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.

Figure 1 |. Simple model organisms can be used to investigate aspects of tumour invasion and metastasis.

Metastasis is a multistep process during which tumour cells breach tissue borders (1); migrate in sheets, strands, streams and clusters (2); cross into and out of blood vessels (3) and form colonies at distant sites (4). Immune cells and endothelial cells in the tumour microenvironment also migrate, either increasing or inhibiting tumour growth and spread. Simple organisms provide models for individual steps or features of this complex process and have been successfully used to contribute key concepts and mechanistic insights to the field of cancer research.

Figure 2 |. Regulation of chemoattraction in Dictyostelium discoideum.

A schematic demonstrating how chemotactic signals give rise to cell polarization — a prerequisite for cell migration — is presented. Following G protein-coupled receptor (GPCR) activation, PI3K and PTEN become spatially restricted to the front and back of Dictyostelium discoideum cells, respectively, giving rise to localized phosphatidylinositol-3,4,5-trisphosphate (PIP₃) and the recruitment of pleckstrin homology (PH) domain-containing proteins at the front of cells. Together with PIP₃-independent pathways, these events lead to polarized signals in which actin assembly occurs at the front and myosin phosphorylation (PO₄–myosin II) occurs at the back of cells. F-actin, filamentous actin; PIP₂, phosphatidylinositol-4,5-bisphosphate.

Figure 3 |. Caenorhabditis elegans anchor cell invasion.

a | During third larval instar development, the anchor cell breaches two basement membranes that separate this uterine cell from vulval cells, eventually connecting the uterus to the vulva. b | The molecular and cellular biological steps in anchor cell invasion begin in the nucleus, where activation of the transcription factor FOS-1A stimulates expression of many downstream target genes involved in the indicated processes, including the transcription factor egl-43 (orthologue of the EVI1 proto-oncogene), the protocadherin cdh-3, the extracellular matrix (ECM) protein him-4 (orthologue of hemicentin genes) and zmp-1 (orthologue of the matrix metalloproteinase (MMP) genes), suggesting a highly conserved programme for basement membrane invasion. DCC, deleted in colorectal carcinoma; F-actin, filamentous actin.

Figure 4 |. Border cell migration in Drosophila melanogaster.

A schematic drawing of a stage 9 egg chamber (upper left) showing the germline cells (nurse cells and oocyte) surrounded by the epithelial layer of follicle cells is presented (part a). The border cells squeeze between the nurse cells as they migrate towards the oocyte. The enlarged view of the migrating cluster shows two non-migratory polar cells, which secrete the cytokine Unpaired 1 (Upd1) to activate Jak–signal transducer and activator of transcription (Stat) signalling and motility in five neighbouring migratory border cells. Secreted platelet-derived growth factor (PDGF)- and vascular endothelial growth factor (VEGF)-related factor 1 (Pvf1) from the germ line activates PDGF- and VEGF-receptor-related (Pvr), while Spitz (Spi), Keren (Krn) and Gurken (Grk) activate epidermal growth factor receptor (Egfr). The receptor tyrosine kinases (RTKs) then activate Rac, which stimulates act in polymerization and protrusion. The border cells migrate in between nurse cells in the absence of detectable extracellular matrix (ECM) and thus use homophilic E-cadherin-mediated adhesion for tract ion on the nurse cells as well as for mechanical coupling between all cells of the cluster. Confocal images of border cell clusters (parts b and d) and breast cancer (parts c and e) that show similarities in forming clusters (parts b and c) and in heterotypic composition (parts d and e) are presented. F-actin, filamentous actin; GEF, guanine nucleotide exchange factor. Part c is reproduced with permission from REF. , Proceedings of the National Academy of Sciences. Part e is reproduced with permission from REF , Elsevier. Parts b and d are the authors’ own images.

Figure 5 |. Jnk pathway signalling is a key part of metastatic spread in Drosophila melanogaster.

Metastasis models in Drosophila melanogaster have revealed that a variety of stresses activate the Jun N-terminal kinase (Jnk) pathway, which at high levels of signalling can lead to apoptosis. Alternatively, at lower levels or in the presence of oncogenic Ras, the Jnk pathway leads to autonomous and non-autonomous proliferation, expression of matrix metalloproteinases (MMPs), loss of E-cadherin and increased motility. Thus, the Jnk pathway is central to metastatic spread in the fly and likely also in human cancer. BMP, bone morphogenetic protein; Dpp, decapentaplegic; Hid, Head involution defective; Jak, Janus kinase; Jnkk, Jnk kinase; Jnkkk, Jnkk kinase; pJun, phosphorylated Jun; ROS, reactive oxygen species; Rpr, Reaper; RTK, receptor tyrosine kinase; Stat, signal transducer and activator of transcription; TNF, tumour necrosis factor; Upd, unpaired; Wg, Wingless; Yap1, Yes-associated protein 1; Zfh2, zinc-finger homeodomain 2.