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A signal that stops normal cells from dividing but, once a cancer is established, switches sides: it builds scar-like stroma, walls out immune cells, and pushes cells into a migratory state.
TGF-β binds TGFBR2/TGFBR1 (ALK5) to phosphorylate SMAD2/3, which with SMAD4 regulates transcription. Early tumour suppressor (cytostatic; SMAD4 and TGFBR2 loss in pancreatic and MSI colorectal cancer) and later promoter of EMT, CAF activation, immune exclusion (T-cell exclusion in bladder and CRC), and metastasis. Bintrafusp alfa (PD-L1/TGF-β trap) failed in phase 3 (NSCLC, biliary); galunisertib was discontinued; SRK-181 (latent TGF-β1) and dalutrafusp continue. Blocking TGF-β to re-sensitise cold tumours remains an active, unproven idea.
A town planner who first refuses all new building (tumour suppressor) and then, corrupted, builds walls and moats around the tumour that keep the police out (immune exclusion).
COMMANDS moved luspatercept from second line (after ESA failure, MEDALIST trial) to first line, offering transfusion-dependent lower-risk MDS patients a better chance of transfusion freedom from the start. It changed guidelines and labels in 2023. Erythropoietin remains a reasonable and cheaper option for patients without ring sideroblasts or with low transfusion burden.
It gives surveillance a target and a timetable: catch high-grade dysplasia and there are about three years before invasion, and TGF-beta pathway loss is the event to detect.
It is the clearest mechanistic answer to why microsatellite-stable colorectal cancer resists immunotherapy, and the rationale for every TGF-beta plus checkpoint combination now in trials in this disease.
With Moffitt's classical and basal-like split (the squamous and basal-like groups overlap) this fixed the molecular vocabulary of the disease and gave Precision-Panc and the UK's Glasgow group their trial framework.
It made TGF-beta the central target of the microsatellite-stable half of the disease, which is the line that leads to Tauriello's immune-evasion work and to the TGF-beta plus checkpoint combinations in trials.
The CMS framework organises colorectal cancer biology and trial stratification; BRAF V600E tumours cluster in CMS1, and CMS4's shorter survival and stromal signalling are targets of ongoing research.
This is the reference for the mechanics behind invasion and metastasis and for why partial EMT states, rather than a full switch, are now thought to matter most in cancer. It also explains the appeal and the difficulty of drugging EMT, since its drivers are transcription factors.
The APGI cohort became the backbone of the QCMG whole-genome and subtype papers; ATM's entry here is the origin of its place on today's germline panels.
Shares Invasion: proteases, adhesion & the invasive front, Fibroblast activation, desmoplasia & matrix stiffness, Epithelial-mesenchymal transition & drug efflux, Tumour microenvironment (TME) and the tag mechanism.
Shares ACVR1 (ALK2), Pancreatic cancer (KEGG map), Fibroblast activation, desmoplasia & matrix stiffness, PD-1 / PD-L1 immune checkpoint & T-cell activation and the tag mechanism.
Shares Hallmark: avoiding immune destruction, NK-cell recognition: missing self & stress ligands, Hot vs cold tumours, PD-1 / PD-L1 immune checkpoint & T-cell activation and the tag mechanism.
Shares The metastatic cascade, Tumour microenvironment (TME), Memorial Sloan Kettering Cancer Center, Pancreatic ductal adenocarcinoma and the tag mechanism.
Shares Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes, Genomic analyses identify molecular subtypes of pancreatic cancer, Pancreatic ductal adenocarcinoma, Colorectal cancer and the tag mechanism.
Shares Genomic characterization of malignant progression in neoplastic pancreatic cysts, Tumour dormancy, The metastatic cascade, Memorial Sloan Kettering Cancer Center and the tag mechanism.
Shares Stromal gene expression defines poor-prognosis subtypes in colorectal cancer, Epithelial-mesenchymal transition & drug efflux, Memorial Sloan Kettering Cancer Center and the tag mechanism.
Shares The consensus molecular subtypes of colorectal cancer, Vall d'Hebron University Hospital / VHIO, Cold Spring Harbor Laboratory, Pancreatic ductal adenocarcinoma and the tag mechanism.