Title: Characterising neutrophil:macrophage cross-talk in metastatic niches
Funder: The Academy of Medical Sciences

Abstract: This projects will study the interactions between neutrophils and macrophages in metastatic niches, to identify novel molecular targets to impair metastasis. Both neutrophils and macrophages, two of the most abundant cellular components in tumours, are known to acquire pro-tumorigenic functions in the tumour microenvironment. However, how they specifically interact with each other in metastasis, and how their cross-talk contributes to establish a tumour-supportive niche remains unknown. An in vivo labelling system I developed (Ombrato et al., Nature 2019) will help identifying molecular mediators of the neutrophil:macrophage cross-talk in a model of murine breast cancer lung metastasis. To achieve this aim: 1) factors involved in neutrophil:macrophage cross-talk will be identified: single cell RNA sequencing data already generated will be analysed by using a state-of-art inference algorithm to predict the molecular interactions between neutrophils and macrophages in metastatic niches; 2) neutrophil:macrophage cross-talk will be perturbed in vitro: the most interesting molecules identified will be tested in a co-culture system including breast cancer cells, neutrophils and macrophages, to analyse whether the inhibition of the signalling pathways they mediate is involved in regulating breast cancer cell proliferation in vitro; 3) the anti-metastatic potential of targeting the neutrophil-macrophage cross-talk will be validated in vivo: the top three candidates identified in vitro will be tested for their anti-metastatic potential in genetically modified mouse models. Moreover, to support the translational potential of these findings, nanoparticle targeting of neutrophils will be used. Overall this study will identify new vulnerabilities in metastatic cancer growth, by targeting the neutrophil-macrophage cross-talk.

Lay abstract: The metastatic disease is responsible for more than 90% of deaths in cancer. Metastasis occurs when cancer cells leave the primary tumour and colonise distant organs. Importantly, to successfully recreate a tumour at distant sites, cancer cells need help from their surrounding non-cancer cells in the host tissue. Targeting the support given to the cancer cells by other cells, and particularly by the immune cells, has been shown to be an extremely valid therapeutic strategy. Indeed, immunotherapy is quickly changing the way cancer patients are treated. However, our understanding of how the immune cells support tumour cells in metastatic sites remains limited. As a consequence, effective therapeutic options are still lacking and metastases remain largely incurable. Neutrophils and macrophages are two highly abundant immune cell populations and both have been shown to support cancer growth. However, how they co-operate to create a tumour-supportive environment in metastasis remains mysterious. In this study, I will use a combination of innovative technologies to specifically identify the “messages” that neutrophils and macrophages send to each other in order to help the breast cancer cells to grow metastases. Next, strategies to interrupt these “communications” will be tested to identify what targets are essential for the metastatic cancer growth. Moreover, to strengthen the clinical translational potential of the findings generated, nanoparticles specifically targeting the cross-talk between neutrophils and macrophages will be generated and tested. Overall, this study will discover new therapeutic strategies to prevent or treat metastasis.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS