesity and cancer metabolism.
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  • In Copyright
Advisor
  • Bustamante-Marin, Ximena
    • Gillings School of Global Public Health, Department of Nutrition
    • Nutrition Research Institute
Degree
  • Bachelor of Science in Public Health
Graduation year
  • 2022
Language
  • English

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