# Metastasis is understood least and studied last

Source: https://onco.cc/bottlenecks/b-metastasis-biology/  
OnCo record `b-metastasis-biology` (Bottleneck). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Metastasis causes about nine in ten cancer deaths but gets a small fraction of research money and almost no trials of its own.

## Summary

Most cancer deaths are attributable to metastatic disease, yet the biology of dissemination is studied far less than the biology of the primary tumour, and almost every drug is developed to shrink lesions rather than to stop spread. The steps that let cells leave a primary, survive shear stress and immune attack in circulation, extravasate, adapt to a foreign organ and either grow or lie dormant involve distinct programmes (epithelial-mesenchymal plasticity, pre-metastatic niche formation, organ-specific tropism) that have few validated drug targets and no approved anti-metastatic agent. Preclinical models seldom metastasise in a human-like pattern, regulatory endpoints reward tumour shrinkage rather than prevention of new lesions, and the patients who would benefit most from an anti-metastatic drug (those with resected early disease) are hard to enrol in long trials. Metastasis-directed local therapy and circulating tumour DNA-defined trials are the first designs to treat spread itself as the target.

## Fields

- Kind: Bottleneck
- Last checked: 2026-09-08
- Stage: biology
- Severity: critical
- Metrics: Share of cancer deaths attributable to metastatic disease (registry-based analysis): ~67% directly; ~90% when metastasis contributed (Dillekås, Rogers & Straume, Cancer Medicine 2019); Estimated share of cancer research funding directed at metastasis: ~5% (estimate) (Sleeman & Steeg, European Journal of Cancer 2010); Adults with cancer who develop brain metastases: ~20% (Achrol et al., Nature Reviews Disease Primers 2019)
- Causes: Metastatic lesions are rarely biopsied or banked, so their biology is inferred from primaries.; Mouse models seldom metastasise spontaneously to human-relevant organs, making anti-metastatic drugs hard to test.; Regulatory endpoints (response rate, progression-free survival) reward shrinkage of existing lesions, not prevention of new ones.; Adjuvant trials to prevent metastasis require thousands of patients and years of follow-up, which industry avoids.; Funding and career incentives favour primary-tumour and cell-intrinsic biology over the multi-organ, systemic biology of spread.

## Sources

- Dillekås et al., Are 90% of deaths from cancer caused by metastases? (Cancer Medicine 2019): https://doi.org/10.1002/cam4.2474
- Steeg, Targeting metastasis (Nature Reviews Cancer 2016): https://doi.org/10.1038/nrc.2016.25
- Cancer Grand Challenges: https://cancergrandchallenges.org/

