{"entity":{"id":"metastatic-cascade","kind":"pathway","name":"The metastatic cascade","aka":[],"tldr":"How cancer spreads: cells leave the tumour, squeeze into blood or lymph vessels, survive the journey, exit into a new organ, often sleep there for years, and finally grow. Metastasis causes about 90% of cancer deaths.","summary":"Invasion (EMT, matrix proteases), intravasation, survival in circulation as CTCs or clusters (platelet cloaking, anoikis resistance), arrest and extravasation, then colonisation, which is the rate-limiting step: most disseminated tumour cells (DTCs) die or stay dormant. Organ tropism follows Paget's seed-and-soil: pre-metastatic niches are prepared by tumour-derived exosomes and myeloid cells. Clinically, ctDNA and MRD assays detect the cascade before imaging; adjuvant therapy targets it blind; no drug specifically blocks colonisation yet.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Metastasis","links":[{"label":"Massagué & Obenauf, Metastatic colonization by circulating tumour cells (Nature 2016)","url":"https://doi.org/10.1038/nature17038"},{"label":"Gerstberger, Jiang & Ganesh, Metastasis (Cell 2023)","url":"https://doi.org/10.1016/j.cell.2023.03.003"}],"tags":["mechanism"],"related":[],"cancers":[],"sections":[],"technologies":["mrd-testing","liquid-biopsy","sbrt","single-cell-spatial"],"targets":[],"drugs":[],"companies":[],"institutions":["mskcc","francis-crick","cold-spring-harbor","dkfz"],"pathways":["emt","tumor-dormancy","tumor-microenvironment","clonal-evolution"],"terms":["mrd","ctdna","oligometastatic","disseminated-tumor-cells"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-massague-nature","paper-gerstberger-cell"],"journals":[],"dependsOn":[],"notes":["Leading programmes: Massagué lab (MSK) on metastasis-initiating cells and dormancy; Swanton/TRACERx (Crick) on evolution and dissemination timing; Egeblad (CSHL) on neutrophils and dormancy awakening; DKFZ Metastasis Research.","Massagué & Ganesh, Cancer Cell 2023 review: https://doi.org/10.1016/j.ccell.2023.02.020"],"analogy":"A seed leaving a plant: it must detach, ride the wind, land somewhere with the right soil, survive the winter, and only then sprout. Almost every seed fails; the few that grow are the metastases.","nodes":[{"id":"primary","label":"Primary tumour","x":8,"y":50},{"id":"emt","label":"Invasion (EMT, MMPs)","x":22,"y":50},{"id":"intra","label":"Intravasation","x":36,"y":50},{"id":"ctc","label":"CTCs in circulation","x":50,"y":50},{"id":"extra","label":"Extravasation","x":64,"y":50},{"id":"dtc","label":"DTC dormancy","x":78,"y":35},{"id":"colon","label":"Colonisation / macrometastasis","x":92,"y":60},{"id":"niche","label":"Pre-metastatic niche (exosomes, myeloid cells)","x":64,"y":82},{"id":"immune","label":"NK / T-cell clearance","x":50,"y":18}],"edges":[{"from":"primary","to":"emt","type":"activates"},{"from":"emt","to":"intra","type":"activates"},{"from":"intra","to":"ctc","type":"activates"},{"from":"ctc","to":"extra","type":"activates"},{"from":"extra","to":"dtc","type":"activates"},{"from":"dtc","to":"colon","type":"activates"},{"from":"extra","to":"colon","type":"activates"},{"from":"primary","to":"niche","type":"activates"},{"from":"niche","to":"colon","type":"activates"},{"from":"immune","to":"ctc","type":"inhibits"},{"from":"immune","to":"dtc","type":"inhibits"}],"interventions":["Adjuvant systemic therapy and ctDNA-guided escalation aim at DTCs before colonisation","Anti-EMT and anti-MMP drugs failed historically; TGF-β blockade is being retried in combinations","Dormancy-maintaining strategies (see tumour dormancy) are the newest idea","Metastasis-directed SBRT for oligometastatic disease"]},"route":"/pathways/metastatic-cascade/","neighbours":{"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/"},{"id":"sbrt","kind":"technology","name":"SBRT / SABR (stereotactic radiotherapy)","route":"/technologies/sbrt/"},{"id":"single-cell-spatial","kind":"technology","name":"Single-cell & spatial profiling","route":"/technologies/single-cell-spatial/"}],"institution":[{"id":"cold-spring-harbor","kind":"institution","name":"Cold Spring Harbor Laboratory","route":"/institutions/cold-spring-harbor/"},{"id":"dkfz","kind":"institution","name":"German Cancer Research Center (DKFZ)","route":"/institutions/dkfz/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"},{"id":"francis-crick","kind":"institution","name":"The Francis Crick Institute","route":"/institutions/francis-crick/"}],"pathway":[{"id":"cancer-neuroscience","kind":"pathway","name":"Cancer neuroscience (nerve-tumour signalling)","route":"/pathways/cancer-neuroscience/"},{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"intravasation-ctc-survival","kind":"pathway","name":"Intravasation & circulating tumour cells","route":"/pathways/intravasation-ctc-survival/"},{"id":"invasion-ecm-degradation","kind":"pathway","name":"Invasion: proteases, adhesion & the invasive front","route":"/pathways/invasion-ecm-degradation/"},{"id":"organ-tropism-seed-soil","kind":"pathway","name":"Organ tropism: seed and soil","route":"/pathways/organ-tropism-seed-soil/"},{"id":"tgf-beta","kind":"pathway","name":"TGF-β signalling","route":"/pathways/tgf-beta/"},{"id":"blood-brain-barrier-metastasis","kind":"pathway","name":"The blood-brain barrier & brain metastasis","route":"/pathways/blood-brain-barrier-metastasis/"},{"id":"pre-metastatic-niche","kind":"pathway","name":"The pre-metastatic niche","route":"/pathways/pre-metastatic-niche/"},{"id":"tumor-dormancy","kind":"pathway","name":"Tumour dormancy","route":"/pathways/tumor-dormancy/"},{"id":"tumor-microenvironment","kind":"pathway","name":"Tumour microenvironment (TME)","route":"/pathways/tumor-microenvironment/"}],"term":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"disseminated-tumor-cells","kind":"term","name":"Disseminated tumour cells (DTCs)","route":"/terms/disseminated-tumor-cells/"},{"id":"activating-invasion-metastasis","kind":"term","name":"Hallmark: activating invasion and metastasis","route":"/terms/activating-invasion-metastasis/"},{"id":"metastasis","kind":"term","name":"Metastasis","route":"/terms/metastasis/"},{"id":"mrd","kind":"term","name":"Minimal / molecular residual disease (MRD)","route":"/terms/mrd/"},{"id":"oligometastatic","kind":"term","name":"Oligometastatic disease","route":"/terms/oligometastatic/"},{"id":"primary-tumour","kind":"term","name":"Primary tumour","route":"/terms/primary-tumour/"},{"id":"seed-and-soil-hypothesis","kind":"term","name":"Seed and soil hypothesis of metastasis (Paget)","route":"/terms/seed-and-soil-hypothesis/"}],"paper":[{"id":"paper-yachida-metastasis-late-genetic-evolution-pancreatic-nature-2010","kind":"paper","name":"Distant metastasis occurs late during the genetic evolution of pancreatic cancer","route":"/key-papers/paper-yachida-metastasis-late-genetic-evolution-pancreatic-nature-2010/"},{"id":"paper-iacobuzio-donahue-dpc4-failure-pattern-autopsy-jco-2009","kind":"paper","name":"DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer","route":"/key-papers/paper-iacobuzio-donahue-dpc4-failure-pattern-autopsy-jco-2009/"},{"id":"paper-kalluri-weinberg-emt-basics-jci-2009","kind":"paper","name":"Kalluri and Weinberg 2009: the basics of epithelial-mesenchymal transition","route":"/key-papers/paper-kalluri-weinberg-emt-basics-jci-2009/"},{"id":"paper-gerstberger-cell","kind":"paper","name":"Metastasis","route":"/key-papers/paper-gerstberger-cell/"},{"id":"paper-massague-nature","kind":"paper","name":"Metastatic colonization by circulating tumour cells","route":"/key-papers/paper-massague-nature/"},{"id":"paper-quail-joyce-microenvironment-metastasis-natmed-2013","kind":"paper","name":"Quail and Joyce 2013: microenvironmental regulation of tumour progression and metastasis","route":"/key-papers/paper-quail-joyce-microenvironment-metastasis-natmed-2013/"},{"id":"paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018","kind":"paper","name":"TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis","route":"/key-papers/paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018/"},{"id":"paper-thiery-emt-tumour-progression-nrc-2002","kind":"paper","name":"Thiery 2002: epithelial-mesenchymal transitions in tumour progression","route":"/key-papers/paper-thiery-emt-tumour-progression-nrc-2002/"}],"idea":[{"id":"idea-dormancy-maintenance-therapy","kind":"idea","name":"Keep them asleep: dormancy maintenance as adjuvant therapy","route":"/ideas/idea-dormancy-maintenance-therapy/"},{"id":"idea-dtc-colonisation-determinants","kind":"idea","name":"What decides which disseminated cells ever colonise?","route":"/ideas/idea-dtc-colonisation-determinants/"}]}}