The pre-metastatic niche
Before a single cancer cell arrives, the primary tumour sends parcels ahead: vesicles and hormones that recruit bone-marrow cells to a distant organ and turn it into fertile soil.
Diagram
Pick a product above a diagram to see the nodes it hits and the escape routes below the block. Hover or tap any node or arrow for what it is; every node opens its target, glossary entry or the pathway page. Violet boxes are druggable targets.
A colonising power that sends engineers, seed and fertiliser to a distant shore before the settlers sail. The settlers (CTCs) that land where the soil has been prepared survive; the ones that land elsewhere starve.
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.
What happens
In plain words, then the glossary entries the stage rests on. Chapter 7, Invasion and metastasis: Metastasis causes about nine in ten cancer deaths, and no approved drug targets it directly.
Before a single cancer cell arrives, the primary tumour sends parcels ahead: vesicles and hormones that recruit bone-marrow cells to a distant organ and turn it into fertile soil.
The pre-metastatic niche. Before a single cancer cell arrives, the primary tumour sends parcels ahead: tiny vesicles (exosomes) and hormones that recruit bone-marrow cells to a distant organ and remodel it into fertile soil. By the time the seed lands, the bed is already made.
The metastatic cascade. 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.
The molecular players
The proteins and genes at this stage, with their role and how many products act on each. Listed players come from the atlas; drawn players sit as nodes in the diagrams above.
The signal tumours use to grow their own blood supply. Blocking it starves tumours and, surprisingly, helps immunotherapy work.
The receptor that macrophages depend on; blocking it shrinks tenosynovial giant cell tumour (a CSF1-driven tumour) and depletes tumour-supporting macrophages, though the latter has not yet helped patients with common cancers.
A master switch that kidney cancer cells leave permanently on when they lose the VHL gene; belzutifan blocks it.
Where medicines act
Products grouped by the node they hit, most advanced first, with the cancers an approved product is linked to. Pick one above the diagram to see it light up.
- AnlotinibApprovedNon-small-cell lung cancerSmall-cell lung cancerSarcomas (soft tissue, bone, GIST)
- AxitinibApprovedRenal cell carcinomaClear cell renal cell carcinomaAdenoid cystic carcinoma
- BevacizumabApprovedColorectal cancerOvarian cancerNon-small-cell lung cancer
- Bevacizumab (glioblastoma use)ApprovedGlioma & glioblastoma
- CabozantinibApprovedHepatocellular carcinomaAdvanced hepatocellular carcinoma (BCLC C)Renal cell carcinoma
- Camrelizumab + rivoceranibApprovedHepatocellular carcinoma
- DonafenibApprovedHepatocellular carcinomaThyroid cancer
- FruquintinibApprovedColorectal cancer
- +21 more at VEGF / VEGFR →
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
Open questions
What is not known at this stage: the atlas's own questions, the bottlenecks it bears on, and the ideas in the corpus that try to answer them.
- Can exosome profiling predict the organ of relapse in patients?
- Is there a drug that stops niche formation without the harms of adjuvant anti-VEGF?
- early clinicalWhat actually holds T cells at the tumour border?
In immune-excluded tumours T cells reach the border but cannot get in, held back by fibroblasts, matrix, abnormal vessels, CXCL12 gradients or myeloid cells, and TGF-β drugs on their own have failed. If single-cell and spatial profiling can show which stromal programme dominates in each tumour, matching the drug (TGF-β, FAP, CXCR4 or VEGF) to it could let immunotherapy work.
- preclinical evidenceWhat decides which disseminated cells ever colonise?
Most cancer cells that spread die or sleep forever; a few grow into lethal metastases. Nobody can yet tell them apart, and doing so would show whom to treat after surgery.
Key evidence
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
- 2025rctHARMONi-2: ivonescimab, a PD-1 x VEGF bispecific, beats pembrolizumab head-to-head in PD-L1-positive lung cancerThe Lancet
- 2023reviewMetastasisCell
- 2021rctCLEAR: lenvatinib plus pembrolizumab versus sunitinib as first treatment for advanced kidney cancerNew England Journal of Medicinechanged practice
- 2020rctIMbrave150: atezolizumab plus bevacizumab replaces sorafenib as first treatment for advanced liver cancerNew England Journal of Medicinechanged practice
- 2019rctPAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumoursNew England Journal of Medicinechanged practice
- 2017reviewPre-metastatic niches: organ-specific homes for metastasesNature Reviews Cancer
- 2016reviewMetastatic colonization by circulating tumour cellsNature
- 2013reviewQuail and Joyce 2013: microenvironmental regulation of tumour progression and metastasisNature Medicine
- 2009reviewKalluri and Weinberg 2009: the basics of epithelial-mesenchymal transitionJournal of Clinical Investigation
- 2005observationalA pooled analysis of bone marrow micrometastasis in breast cancerNew England Journal of Medicine
- 2004rctHurwitz 2004: bevacizumab with chemotherapy for metastatic colorectal cancer, the first anti-angiogenic drug to extend lifeNew England Journal of Medicinechanged practice
- 2002reviewThiery 2002: epithelial-mesenchymal transitions in tumour progressionNature Reviews Cancer
src/data/mechanics-atlas.ts). Players, medicines, escape routes, tests, ideas and papers are resolved from the knowledge graph at build time through the stage's pathways, targets and terms, so every item here has its own page and sources. Where a section is missing, the corpus has no record tied to the stage yet. Nothing here is medical advice; see about and methodology. Stage 7.4 of 56.