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Discovery of fundamental mechanisms underlying the development of cancer metastasis

Applicant Aceto Nicola
Number 163938
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 01.04.2016 - 31.03.2020
Approved amount 1'590'404.00
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Keywords (10)

Breast Cancer; Cell-cell junctions; Circulating tutor cell clusters; Single cell analysis; Metastasis-tailored therapy; Breast Cancer Tropism; Metastasis; RNA-sequencing; Circulating tumor cells; Microfluidics

Lay Summary (Italian)

Lead
Scoperta dei meccanismi chiave nello sviluppo di metastasi in pazienti affetti da cancro
Lay summary

Più del 90% delle morti causate dal cancro sono da attribuirsi allo sviluppo di metastasi. Questi numeri riflettono il fatto che I meccanismi molecolari responsabili dello sviluppo di metastasi in pazienti con il cancro sono poco chiari, e nuovi esperimenti sono necessari per comprendere a fondo gli eventi alla base di questa patologia.

Cellule che si distaccano da un tumore primario ed entrano nella circolazione sanguigna sono chiamate “circulating tumor cells” (CTCs). Una volta entrate in circolazione, CTCs possono raggiungere organi secondari, dando luogo a metastasi. Lo studio di CTCs può facilitare la compresione degli eventi che caratterizzano la progressione metastatica, e facilitare lo sviluppo di nuovi farmaci per prevenire o sopprimere lo sviluppo di metastasi. Recentemente, abbiamo scoperto che aggregati di cellule di cancro nel sangue (CTC-clusters) agiscono come precursori di metastasi in pazienti con cancro al seno. L’analisi molecolare di questi CTC-clusters ci ha permesso di capire che alcune proteine che compongono le giunzioni cellulari tra cellule cancerogene sono responsabili del mantenimento della struttura multicellulare dei CTC-clusters (Aceto et al., Cell, 2014). Analisi di CTCs ci ha anche permesso di individuare geni potenzialmente responsabili dello sviluppo di metastasi ossee in pazienti con cancro al seno. Sia il ruolo delle giunzioni cellulari nei CTC-clusters, che il ruolo dei geni specifici alle metastasi ossee deve essere investigato, e può rivelare nuove opportunità per sviluppare una terapia contro I tumori metastatici.

In questo progetto, I nostri obiettivi sono:

(1) Definire il ruolo delle giunzioni cellulari in cellule tumorali durante lo sviluppo di metastasi

(2) Caratterizzare gli effetti di geni specifici sullo sviluppo di metastasi ossee

I risultati della nostra ricerca ambiscono a generare una nuova classe di bersagli farmacologici per sopprimere la formazione di CTC-clusters e metastasi in pazienti affetti da cancro. 

