Fibroblasts and the extracellular matrix
Tumours keep the body's repair cells in wound-healing mode forever. The scar they lay down squeezes vessels shut, walls out immune cells, and its very stiffness tells cancer cells to grow. Demolishing it made pancreatic cancer worse; retraining it is the new plan.
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.
Builders hired to repair a wall who never stop: they pour concrete around the tumour until the roads are blocked (vessels), the police cannot get in (T cells), and the very hardness of the concrete tells the tenants to multiply. Demolishing the builders' work made things worse; the newer plan is to retrain them.
A castle under siege from the inside: the cancer conscripts the town's builders (fibroblasts) to raise walls, bribes the guards (macrophages) to look away, and diverts the water supply (vessels) so that reinforcements (T cells, drugs) never arrive.
A building inspector (Hippo) who checks that the block is full and stops new floors. Cancers fire the inspector, and the architect (YAP/TAZ) keeps adding storeys.
What happens
In plain words, then the glossary entries the stage rests on. Chapter 8, The tumour ecosystem: A tumour is a corrupted organ: cancer cells plus the fibroblasts, matrix, vessels, nerves, microbes and immune cells they recruit, and the signals they send to the rest of the body.
Tumours keep the body's repair cells in wound-healing mode forever. The scar they lay down squeezes vessels shut, walls out immune cells, and its very stiffness tells cancer cells to grow. Demolishing it made pancreatic cancer worse; retraining it is the new plan.
Fibroblast activation, desmoplasia & matrix stiffness. Tumours recruit the body's repair cells, fibroblasts, and keep them in wound-healing mode forever. The scar tissue they lay down (desmoplasia) squeezes blood vessels shut, walls out immune cells, stiffens the tissue in a way that itself tells cancer cells to grow, and is why pancreatic cancer is so hard to treat.
Tumour microenvironment (TME). A tumour is not just cancer cells. It is a neighbourhood of fibroblasts, immune cells, blood vessels, nerves, and scaffolding that the cancer recruits and corrupts, and that decides whether drugs and immune cells can get in.
Hippo-YAP/TAZ. The pathway that tells organs when to stop growing. Cancers disable it so YAP and TAZ stay in the nucleus driving growth; in mesothelioma, NF2 loss does exactly that, and the first drugs against the YAP-TEAD switch are in trials.
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 switch in the hedgehog developmental pathway that is stuck on in basal cell carcinoma and some medulloblastomas; three approved pills block it.
FAP (fibroblast activation protein) sits on the cancer-associated fibroblasts that scaffold more than 90% of epithelial cancers and is almost absent from normal adult tissue. FAPI PET tracers therefore light up tumours with high contrast, including pancreatic, gastric and low-grade cancers where FDG PET is weak, and FAP-targeted radioligands are in development.
PD-1 is a brake on T cells. Blocking it releases the immune system against the tumour and has cured some previously incurable cancers.
The signal tumours use to grow their own blood supply. Blocking it starves tumours and, surprisingly, helps immunotherapy work.
The first immune brake ever targeted for cancer; releasing it won a Nobel Prize and cures a fraction of melanomas.
The signalling enzyme that tells marrow cells to make red cells and platelets; a single mutation (V617F) leaves it switched on in most myeloproliferative neoplasms.
CD47 is the 'don't eat me' signal: it binds SIRP-alpha on macrophages to stop them engulfing the cell, and over 90% of AML blasts and large B-cell lymphoma cells display it. Blocking it should let macrophages eat tumour cells, but red cells carry CD47 too, so anaemia is built in, and the lead antibody magrolimab was dropped after failed trials.
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.
