Title: Exploiting the heterogeneity of circulating extracellular vesicles to predict response to therapy
Funder: The Academy of Medical Sciences

Abstract: Cancer metastasis is still the major cause of cancer related death and predicting risk of metastasis therapy resistance remains an obstacle to improved treatment. Extracellular vesicles (EV) are mediators of heterotypic cell-to-cell interactions and therefore modulate biological processes implicated in cancer. I have recently shown that neoadjuvant chemotherapy induces the release of EVs containing high levels of annexin-a6 (ANXA6) protein from cancer cells, which precondition the lung to facilitate metastatic seeding (Keklikoglou et al., Nature Cell Biology 2019). Tumour-derived EVs (tEVs) comprise a mixture of EVs secreted from malignant and non-malignant cells of the tumour, which are released into biological fluids such as blood. Thus, exploiting the heterogeneity of circulating tEVs to predict response to therapy could be an exciting route towards improved patient stratification and treatment of choice. The main objective of my study is to identify the predictive and functional relevance of circulating tEV subpopulations using breast cancer mouse models and human samples from breast cancer patients by deconvoluting the tEV-associated transcriptomic and proteomic profiles. The ultimate goal of my study is to generate tEV-associated RNA and protein signatures that could be used in liquid biopsies to predict the tumour microenvironment (TME) composition and response to therapy. The long-term broad value of my Springboard project is versatile and could be applied to any other cancer or disease studies aiming to elucidate the role of cell type- or tissue-specific EVs in modulating biological functions of the disease and to enable their detection in tissues and liquid biopsies.

Lay abstract: Just like sending letters to our friends in the post, all the cells in our body release tiny membrane ‘packages’ called vesicles, which are means of communication between different cell types. Cancers are made of different cell types, the cancer cells themselves and other cells non-cancerous cells such as immune cells and cells that form blood vessels that help the cancer to grow. Our recent study showed that when a breast tumour is treated with chemotherapy the cancer cells release vesicles in the bloodstream, which transfer “malignant” signals to normal, non-cancerous cells in distant organs where secondary cancers can form. However, methods to reliably detect cancer-derived vesicles in the blood of patients in order to establish biomarkers that predict disease aggressiveness or response to treatment are lacking. We will develop a method to isolate these vesicles that are released from different cell types to understand their functional role and create their unique “profile” based on the information they carry. We will further investigate whether vesicles with different “profiles” regulate different biological functions in cancer and whether these “signatures” can be detected in the blood of breast cancer patients with the ultimate goal of developing biomarkers of breast cancer screening and response to treatment.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS