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

Projektbeschreibung

Rolle von Neutrophilen bei der Knochenmetastasierung

Solide Tumormetastasen treten häufig im Knochen auf. Drei Viertel der Patientinnen mit Brustkrebs im Spätstadium haben Rezidive im Knochen – und die einzige Behandlungsoption ist bisher Palliativmedizin. Pilotforschung deutete darauf hin, dass Neutrophile tumorunterstützende Funktionen haben. Das EU-finanzierte Projekt ProMetNeu wollte nachweisen, dass Neutrophile pro-tumorigene Phänotypen erwerben, wenn sie sich in der Nähe von Krebszellen befinden, und das Fortschreiten von Metastasen unterstützen, indem sie die Tumornische regulieren. Das Projekt wird die tumorfördernde Rolle von Neutrophilen unter Verwendung von RNS-Sequenzierung sowie kombinierter MALDI-MSI- und Antikörper-basierter Bildgebung bewerten. Um neue Wege zur Hemmung von Knochenmetastasen zu finden, verwendete das Projekt Modelle von extrazellulären Fallen für Neutrophile, ohne die kritischen Funktionen der Neutrophilen bei Entzündungen zu beeinträchtigen.

Ziel

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.