## Connected records

- ideas: [A billion-dollar prize for the first durable cure of a lethal metastatic cancer](https://onco.cc/ideas/idea-fund-cure-prize/), [A blood test for the pre-metastatic niche](https://onco.cc/ideas/idea-bio2-premetastatic-niche-assay/), [A global rapid tissue donation network for metastatic disease](https://onco.cc/ideas/idea-bio2-rapid-autopsy-commons/), [A national rapid research autopsy network for end-stage cancer](https://onco.cc/ideas/idea-bio1-rapid-autopsy-network/), [A regulatory endpoint for drugs that block spread, not tumours](https://onco.cc/ideas/idea-bio2-antimetastatic-endpoint/), [A ring-fenced metastasis programme with metastasis-specific endpoints](https://onco.cc/ideas/idea-fund-metastasis-moonshot/), [A standard platform to get drugs into the brain: focused ultrasound plus shuttle-engineered therapeutics](https://onco.cc/ideas/idea-moon-brain-delivery-platform/), [A test to tell true oligometastatic disease from hidden widespread spread](https://onco.cc/ideas/idea-bio2-oligometastatic-signature/), [An organotropism atlas that predicts where a cancer will spread](https://onco.cc/ideas/idea-bio2-organotropism-atlas/), [Blunt the inflammation that wakes sleeping cancer cells](https://onco.cc/ideas/idea-bio2-il1-awakening-blockade/), [Break the neutrophil DNA nets that catch tumour cells after surgery](https://onco.cc/ideas/idea-bio2-net-blockade-perioperative/), [Build laboratory models of the organs cancer spreads to](https://onco.cc/ideas/idea-bio1-metastatic-niche-models/), [Cheap perioperative beta-blocker plus anti-inflammatory to blunt surgical stress](https://onco.cc/ideas/idea-bio2-perioperative-betablocker-nsaid/), [Circulating tumour cell clearance as the phase 2 gate for anti-metastatic drugs](https://onco.cc/ideas/idea-bio2-ctc-clearance-go-nogo/), [ctDNA-guided adjuvant therapy as the default in stage II-III colon cancer](https://onco.cc/ideas/idea-ctdna-guided-adjuvant-crc/), [Deliver CAR-T cells straight into the fluid around the brain](https://onco.cc/ideas/idea-bio2-intraventricular-car-t/), [Eradicate dormant cancer cells: a programme to wake and kill or lock asleep disseminated cells](https://onco.cc/ideas/idea-moon-dormancy-eradication-programme/), [Flush dormant cells out of bone marrow, then kill them](https://onco.cc/ideas/idea-bio2-cxcr4-mobilise-then-kill/), [Grow blood-borne tumour cells to test drugs on the cells that actually spread](https://onco.cc/ideas/idea-bio2-ctc-culture-functional-testing/), [Inhaled immune therapy to make the lung hostile to arriving tumour cells](https://onco.cc/ideas/idea-bio2-inhaled-lung-niche-immunotherapy/), [Keep dormant cells asleep instead of trying to kill them](https://onco.cc/ideas/idea-bio2-pro-dormancy-therapy/), [Make in vivo metastasis screens a required step in drug discovery](https://onco.cc/ideas/idea-bio2-metastasis-screen-standard/), [Match each blood-detected clone to the lesion it comes from on the scan](https://onco.cc/ideas/idea-bio1-clone-to-lesion-mapping/), [Measure brain metastasis prevention as a primary endpoint, not as a secondary one](https://onco.cc/ideas/idea-lung-brain-metastasis-prevention-as-a-primary-endpoint/), [Metastasis prevention as a formal indication with its own trials and regulatory pathway](https://onco.cc/ideas/idea-moon-metastasis-prevention-indication/), [Perioperative beta-blocker plus COX-2 inhibitor to reduce metastasis after surgery](https://onco.cc/ideas/idea-reg-perioperative-propranolol-etodolac/), [Peritoneal-directed therapy for gastric cancer](https://onco.cc/ideas/idea-peritoneal-directed-gastric/), [Prevention trials aimed only at brain metastasis](https://onco.cc/ideas/idea-bio2-brain-met-prevention-trials/), [PSMA-PET-guided metastasis-directed therapy as a curative strategy in oligorecurrent prostate cancer](https://onco.cc/ideas/idea-psma-pet-guided-mdt/), [Reprogramme the liver's own immune cells to refuse metastases](https://onco.cc/ideas/idea-bio2-liver-niche-kupffer-reprogramming/), [Ring-fence a fifth of national cancer research money for metastasis](https://onco.cc/ideas/idea-bio2-metastasis-funding-floor/), [Soften the tissue that new metastases