How Breast Cancer Genotypes Imprint the Myeloid Compartment

Breast cancer is the most common cancer in women worldwide. Despite major advances in treatment, many patients still do not respond well to modern immunotherapies. One reason lies in the complex interaction between cancer cells and the surrounding immune system. Among immune cells, so-called myeloid cells - including macrophages and neutrophils - play a key role. These cells can either fight the tumor or, conversely, support its growth and help cancer cells escape immune attack. This project investigates how specific genetic alterations in breast cancer cells influence the composition and behavior of these myeloid immune cells. The focus lies on frequent mutations in the tumor suppressor genes BRCA1, BRCA2, TP53 and the oncogene PIK3CA. The central hypothesis is that these genetic changes reprogram the immune microenvironment in a way that affects tumor progression and resistance to immunotherapy. To explore this connection, state-of-the-art single-cell and spatial analyses will be used. These techniques allow the study of thousands of individual tumor and immune cells simultaneously, creating detailed maps of the tumor microenvironment. In addition, the study will use genetically engineered mouse models and 3D tumor organoids, miniature tumor models grown from patient tissue, to experimentally test how cancer cell mutations shape immune cell behavior. In the long term, the project aims to identify new therapeutic targets that could enhance the effectiveness of immunotherapy in genetically defined subtypes of breast cancer. The research will be conducted at the Breast Cancer Laboratory at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne, Australia, under the supervision of Prof. Jane Visvader and Prof. Geoffrey Lindeman. By uncovering how the genetic makeup of breast cancer affects its immune environment, this project seeks to advance our understanding of tumor biology and pave the way for more precise and effective treatment strategies tailored to each patients tumor genetics and immune response.