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Discovery of fundamental mechanisms underlying the development of cancer metastasis

Applicant Aceto Nicola
Number 190077
Funding scheme SNSF Professorships
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Experimental Cancer Research
Start/End 01.04.2020 - 31.03.2022
Approved amount 608'226.00
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Keywords (4)

Circulating tumor cells; Metastasis; Tropism; Breast cancer

Lay Summary (Italian)

Lead
Studio dei meccanismi fondamentali per lo sviluppo di metastasi
Lay summary

La formazione di metastasi è la principale causa di morte per pazienti perdono la loro battaglia contro il cancro. Ciò evidenzia la necessità di comprendere meglio la biologia del processo metastatico e di identificare nuovi agenti che sopprimono la formazione di metastasi. Le cellule tumorali che si distaccano dal tumore primario ed entrano nel flusso sanguigno sono chiamate cellule tumorali circolanti (CTC). Si trovano sotto forma di singole cellule o aggregati (CTC cluster), con proprietà fisiche e biologiche distinte. Le CTC sono considerate precursori delle metastasi in vari tipi di cancro e la loro caratterizzazione è chiave per ottenere informazioni sulla loro biologia. Ad esempio, dati recenti del nostro laboratorio hanno dimostrato che la dissociazione dei CTC cluster riduce drasticamente la formazione di metastasi in modelli animali (Gkountela et al., Cell, 2019). Inoltre, abbiamo scoperto che l'interazione tra le CTC e i neutrofili aumenta la proliferazione delle CTC, rendendo gli aggregati CTC-neutrofili estremamente metastatici (Szczerba et al., Nature, 2019). Complessivamente, i nostri dati recenti indicano i CTC cluster e gli aggregati CTC-neutrofili come principali mediatori delle metastasi nel cancro al seno. Nel progetto qui descritto, applicheremo nuove tecniche di analisi su CTC da pazienti per studiare i meccanismi chiave che guidano la metastatizzazione in diversi organi. Questo progetto è attualmente in corso, rappresenta il focus principale della nostra ricerca attuale e sarà organizzato in due obiettivi principali. In primo luogo, completeremo l'analisi dei dati per tutte le CTC dei pazienti con cancro al seno finora isolate. In secondo luogo, convalideremo il ruolo di geni candidati per metastasi utilizzando la tecnologia CRISPR, già consolidata nel nostro laboratorio. Nel suo insieme, questo progetto mira a comprendere i meccanismi molecolari fondamentali che guidano la formazione di metastasi in vari organi in pazienti con cancro al seno, nonché a valutare nuove strade che possono essere sfruttate per la generazione di farmaci contro le metastasi.

Direct link to Lay Summary Last update: 30.10.2019

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
163938 Discovery of fundamental mechanisms underlying the development of cancer metastasis 01.04.2016 SNSF Professorships

Abstract

Metastasis formation is the leading cause of cancer-related death. Patients with metastatic disease are considered incurable, highlighting the need to better understand the biology of the metastatic process and to identify new metastasis-suppressing agents.Cancer cells that leave the primary tumor and enter the bloodstream are referred to as circulating tumor cells (CTCs). They are found in the form of single CTCs or small CTC aggregates (CTC clusters), featuring distinct physical and biological properties. CTCs are considered to be precursors of metastasis in various cancer types, and their isolation and characterization is key to gain insights into their biology and vulnerabilities. Latest advances in microfluidic technologies and single cell-resolution sequencing techniques have allowed CTC interrogation, highlighting important features. For example, recent data from our laboratory has demonstrated that CTC clusters feature a distinct DNA methylation pattern as compared to single CTCs, and that dissociation of CTC clusters dramatically reduces metastasis formation in animal models (Gkountela et al., Cell, 2019). Further, we identified a new type of CTCs, i.e. those traveling in association to neutrophils. The interaction between CTCs and neutrophils, mediated by specific cell-cell junction components such as VCAM-1, boosts CTC proliferation, making CTC-neutrophil clusters the most metastasis-competent CTC subtype (Szczerba et al., Nature, 2019). Together, our recent data points to CTC clusters and CTC-neutrophil clusters as the main mediators of metastasis in breast cancer, and pinpoints specific cell-cell junction components whose inhibition reduces metastasis formation. These findings are fully aligned with the first aim of my 4-year SNF Professorship grant, which has been achieved in full.The second aim of the 4-year SNF Professorship grant was to apply single cell resolution RNA sequencing to CTCs of breast cancer patients to investigate key determinants of breast cancer metastatic tropism to different metastatic sites. This aim is currently ongoing, it represents the major focus of our current research and it will be organized into two major goals. First, we will complete RNA sequencing and data analysis for all CTCs of breast cancer patients isolated so far (more than 200 patients), aiming to identify genes that are upregulated in CTCs that derive from specific metastatic sites. Second, we will validate the requirement of these candidate genes for organ-specific metastasis using the CRISPR technology, already well-established in our laboratory. Together, this project aims at understanding fundamental signaling networks that drive metastatic tropism in breast cancer, as well as new vulnerabilities of metastatic breast cancer cells that can be exploited for the generation of anti-metastasis agents.
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