Poster Presentation 43rd Lorne Genome Conference 2022

Understanding The Tumour Microenvironment And Metastasis On Triple-negative Breast Cancer (#202)

Laura Rodriguez de la Fuente 1 2 3 , Yolanda Colino Sanguino 2 4 , Jeron Venhuizen 1 , Andrew MK. Law 1 3 , Fatima Valdes-Mora 2 4 , David Gallego-Ortega 1 3 5
  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. Centre for Single Cell Technology, School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Sydeney, NSW, Australia

Breast cancer is one of the most common malignancies worldwide. Despite the success of the current treatments for specific subtypes of breast cancer, there are still limited therapeutic options for patients diagnosed with triple-negative subtype (TNBC) [1]. Although immunotherapies have improved the clinical outcomes in other cancer types, they have produced limited benefits in TNBC. A key factor for this failure has been attributed to the presence of an immunosuppressive microenvironment [2]. Myeloid-derived suppressor cells (MDSCs) are a highly heterogeneous immune population with potent immunosuppressive functions that play an active role in the development of metastasis, the primary cause of death in TNBC patients [3,4]. Targeting MDSCs thus presents an attractive and innovative therapeutic strategy to improve the efficacy and get better response rates in immunotherapy. However, due to their heterogeneous nature, the biggest challenge remains how to selectively target pro-metastatic MDSCs. Understanding the specific molecular features that define MDSCs will open the possibility to implement new therapeutic strategies to improve the clinical outcomes of breast cancer patients. Using a single-cell transcriptomic (scRNAseq) and epigenomic (scATACseq) approach, we interrogated the tumour microenvironment and lung cellular ecosystem before and after metastatic colonization in two different preclinical mouse models of TNBC (the metastatic 4T1.2 and the non-metastatic 67NR), with the aim to functionally classify MDSCs and unravel the inflammatory mechanisms that these cells employ to drive metastatic spread. In this project, we have generated a temporal and spatial single-cell RNAseq map of TNBC in mouse models. We provide a high-resolution characterisation of the myeloid lineage structure dynamics from primary tumours and lung metastasis, identifying the pro-metastatic MDSC subpopulation and their molecular malignant activation. This study lays the first stone to identify and target the pro-metastatic MDSCs to combat TNBC.

  1. Collignon, J., et al., Triple-negative breast cancer: treatment challenges and solutions. Breast Cancer (Dove Med Press), 2016. 8: p. 93-107.
  2. 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.
  3. 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).
  4. Bronte, V., et al., Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun, 2016. 7: p. 12150.