Periodic Reporting for period 1 - ProMetNeu (Dissecting the neutrophil-cancer cell interactome in the metastatic bone niche)
Okres sprawozdawczy: 2023-07-01 do 2025-06-30
Bone is one of the most common organs for solid tumour metastasis. 75% of patients with late-stage breast cancer develop recurrence in bone. Current treatments are palliative, leaving this condition incurable, with an unmet need to identify new therapies. The bone microenvironment acts as a reservoir of disseminated tumour cells, supporting their dormant state. Tumour cell awakening from dormancy it is likely to occur following perturbations of the niche and can take place even years after diagnosis and treatment of the primary tumour. In bone, the bone marrow is site of neutrophil production. Neutrophils are the most abundant leukocytes circulating in human blood and important first-responders during inflammation and infection. In cancer, neutrophil pro- and anti-tumour functions have been described, with recent reports favoring tumour-supportive roles. Nevertheless, in the bone (marrow) metastatic niche, where, paradoxically, tumour cells infiltrate the neutrophil niche, the role of neutrophils remains unexplored. Using spectral cytometry and multiplexed-antibody imaging in a combination of in vivo models of cancer and neutrophil biology, we have interrogated the importance of neutrophil-tumour cell interaction in the preparation of the bone marrow niche for the initiation and progression of metastatic outgrowth.
In this project, we found that neutrophils are rare encounters within bone metastases. Nevertheless, depletion methods have shown that neutrophils are required for the establishment of bone metastasis. Neutrophil impairment in in vivo models is a powerful approach to define causality between neutrophils and bone metastasis, however, therapeutic depletion of neutrophils is not feasible due to their essential functions in curbing infections. Therefore, we have been blocking core mechanisms of neutrophil biology to tease out neutrophil means of advancing bone metastasis. Our work so far has revealed an important part played by the developing metastasis itself on neutrophil regulation. In particular, by co-registering multiplexed antibody based imaging with other spatial technologies, we are dissecting the cellular and molecular landscape of the bone metastatic niche. This approach will decipher the advantage of close cell-cell interaction between bone metastasis and neutrophils in the bone marrow and its consequences in the successful neutrophil-driven establishment of bone metastasis. We have also developed novel models to dissect neutrophil dynamics during bone metastasis to further unravel how bone marrow disruption by rapidly growing tumour cells impact on neutrophil functions.
The cancer burden continues to grow globally, exerting tremendous physical, emotional and financial strain on individuals, families, communities and health systems. Bone metastases associate with skeletal morbidity, spinal cord compression, hypercalcemia and can lead to radiotherapy, pathological fractures and surgery to bone. Skeletal-related events in bone metastases cause loss of mobility, decreased quality of life and increased medical costs. Identifying neutrophils as important regulators of the bone metastatic niche and, in turns, pinpointing the interplay between neutrophils and tumour cells as a central player in neutrophil biology go beyond the state-of-the-art, opening a novel perspective in our understanding of, specifically, neutrophils in bone metastasis and, generally, neutrophils in cancer.
This project has greatly strengthened the knowledge and skills of the fellow in neutrophil biology and inflammation. During the fellowship, the researcher has also established novel collaborations, embedded in the best host environment. The fellow will continue on this project and expand her work on neutrophils in cancer to ultimately establish an independent career in collaboration with her host at the University of Muenster.
This project has greatly strengthened the knowledge and skills of the fellow in neutrophil biology and inflammation. During the fellowship, the researcher has also established novel collaborations, embedded in the best host environment. The fellow will continue on this project and expand her work on neutrophils in cancer to ultimately establish an independent career in collaboration with her host at the University of Muenster.