need in order to grow](https://onco.cc/ideas/idea-bio2-matrix-stiffness-prevention/), [Strip the platelet coat off travelling tumour cells in ctDNA-positive patients](https://onco.cc/ideas/idea-bio2-platelet-cloak-aspirin-mrd/), [Ten-year awards for scientists who commit to one hard problem](https://onco.cc/ideas/idea-fund-ten-year-hard-problem-awards/), [Treat the body cavity, not the bloodstream, for surface spread](https://onco.cc/ideas/idea-bio2-intracavitary-immunotherapy/), [Treat the draining lymph node before removing it](https://onco.cc/ideas/idea-bio2-lymph-node-immune-priming/), [Trials that include, and report, brain metastases in triple-negative breast cancer](https://onco.cc/ideas/idea-tnbc-brain-metastasis-trials/), [When the blood test is positive, hunt for the lesion with sensitive imaging](https://onco.cc/ideas/idea-bio2-localise-the-mrd/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Melanoma](https://onco.cc/cancers/melanoma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [MRD / molecular residual disease testing](https://onco.cc/technologies/mrd-testing/), [PSMA PET](https://onco.cc/technologies/psma-pet/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/), [Sentinel lymph node biopsy](https://onco.cc/technologies/sentinel-node/), [Whole-body MRI](https://onco.cc/technologies/whole-body-mri/)
- institutions: [Breast Cancer Research Foundation](https://onco.cc/institutions/bcrf/), [Cancer Research UK](https://onco.cc/institutions/cruk/), [Champalimaud Foundation, Champalimaud Clinical Centre](https://onco.cc/institutions/champalimaud/), [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/), [Montefiore Einstein Comprehensive Cancer Center](https://onco.cc/institutions/montefiore-einstein/), [National Cancer Institute (NIH)](https://onco.cc/institutions/nci/), [Nationwide Children's Hospital](https://onco.cc/institutions/nationwide-childrens/), [Rosalind and Morris Goodman Cancer Institute, McGill University](https://onco.cc/institutions/mcgill-goodman/), [The Mark Foundation for Cancer Research](https://onco.cc/institutions/mark-foundation/), [University Hospital Basel / Tumour Centre](https://onco.cc/institutions/usb-basel/)
- pathways: [Epithelial-mesenchymal transition & drug efflux](https://onco.cc/pathways/emt/), [Intravasation & circulating tumour cells](https://onco.cc/pathways/intravasation-ctc-survival/), [Organ tropism: seed and soil](https://onco.cc/pathways/organ-tropism-seed-soil/), [The pre-metastatic niche](https://onco.cc/pathways/pre-metastatic-niche/)
- terms: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Minimal / molecular residual disease (MRD)](https://onco.cc/terms/mrd/), [Oligometastatic disease](https://onco.cc/terms/oligometastatic/), [Oligoprogression](https://onco.cc/terms/oligoprogression/), [Peritoneal metastasis](https://onco.cc/terms/peritoneal-metastasis/), [Stage shift](https://onco.cc/terms/stage-shift/)
- trials: [CIRCULATE-Japan (GALAXY / VEGA / ALTAIR)](https://onco.cc/trials/circulate-japan/), [DYNAMIC](https://onco.cc/trials/dynamic/), [IMvigor011](https://onco.cc/trials/imvigor011/), [MSLT-II](https://onco.cc/trials/mslt-ii/), [Peritumoral lidocaine before breast cancer surgery (Tata Memorial)](https://onco.cc/trials/lidocaine-peritumoral-tmh/)
- key papers: [Are 90% of deaths from cancer caused by metastases?](https://onco.cc/key-papers/paper-dillekas-cancer-med/), [Geographic and age variations in mutational processes in colorectal cancer](https://onco.cc/key-papers/paper-diaz-gay-colibactin-geographic-age-mutational-processes-nature-2025/), [Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases](https://onco.cc/key-papers/paper-lin-tnbc-cns-metastases-dfci-cancer-2008/), [Targeting metastasis](https://onco.cc/key-papers/paper-steeg-nat-rev-cancer/), [The evolutionary history of lethal metastatic prostate cancer](https://onco.cc/key-papers/paper-gundem-evolutionary-history-lethal-metastatic-prostate-nature-2015/), [TRACERx 421: the full-cohort picture of how lung cancer evolves and which subclones drive relapse](https://onco.cc/key-papers/paper-tracerx-evolution-nature-2023/)

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