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. |