Cell motility in cancer invasion and metastasis: insights from simple model organisms

Abstract

Metastasis remains the greatest challenge in the clinical management of cancer. Cell motility is a fundamental and ancient cellular behaviour that contributes to metastasis and is conserved in simple organisms. In this Review, we evaluate insights relevant to human cancer that are derived from the study of cell motility in non-mammalian model organisms. Dictyostelium discoideum, Caenorhabditis elegans, Drosophila melanogaster and Danio rerio permit direct observation of cells moving in complex native environments and lend themselves to large-scale genetic and pharmacological screening. We highlight insights derived from each of these organisms, including the detailed signalling network that governs chemotaxis towards chemokines; a novel mechanism of basement membrane invasion; the positive role of E-cadherin in collective direction-sensing; the identification and optimization of kinase inhibitors for metastatic thyroid cancer on the basis of work in flies; and the value of zebrafish for live imaging, especially of vascular remodelling and interactions between tumour cells and host tissues. While the motility of tumour cells and certain host cells promotes metastatic spread, the motility of tumour-reactive T cells likely increases their antitumour effects. Therefore, it is important to elucidate the mechanisms underlying all types of cell motility, with the ultimate goal of identifying combination therapies that will increase the motility of beneficial cells and block the spread of harmful cells.

Neuronal calcium sensor 1 (NCS1) promotes motility and metastatic spread of breast cancer cells in vitro and in vivo

“…Large cellular protrusions were seen exclusively in the NCS1-OE context (Supplemental Fig. S4), suggesting that this newly acquired phenotype predicts the functional consequences of cellular motility, metastatic behavior, and survival (46,47).…”

The histone acetyltransferase hMOF promotes vascular invasion in hepatocellular carcinoma

“…Zebrafish embryos are particularly suitable for in vivo, high‐resolution single‐cell imaging as they are transparent and develop outside the mother. Indeed, this model has been widely applied to study the mechanisms involved in the metastatic multistep process, from intravasation to extravasation and formation of metastasis . In a xenograft model of Zebrafish embryos, we were able to demonstrate that downregulation of hMOF in HLF cell line significantly reduced the number of tumour cells in the CHT (ie metastasis), suggesting that tumour cell intravasation was impaired.…”

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

“…Drosophila border cells represent a genetically tractable model of collective cell migration within an intact tissue. Many genes known to regulate border cell migration are highly conserved in humans and have been implicated in cancer 31,39,40 .…”

“…The border cell cluster migrates during oogenesis in two phases, both of which respond to specific ligands secreted by the oocyte: in the posterior phase, border cells undergo a long-range movement from the anterior end of the egg chamber to the oocyte at the posterior; in the dorsal phase, the cells undergo short-range migration along the oocyte towards the dorsal-anterior side of the egg chamber 29,30 . The ability to genetically manipulate and observe border cell migration in its native tissue environment in real time makes it a powerful tool for identifying conserved regulators of collective invasion in development and in cancer 29,31,32 . Moreover, the use of the Drosophila system has also recently been leveraged for studies to identify conserved molecular mechanisms that drive GBM cell proliferation, survival, and self-renewal 33,34,35,36,37 .…”