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The Role of Plakoglobin in Signal Transduction and Cell Fate of Metastatic Cancer Cells
Third-party funded project
Project title The Role of Plakoglobin in Signal Transduction and Cell Fate of Metastatic Cancer Cells
Principal Investigator(s) Aceto, Nicola
Project Members Gkountela, Sofia
Organisation / Research unit Departement Biomedizin / Cancer Metastasis (Aceto)
Project start 01.11.2015
Probable end 31.03.2016
Status Completed
Abstract

Breast cancer is the most common cancer in women, resulting in as many as 500,000 deaths per year

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 signaling pathways influencing metastasis is critical to develop therapies tailored to this

disease.

The current understanding of how metastasis occurs is derived primarily from mouse models and

largely dominated by the notion that single migratory cancer cells within the primary tumor can actively

disseminate to distant sites and develop as metastatic deposits. Unexpectedly, our very recent study on

patient blood samples has shown instead that cancer cell groupings, a.k.a. circulating tumor cell

(CTC)-clusters, held together through plakoglobin-dependent intercellular junctions, can break off

the primary tumor and form a metastatic lesion up to 50 times more efficiently than single migratory

cancer cells (Aceto et al., Cell, 2014). These findings lead to new open questions, yet highlight a

previously unappreciated and targetable mechanism of cancer dissemination. While targeting

plakoglobin is a challenge given its lack of extracellular or catalytic domains, the understanding of the

signaling networks regulated by plakoglobin (and more broadly, by cell-cell junctions) in metastatic cells

has the potential to reveal key vulnerabilities. Currently, the role of plakoglobin in cellular signaling and

cell fate is unknown, and no therapies are available to target CTC-clusters.

Our preliminary results suggest that neoplastic cells are more sensitive than normal cells to

plakoglobin knockdown, highlighting an exciting therapeutic window. Further, we developed first-of-akind

human CTC-derived models of breast cancer metastasis that position us exclusively to study

relevant signaling networks of rare metastatic cells. Altogether, we aim to a) define the effects of

plakoglobin-dependent cancer cell clustering on signaling and cell fate, and b) identify targetable

signaling nodes downstream of plakoglobin. Our research has the long-term ambition to lead to a novel

class of therapeutic agents tailored to target CTC-clusters and prevent the metastatic spread of cancer.

Keywords plakoglobin, circulating tumor cells, metastasis
Financed by Swiss National Science Foundation (SNSF)
   

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