Dissecting fundamental mechanisms underlying cancer metastasis

More than 90% of cancer-related deaths are due to the development of a metastatic disease (WHO). Worldwide, cancer metastasis accounts for more than 7 million deaths each year, and little is known about how to suppress metastasis in patients.

Our laboratory is interested in understanding the molecular mechanisms that drive the development and maintenance of cancer metastasis, with a particular focus on the analysis of circulating tumor cells. In our studies, we use a combination of microfluidics technologies, patient samples, in vivo models, next-generation sequencing, molecular and computational biology to study how cancer spreads. We strive to identify metastasis-specific therapeutic targets to enable the development of new therapies that will suppress this disease.

How does cancer spread?

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). While CTCs are extraordinarily rare in patients with cancer (approximately one CTC per billion normal blood cells), they hold the key to dissecting fundamental aspects of how metastasis occurs. Recently, we understood that CTC-clusters, i.e. cancer cell aggregates in circulation held together by interepithelial cell-cell junctions, are precursors of breast cancer metastasis (Aceto et al., Cell, 2014) (see Figure 1).

More generally, cancer cells that leave the primary tumor site and enter the bloodstream tend to undergo anoikis. It is in this context that either mesenchymal transformation, stromal-derived factors, or persistent interepithelial cell junctions may provide key survival signals that facilitate metastasis (Aceto et al., Trends in Cancer, 2015) (see Figure 2).

Recently, CTC-clusters isolated with a newly developed and specialized bifurcating trap have been found in patients with metastatic breast or prostate cancer or melanoma (Sarioglu and Aceto et al., Nature Methods, 2014). Further characterization of these metastatic precursors from patients with various cancer types will be needed to gain fundamental insights into the metastatic process.

Fig1. CTC-clusters, held together by the cell-cell junction component plakoglobin, are precursors of breast cancer metastasis. See Bottos and Hynes, Nature 2014 – a commentary on Aceto et al., Cell 2014

Figure 1. CTC-clusters, held together by the cell-cell junction component plakoglobin, are precursors of breast cancer metastasis. See Bottos and Hynes, Nature 2014 – a commentary on Aceto et al., Cell 2014

Cancer cells in circulation adopt clustering, interaction with stromal cells and expression of mesenchymal-like genes to enhance their metastatic potential. See Aceto et al., Trends in Cancer 2015

Figure 2. Cancer cells in circulation adopt clustering, interaction with stromal cells and expression of mesenchymal-like genes to enhance their metastatic potential. See Aceto et al., Trends in Cancer 2015

What can we learn from circulating tumor cells?

CTCs are isolated with microfluidics technologies from the peripheral blood of patients with cancer. We believe that CTC analysis is not only an exceptional opportunity to define the characteristics and vulnerabilities of metastatic precursors, but it also represents a non-invasive source to study:

  • the involvement of specific cell-cell junction components in the formation of CTC-clusters
  • the molecular determinants of organ-specific metastasis
  • the evolving mutational profile of metastatic cancers during the course of treatment and disease progression.

For example, molecular analysis of human CTC-clusters has revealed that these metastatic precursors rely upon the expression of specific cell-cell junction components such as plakoglobin (Aceto et al., Cell, 2014). Expression of several other cell-cell junction markers is also evident in human CTC-clusters (see Figure 3).

We believe that targeting cell-cell junctions may represent a potent and previously under appreciated strategy to suppress CTC-clustering and cancer metastasis.

Additionally, human CTCs from patients with metastatic breast cancer have been first isolated, and then propagated ex vivo using specific culture conditions. Genome sequencing of those CTC-derived cell lines revealed patient-specific mutations, and along with ex vivo drug screening, this approach helped to identify the best therapy for individual cancer patients over the course of their metastatic disease (Yu, Bardia, Aceto et al., Science, 2014).

Figure 3. Human CTC-clusters expressing cytokeratin (CK), and the cell-cell junction components desmoplakin and E-Cadherin. See Aceto et al., Cell 2014

Figure 3. Human CTC-clusters expressing cytokeratin (CK), and the cell-cell junction components desmoplakin and E-Cadherin. See Aceto et al., Cell 2014

Where does our research lead us?

All together, we use a highly multidisciplinary approach to define the molecular features of cancer metastasis. We aim to describe those key networks that influence the development and maintenance of a metastatic disease, and learn about the biology that underlies CTC generation, the formation of CTC-clusters, and organ-specific metastasis in several cancer types.

In the longer run, our research aims to enable the development of metastasis-tailored therapies to improve the clinical management of patients who suffer from cancer metastasis.

Our research is supported by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, the Swiss Cancer League Basel (Krebsliga Beider Basel), the ETH Zürich personalised medicine initiative, and the University of Basel.