Dissecting the biology of metastasis

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

Our laboratory is interested in understanding the molecular mechanisms that drive cancer and its metastatic progression, with a particular focus on the analysis of circulating tumor cells. In our studies, we use a combination of molecular biology, next-generation sequencing, computational biology, microfluidic and robotic technologies, patient samples, in vivo models, genetic engineering, CRISPR screens and drug screens to better understand the biology and vulnerabilities of aggressive cancers. We collaborate very actively with a number of academic research groups, hospitals, and healthcare companies throughout the world. We strive to identify novel metastasis-relevant therapeutic opportunities to fight against the metastatic spread of cancer.

Fig.1 Cover story in Cell: artistic coloration of a CTC cluster isolated form a breast cancer patient and imaged with electron microscopy. Source: Gkountela et al., Cell, 2019

Fig.1 Cover story in Cell: artistic coloration of a CTC cluster isolated form a breast cancer patient and imaged with electron microscopy. Source: Gkountela et al., Cell, 2019

Circulating tumor cells and their clusters

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 the peripheral circulation of patients with cancer (approximately one CTC per billion normal blood cells), they hold the key to dissecting fundamental aspects of how metastasis occurs. We isolate CTC from the blood of cancer patients with the use of specialized microfluidic technologies, and interrogate them at the molecular and functional level to uncover their fundamental biological properties and vulnerabilities.

For example, we recently discovered a major role for CTC clusters (aggregates of cancer cells in circulation) in the metastatic process in breast cancer. We also found that CTC clusters are derivatives of hypoxic tumor areas and are characterized by hypomethylation of the binding sites for transcription factors that simultaneously regulate stemness and proliferation, such as OCT4, NANOG, SOX2 and SIN3A. Our results clearly link clustering and stemness features, and suggest that CTC cluster dissociation might be a valuable therapeutic strategy to reduce metastasis formation (Aceto et al., Cell, 2014; Gkountela et al, Cell, 2019; Donato et al., Cell Rep, 2020) (Fig. 1).

We also discovered a new role for neutrophils in boosting the metastatic potential of CTCs. Particularly, we find that the association CTC-neutrophils enhances CTC proliferation through the release of specific cytokines. When this crosstalk is blocked, we observe a significant reduction in the metastatic spread of breast cancer cells (Szczerba et al., Nature, 2019).

Together, our recent investigations on CTCs allowed us to better understand some of the key properties of the metastatic process, including the formation of homotypic and heterotypic CTC clusters, as well as some of their driving principles (Fig. 2).

 

Fig.2 CTC clusters and CTC-neutrophil clusters depart from the primary tumor, on their way to metastasis. Source: Saini, Szczerba and Aceto, Cancer Res, 2019

Fig.2 CTC clusters and CTC-neutrophil clusters depart from the primary tumor, on their way to metastasis. Source: Saini, Szczerba and Aceto, Cancer Res, 2019

Research funding

Our research is generously supported by the ETH Zurich and by funding agencies such as the European Research Council, the Swiss National Science Foundation, the Future and Emerging Technology grant scheme of the European Commission, and the Swiss Cancer League.