- VismodegibApprovedBasal cell carcinomaMedulloblastomaSHH-activated medulloblastoma
- GlasdegibApprovedAcute myeloid leukaemiaAcute myeloid leukaemia in older or unfit patients
- SonidegibApprovedBasal cell carcinomaSHH-activated medulloblastomaLocally advanced and metastatic basal cell carcinoma
- PatidegibPhase 3
- FAP-2286 (177Lu / 68Ga)Phase 2
- EB-MF-CAR-NK-01Phase 2
- CadonilimabApprovedCervical cancerGastric & gastro-oesophageal junction cancer
- CamrelizumabApprovedOesophageal cancerHepatocellular carcinomaNon-small-cell lung cancer
- Camrelizumab + rivoceranibApprovedHepatocellular carcinoma
- CemiplimabApprovedNon-small-cell lung cancerMelanomaPD-L1-high non-small-cell lung cancer without a driver mutation
- DostarlimabApprovedMismatch repair deficient (MSI-high) pancreatic ductal adenocarcinomaEndometrial cancerColorectal cancer
- IvonescimabApprovedNon-small-cell lung cancerColorectal cancerTriple-negative breast cancer (TNBC)
- NivolumabApprovedMelanomaNon-small-cell lung cancerRenal cell carcinoma
- PembrolizumabApprovedMismatch repair deficient (MSI-high) pancreatic ductal adenocarcinomaTriple-negative breast cancer (TNBC)Non-small-cell lung cancer
- +23 more at PD-1 →
- 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
- DonafenibApprovedHepatocellular carcinomaThyroid cancer
- FruquintinibApprovedColorectal cancer
- LenvatinibApprovedHepatocellular carcinomaAdvanced hepatocellular carcinoma (BCLC C)Intermediate hepatocellular carcinoma (BCLC B)
- +18 more at VEGF / VEGFR →
- IpilimumabApprovedMelanomaRenal cell carcinomaColorectal cancer
- TremelimumabApprovedNon-small-cell lung cancerHepatocellular carcinomaAdvanced hepatocellular carcinoma (BCLC C)
- GotistobartPhase 3
- ADG126Phase 2
- BA3071Phase 2
- BotensilimabPhase 2
- JK08Phase 2
- FedratinibApprovedMyeloproliferative neoplasms (PV, ET, myelofibrosis)Primary myelofibrosis
- MomelotinibApprovedMyeloproliferative neoplasms (PV, ET, myelofibrosis)Primary myelofibrosis
- PacritinibApprovedMyeloproliferative neoplasms (PV, ET, myelofibrosis)Primary myelofibrosis
- Ropeginterferon alfa-2bApprovedMyeloproliferative neoplasms (PV, ET, myelofibrosis)Polycythaemia vera (PV)Essential thrombocythaemia (ET)
- RuxolitinibApprovedMyeloproliferative neoplasms (PV, ET, myelofibrosis)Polycythaemia vera (PV)Primary myelofibrosis
- INCA033989Phase 1
- PeluntamigPhase 2
- SpevatamigPhase 2
- MagrolimabWithdrawn
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
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.
- Which fibroblast subtypes protect the tumour and which restrain it?
- Can FAP radioligands treat stroma-rich cancers without harming healing tissue?
- early clinicalindustryClear the suppressive neutrophils out of pancreatic tumours first
Pancreatic tumours are packed with a type of white blood cell that shuts down the immune attack. Blocking the signal that recruits them may open the tumour to immunotherapy.
- early clinicalFAP theranostics as a pan-cancer stromal strategy
Instead of finding a different target for each cancer, hit the scaffolding cells that almost all solid tumours share.
- early clinicalengineeringImplant a tiny device that tests twenty drugs inside the patient's own tumour
A rice-grain-sized implant releases microdoses of up to 20 drugs into separate spots of a tumour for one to three days, then is removed so pathologists can see which drug worked in that person's own tumour. First-in-human studies have been done in breast, sarcoma and brain tumours.
- 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 clinicalclinicMechanically pulverise one tumour with ultrasound to wake the immune system
Focused ultrasound can break a tumour apart without heat or cuts, leaving debris the immune system can learn from. Doing that to one tumour may help treat the rest.
- early clinicalindustryOncolytic viruses that make interleukin-12 only inside the tumour
Interleukin-12 is an immune-stimulating cytokine that caused severe toxicity when injected into the bloodstream in the 1990s and was abandoned. An oncolytic herpes or adenovirus carrying the interleukin-12 gene under a drug-inducible promoter makes it only inside the tumour, keeping exposure local; trials include recurrent glioblastoma.
- early clinicalindustryReprogramme suppressive macrophages instead of trying to delete them
Tumours fill with immune cells that protect them. Earlier drugs tried to remove those cells and failed. Newer ones aim to switch them to the attacking side.
- early clinicalresearchTake faecal transplant plus immunotherapy to a definitive trial
Transferring gut bacteria from patients who responded to immunotherapy has helped some patients who had stopped responding. It is time for a proper large trial.
- early clinicalresearchTest a high-fibre diet as an immunotherapy adjunct
People who eat more fibre appear to respond better to immunotherapy, while some probiotic supplements may do the opposite. A proper trial would settle it.
- early clinicalclinicTreat the body cavity, not the bloodstream, for surface spread
Intracavitary immunotherapy targets cancer that coats the lining of the abdomen or chest, which drugs given by drip barely reach. Delivering it straight into the cavity gives far higher local doses.
23 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.
- 2023reviewInsights into recent findings and clinical application of YAP and TAZ in cancerNature Reviews Cancer
- 2023rctNAPOLI-3: NALIRIFOX versus gemcitabine plus nab-paclitaxel as first treatment for metastatic pancreatic cancerThe Lancetchanged practice
- 2023translationalRojas 2023: a personalised mRNA vaccine trained T cells against each patient's pancreatic cancer, and those who responded stayed cancer-free longerNature
- 2023reviewThe evolving tumor microenvironment: From cancer initiation to metastatic outgrowthCancer Cell
- 2020reviewA framework for advancing our understanding of cancer-associated fibroblastsNature Reviews Cancer
- 2019observationalEstimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy DrugsJAMA network open
- 2017reviewElements of cancer immunity and the cancer-immune set pointNature
- 2016observationalGenomic analysis identifies new drivers and progression pathways in skin basal cell carcinomaNature Genetics
- 2016reviewThe biology and function of fibroblasts in cancerNature Reviews Cancer
- 2013reviewQuail and Joyce 2013: microenvironmental regulation of tumour progression and metastasisNature Medicine
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 8.1 of 56.