E-Poster Presentation 33rd Lorne Cancer Conference 2021

Understanding the pre-metastatic niche formation of triple-negative breast cancer at single-cell resolution (#191)

Laura Rodriguez de la Fuente 1 2 3 , Jeron Venhuizen 1 , Andrew MK Law 1 3 , Yolanda Colino-Sanguino 2 4 , Clare Stirzaker 5 , Fatima Valdes-Mora 2 4 , David Gallego Ortega 1 3
  1. Tumour Development Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. Cancer Epigenetic Biology and Therapeutics, Children's Cancer Institute, Sydney, New South Wales, Australia
  3. St. Vincent's Clinical School, Faculty of Medicine, UNSW, Sydney, NSW, Australia
  4. School of Women's and Children's Health, Faculty of Medicine, UNSW, Sydney, NSW, Australia
  5. Epigenetic Deregulation in Cancer, Garvan Institute of Medical Research, Sydney, NSW, Australia

One of the most common malignancies worldwide is breast cancer[1]. Despite the success of the current treatments for specific subtypes of breast cancer, there are still no targeted options for patients diagnosed with triple negative subtype (TNBC), which represent 25% of breast cancer patients. TNBC cells are defined by lack of expression of estrogen, progesterone and HER-2 receptors[2], which result in a non-response to hormonal therapy. This phenotype and its contribution to the immunosuppression in the tumour microenvironment (TME) are two key points to explain the malignant progression compared with other breast cancer subtypes[3-5].  

Besides neoplastic cells, tumours are comprised of cancer-associated cell species that form the TME[6]. In the last few years, myeloid-derived suppressor cells (MDSCs) have emerged as crucial regulators of immune responses in the TME and cancer progression[7,8]. These cells are defined as a heterogeneous population composed of precursors of the myeloid-cell lineage that infiltrate the tumour and promote cancer progression by suppressing the cytotoxic activity of the immune system and participating in the development of metastasis through the establishment of the pre-metastatic niche[8,9]. The presence of MDSCs in the TME and their immunosuppressive effect has been widely described in highly aggressive cancers, such as TNBC[10]. 

This project will characterise the molecular features of the TME and the pre-metastatic niche formation in TNBC, as well as study the role of the pro-tumorigenic myeloid population. Comparative immunophenotyping analysis using flow cytometry analysis is performed to identify the infiltration of MDSCs in the lungs of mouse models of breast cancer with the well-established metastatic 4T1.2 and the non-metastatic 67NR cell lines. Additionally, using a single cell transcriptomic approach (scRNAseq), we interrogate the heterogeneity and molecular features of tumour infiltrated populations involved in carcinogenesis and lung metastasis.

These studies will establish the foundations to develop a strategy for MDSC isolation using specific cell surface markers and identify potential targetable activated signalling pathways involved in the pro-metastatic function of MDSCs.

  1. GLOBOCAN. Cancer Fact sheets, Breast. The Global Cancer Observatory - World Health Organization, 2018.
  2. Denkert, C., et al., Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. Lancet, 2017. 389(10087): p. 2430-2442.
  3. de Ruijter, T.C., et al., Characteristics of triple-negative breast cancer. J Cancer Res Clin Oncol, 2011. 137(2): p. 183-92.
  4. Liu, Z., et al., A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer. Transl Oncol, 2018. 11(2): p. 311-329.
  5. Yu, T. and G. Di, Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance. Chin J Cancer Res, 2017. 29(3): p. 237-252.
  6. Whiteside, T.L., The tumor microenvironment and its role in promoting tumor growth. Oncogene, 2008. 27(45): p. 5904-12.
  7. Condamine, T., et al., Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu Rev Med, 2015. 66: p. 97-110.
  8. Law, A.M.K., F. Valdes-Mora, and D. Gallego-Ortega, Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer. Cells, 2020. 9(3).
  9. Wang, Y., et al., MDSCs: Key Criminals of Tumor Pre-metastatic Niche Formation. Front Immunol, 2019. 10: p. 172.
  10. Gallego-Ortega, D., et al., ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells. PLoS Biol, 2015. 13(12): p. e1002330.