Metastasis has long been understood to lead to the overwhelming majority of cancer-related deaths. However, our understanding of the metastatic process, and thus our ability to prevent or eliminate metastases, remains frustratingly limited. This is largely due to the complexity of metastasis, which is a multistep process that likely differs across cancer types and is greatly influenced by many aspects of the in vivo microenvironment. In this Review, we discuss the key variables to consider when designing assays to study metastasis: which source of metastatic cancer cells to use and where to introduce them into mice to address different questions of metastasis biology. We also examine methods that are being used to interrogate specific steps of the metastatic cascade in mouse models, as well as emerging techniques that may shed new light on previously inscrutable aspects of metastasis. Finally, we explore approaches for developing and using anti-metastatic therapies, and how mouse models can be used to test them.
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The authors apologize to those whose excellent work could not be highlighted owing to space limitations. The authors thank N.E. Reticker-Flynn and members of the Winslow laboratory for helpful comments. J.D.H. was supported by an American Cancer Society postdoctoral fellowship (PF-21-112-01-MM) and a Tobacco-Related Disease Research Program (TRDRP) fellowship (T31FT1619). J.D.H. and M.M.W. were supported by National Institutes of Health (NIH) R01-CA234349, NIH R01-CA230919 and a grant from the Cancer League.
J.W.N. has received research support from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GSK, Janssen and AbbVie; has served in a consulting or advisory role for AstraZeneca, Genentech/Roche, Exelixis, Jounce Therapeutics, Takeda Pharmaceuticals, Eli Lilly and Company, Calithera Biosciences, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi/Regeneron, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, Gilead Sciences and AbbVie; and has received honoraria from CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME, MJH Life Sciences CME, Medical Educator Consortium and HMP Education. M.M.W. is a co-founder of and holds equity in D2G Oncology. J.D.H. declares no competing interests.
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Tissues or cells shared between non-genetically identical members of the same species, as in transplantation of mouse cell lines into mice of a different strain.
A type of programmed cell death induced by lack of attachment to the extracellular matrix (ECM).
- Autochthonous models
Models in which cancer arises de novo in its natural site from normal, transformed cells, rather than through transplantation of already cancerous cells.
- Experimental metastases
The process of metastatic colonization in animal models in which cancer cells are injected into circulation.
The exit of cancer cells from the vasculature into the surrounding tissue.
An iron-dependent type of programmed cell death characterized by build-up of reactive oxygen species.
- Intralymphatic microinfusion
The injection of cells into afferent lymph vessels to transplant them into a lymph node.
The entry of cancer cells into the vasculature.
- Karyotypic abnormalities
Cells, tissues or individuals possessing an unusual number of chromosomes, either through the gain or loss of individual chromosomes (aneuploidy) or the gain of entire sets of chromosomes (whole genome duplication).
Sizeable metastatic tumours that can be detected by imaging.
Very small metastatic tumours that are difficult to detect by imaging.
- Spontaneous metastasis
Metastasis of cancer cells that disseminate from an existing primary tumour.
Cells, tissues or individuals that are genetically identical and compatible for transplantation without immune rejection.
- Tumour mutational burden
(TMB). A metric of the overall number of mutations present in a tumour.
Tissue or cells that are from different species, such as the transplantation of human cells into mice.
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Hebert, J.D., Neal, J.W. & Winslow, M.M. Dissecting metastasis using preclinical models and methods. Nat Rev Cancer 23, 391–407 (2023). https://doi.org/10.1038/s41568-023-00568-4