Epithelial-mesenchymal transition
A brick in a wall becomes a nomad: it lets go of its neighbours, packs pumps to spit out drugs, and puts on camouflage. Most tumour cells stop halfway, in a partial state that is the most dangerous of all.
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 brick in a wall (epithelial cell) turning into a nomad: it lets go of its neighbours, packs pumps to spit out poison, and puts on camouflage. The wall-brick was easy to hit; the nomad is not.
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.
A brick in a wall becomes a nomad: it lets go of its neighbours, packs pumps to spit out drugs, and puts on camouflage. Most tumour cells stop halfway, in a partial state that is the most dangerous of all.
Epithelial-mesenchymal transition & drug efflux. How a cancer cell changes shape to migrate and to shrug off drugs. Transcription factors like ZEB1 and SNAIL loosen the cell, switch on pumps that eject chemotherapy, and hide it from the immune system.
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.
TROP2 is a surface glycoprotein present at high levels on most epithelial cancers (breast, lung, urothelial, gastric, pancreatic) and at low levels on normal tissue. It does not drive the cancer; it is a delivery address, used by the approved ADCs sacituzumab govitecan and datopotamab deruxtecan and by sacituzumab tirumotecan, with a TROP2 PET tracer in development to pick patients.
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.
- Datopotamab deruxtecanApprovedTriple-negative breast cancer (TNBC)HR-positive / HER2-negative breast cancerNon-small-cell lung cancer
- Sacituzumab govitecanApprovedTriple-negative breast cancer (TNBC)HR-positive / HER2-negative breast cancerBladder & urothelial cancer
- Sacituzumab tirumotecanApprovedTriple-negative breast cancer (TNBC)Non-small-cell lung cancerHR-positive / HER2-negative breast cancer
- BIO-106Phase 2
- EB-NK-301Phase 2
- LCB84Phase 2
- AK146D1Phase 1
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
- early clinicalresearchStrip the platelet coat off travelling tumour cells in ctDNA-positive patients
Cancer cells in the blood wrap themselves in platelets as camouflage. Aspirin may remove that cloak, and it is cheapest to test in the patients at highest risk of relapse.
- preclinical evidenceresearchCombination baskets defined by resistance mechanism rather than by cancer type
Group patients by why their last drug stopped working, then test the combination designed to fix that specific failure, whatever the cancer.
- preclinical evidenceEfflux-agnostic therapy for mesenchymal TNBC
Some tumours pump out every drug. Use treatments the pumps cannot touch: radiation, radioligands, immune cells, and payloads designed to evade them.
- preclinical evidenceKill drug-tolerant persisters through ferroptosis
The cells that survive targeted therapy change shape and become unusually dependent on an antioxidant enzyme, GPX4. Hitting them in that window might stop resistance before it evolves.
- speculativeDual-payload ADCs in first line to prevent resistance
Rather than waiting for resistance to one payload and then switching, give two mechanisms from day one, as HIV therapy does.
Measured by
Biomarkers, tests and assays in the corpus that read this stage in a patient.
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.
- Is EMT required for metastasis in patients, or mainly for drug resistance?
- Can partial-EMT states be targeted through their ferroptosis sensitivity?
- early clinicalclinicCheap perioperative beta-blocker plus anti-inflammatory to blunt surgical stress
The stress of an operation may help stray cancer cells survive and settle. A few days of two cheap old drugs around surgery might reduce that risk.
- early clinicalresearchLosartan to loosen the stroma of pancreatic cancer before chemotherapy: a phase 3
A cheap blood pressure drug may soften the dense scar tissue around pancreatic tumours so chemotherapy and immune cells can get in. Early trials look encouraging.
- early clinicalTROP2 PET to choose and sequence TROP2 ADCs
Use a whole-body TROP2 scan instead of a single tissue stain to decide which patients get a TROP2 ADC, which one, and when to switch.
- preclinical evidenceindustryBispecific antibodies that engage macrophages instead of T cells
Drugs that grab T cells and drag them onto tumours work well in blood cancers. The same trick aimed at tumour-eating cells might work where T cells are absent.
- preclinical evidencePayload-class switching as the rule for ADC sequencing
When one ADC fails, the next should carry a different kind of poison, not just aim at a different protein.
- preclinical evidenceresearchSoften the tissue that new metastases need in order to grow
Cancer cells need stiff, cross-linked tissue scaffolding to settle and grow in a new organ. Blocking the enzymes that build it may stop new colonies taking hold.
- preclinical evidenceindustryUse the brain's own transport door to carry antibody drugs across
The brain imports iron through the transferrin receptor. Antibody shuttle domains that bind that receptor raise brain exposure roughly ten to fifty-fold in primates and are already used in clinical Alzheimer's antibodies; the same engineering could carry antibody-drug conjugates or T-cell engagers to brain metastases.
- speculativeAlpha radioligands after ADC failure
When ADCs against a surface protein stop working because the payload no longer kills, use the same protein to deliver radiation instead.
- speculativeclinicRe-map the tumour's surface proteins before choosing the next antibody drug
Antibody drugs need their target to still be present. After one fails, checking which surface markers remain would guide the choice of the next one instead of guessing.
- speculativeresearchSequential multiple-assignment randomised trials to find the best order of ADCs
Patients are randomised at each decision point, not just at the start, so one trial can compare whole treatment sequences rather than single drugs.
1 more ideas are linked to this stage's pathways, targets and terms; see the rankings →
Key evidence
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
- 2024rctTROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survivalJournal of Clinical Oncology
- 2021rctASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancerNew England Journal of Medicinechanged practice
- 2014reviewLamouille 2014: molecular mechanisms of epithelial-mesenchymal transitionNature Reviews Molecular Cell Biology
- 2009reviewKalluri and Weinberg 2009: the basics of epithelial-mesenchymal transitionJournal of Clinical Investigation
- 2008basicMani 2008: the epithelial-mesenchymal transition generates cells with properties of stem cellsCell
- 2002reviewThiery 2002: epithelial-mesenchymal transitions in tumour progressionNature Reviews Cancer
- 2000reviewThe Hallmarks of Cancer: six capabilities every tumour must acquireCell
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 7.1 of 56.