Delineating cancer immunotolerance of metastatic triple-negative breast cancer

Project Member(s): Gallego Ortega, D., Valdes Mora, F.

Funding or Partner Organisation: The Cancer Council NSW (NSW Cancer Council Project Grants)
National Health & Medical Research Council (NHMRC - Ideas Grants)

Start year: 2023

Summary: Cancer metastasis is the primary cause of cancer morbidity and mortality; thus, major research efforts need to focus on identifying new therapeutic targets to stop the spread of cancer. Breast cancer is the most common malignancy in women, despite the success of targeted therapy for some breast cancer subtypes, there are still 1/4 of patients (about 2,500 per year in Australia) diagnosed with metastatic triple negative subtype (TNBC) with no targeted options. Myeloid-Derived Suppressor Cells (MDSCs) are a heterogeneous and poorly defined group of tumour-infiltrating myeloid progenitors that promote cancer progression and metastasis. These immune cells are found infiltrated in all solid tumours and one of the most intriguing roles attributed to MDSC is their contribution to the formation of pre-metastatic niche. In fact, abatement of MDSCs results in dramatic reduction of metastasis. However, the mechanisms of infiltration of MDSC in tissues and specific regulation of cancer cell seeding at metastatic sites driven by MDSC remain poorly understood. MDSCs are a compelling target for cancer therapy, but their high heterogeneity and poor definition hampers the development of a MDSC-based therapy. This project aims to: - unmask the pro-metastatic MDSCs subpopulation(s) and their mechanisms of action to promote breast cancer metastasis in preclinical mouse models of TNBC and using a combination of single-cell multi-omic analysis and functional validation assays. - evaluate the potential diagnostic and therapeutic value of the novel prometastatic-MDSC definition in order to validate and translate our findings into tangible clinical outcomes. The unprecedented capacity of combinatorial single-cell approaches (scRNAseq and CITEseq) and subsequent functional validation is set to resolve the long-standing controversy about the prometastatic MDSCs identity, laying the first stone for the development of targeted anti-MDSC therapy.

FOR Codes: Cancer cell biology, Cancer therapy (excl. chemotherapy and radiation therapy), Innate immunity, Genomics and transcriptomics, Epigenetics (incl. genome methylation and epigenomics), Treatment of human diseases and conditions, Diagnosis of human diseases and conditions

Acknowledgement of Country

UTS acknowledges the Gadigal people of the Eora Nation, the Boorooberongal people of the Dharug Nation, the Bidiagal people and the Gamaygal people, upon whose ancestral lands our university stands. We would also like to pay respect to the Elders both past and present, acknowledging them as the traditional custodians of knowledge for these lands.