ProMetNeu — Dissecting the neutrophil-cancer cell interactome in the metastatic bone niche

Results in brief

Dissecting the neutrophil-cancer cell interactome in the metastatic bone niche

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.

Data: CORDIS, © European Union

Project objective

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. Inflammation is an important player in cancer. My pilot data show that depletion of a specific immune cell type, neutrophils, impairs bone metastasis in vivo, suggesting that neutrophils have tumour-supporting functions. However, the role of neutrophils in the metastatic bone niche remains largely unexplored, it is unknown whether they contribute to the seeding or the expansion phase of bone metastasis and if tumour cells regulate neutrophil plasticity, therefore skewing the balance towards pro-tumourigenic neutrophil subsets. I hypothesise that neutrophils acquire pro-tumourigenic phenotypes when in close proximity to cancer cells and support metastatic progression by regulating the tumour niche. By using a liposoluble fluorescent protein expressed by cancer cells, neighbouring neutrophils will be characterised: Neutrophil subsets will be identified by spectral cytometry, their transcriptomic signature analysed using RNA sequencing and their pro-tumourigenic role functionally assessed in vitro and in vivo. By employing a combination of MALDI-MSI and multiplex antibody-based imaging, neutrophil-cancer cell interactome will be established in order to identify candidate molecular mechanisms regulating neutrophil pro-tumourigenic functions. By using in vivo models of neutrophil extracellular traps (NETs) blockade, neutropenia, neutrophilia and enhanced neutrophil retention in the bone marrow, neutrophil candidate mechanisms shaping the metastatic niche will be determined. Dissecting the molecular mechanisms regulating pro-tumourigenic neutrophil subsets is fundamental to identify novel means of inhibiting bone metastasis without affecting neutrophil critical functions in inflammation.

Original text from CORDIS.

Participants

UNIVERSITAET MUENSTER · MuensterCoordinatorGermany

ProMetNeu · Dissecting the neutrophil-cancer cell interactome in the metastatic bone niche

Results in brief

Dissecting the neutrophil-cancer cell interactome in the metastatic bone niche

Project objective

Participants

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