Direct link to Lay Summary Last update: 05.04.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Neutrophils escort circulating tumour cells to enable cell cycle progression
Szczerba Barbara Maria, Castro-Giner Francesc, Vetter Marcus, Krol Ilona, Gkountela Sofia, Landin Julia, Scheidmann Manuel C., Donato Cinzia, Scherrer Ramona, Singer Jochen, Beisel Christian, Kurzeder Christian, Heinzelmann-Schwarz Viola, Rochlitz Christoph, Weber Walter Paul, Beerenwinkel Niko, Aceto Nicola (2019), Neutrophils escort circulating tumour cells to enable cell cycle progression, in Nature, 566(7745), 553-557.
Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding
Gkountela Sofia, Castro-Giner Francesc, Szczerba Barbara Maria, Vetter Marcus, Landin Julia, Scherrer Ramona, Krol Ilona, Scheidmann Manuel C., Beisel Christian, Stirnimann Christian U., Kurzeder Christian, Heinzelmann-Schwarz Viola, Rochlitz Christoph, Weber Walter Paul, Aceto Nicola (2019), Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding, in Cell, 176(1-2), 98-112.e14.
Denosumab treatment is associated with the absence of circulating tumor cells in patients with breast cancer
Vetter Marcus, Landin Julia, Szczerba Barbara Maria, Castro-Giner Francesc, Gkountela Sofia, Donato Cinzia, Krol Ilona, Scherrer Ramona, Balmelli Catharina, Malinovska Alexandra, Zippelius Alfred, Kurzeder Christian, Heinzelmann-Schwarz Viola, Weber Walter Paul, Rochlitz Christoph, Aceto Nicola (2018), Denosumab treatment is associated with the absence of circulating tumor cells in patients with breast cancer, in Breast Cancer Research, 20(1), 141-141.
Detection of circulating tumour cell clusters in human glioblastoma
Krol Ilona, Castro-Giner Francesc, Maurer Martina, Gkountela Sofia, Szczerba Barbara Maria, Scherrer Ramona, Coleman Niamh, Carreira Suzanne, Bachmann Felix, Anderson Stephanie, Engelhardt Marc, Lane Heidi, Evans Thomas Ronald Jeffry, Plummer Ruth, Kristeleit Rebecca, Lopez Juanita, Aceto Nicola (2018), Detection of circulating tumour cell clusters in human glioblastoma, in British Journal of Cancer, 119(4), 487-491.
Cancer Diagnosis Using a Liquid Biopsy: Challenges and Expectations
Castro-Giner Francesc, Gkountela Sofia, Donato Cinzia, Alborelli Ilaria, Quagliata Luca, Ng Charlotte, Piscuoglio Salvatore, Aceto Nicola (2018), Cancer Diagnosis Using a Liquid Biopsy: Challenges and Expectations, in Diagnostics, 8(2), 31-31.

Associated projects

Number Title Start Funding scheme
170809 Super Resolution and Endoscopic Two Photon Microscopy - Imaging of Cell Migration in Inflammation, Metastasis and Regeneration 01.01.2017 R'EQUIP
190077 Discovery of fundamental mechanisms underlying the development of cancer metastasis 01.04.2020 SNSF Professorships
148361 Clusters of circulating tumor cell as critical mediators of breast cancer metastasis 01.09.2013 Advanced Postdoc.Mobility

Abstract

Each year, breast cancer is diagnosed in more than one million women, and as many as 500’000 lives are lost to this disease worldwide. Patients with breast cancer die unequivocally because of the development of incurable distant metastases and not because of symptoms related to the primary site. Understanding the complex, yet fundamental mechanisms driving breast cancer metastasis is hence critical to develop therapies tailored for this disease.Cancer cells that leave the primary tumor site and are transported through the circulation to distant organs are referred to as circulating tumor cells (CTCs), and they hold the key to understanding the biology of blood-borne metastasis. CTCs are extraordinarily rare in patients with cancer (approximately one CTC per billion normal blood cells), and their isolation is greatly dependent upon technological constraints. However, recent breakthrough advances in microfluidics technology have made it possible for the first time to analyze human CTCs with great precision, revealing unexpected features. For instance, our recent findings showed that CTC-clusters, held together by interepithelial cell-cell junctions, are precursors of breast cancer metastasis (Aceto et al., Cell, 2014). This represents a previously unappreciated and potentially targetable mechanism of cancer dissemination. Further, our preliminary data obtained with single cell resolution RNA sequencing of CTCs from breast cancer patients with bone metastasis, highlighted the expression of specific candidate genes that could explain breast cancer tropism to the bone as a primary metastatic site.Altogether, our observations lead to two major goals. First, we aim to identify and target those cell-cell junction components required for CTC-clustering and metastasis. Second, we aim to apply single cell resolution analysis of human CTCs to dissect major signals driving breast cancer to specific metastatic sites (i.e. bone, lung and brain). Our research has the long-term ambition to identify major drivers of breast cancer metastasis and enable the development of metastasis-tailored therapies for patients with cancer.
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