{"entity":{"id":"invasion-ecm-degradation","kind":"pathway","name":"Invasion: proteases, adhesion & the invasive front","aka":[],"tldr":"To invade, a cancer cell must grip the scaffolding around it, dissolve a path with enzymes, and pull itself forward, alone or in a chain led by a scout cell. Fibroblasts often cut the trail first. The enzyme blockers of the 1990s failed; today's targets are the grip (integrins, FAK) and the trail-makers.","summary":"Invasion cycles through protrusion (RAC1-driven lamellipodia, actin-rich invadopodia with cortactin and TKS5), adhesion (integrins α5β1, αvβ3, αvβ6 to fibronectin/collagen, signalling via FAK-SRC and ILK), matrix degradation (membrane-anchored MT1-MMP/MMP14 activating MMP2, secreted MMP9, uPA-uPAR-plasmin, cathepsins), and RHO-ROCK-myosin contraction. Modes: mesenchymal (protease-dependent, elongated), amoeboid (protease-independent squeezing through pores, RHO/ROCK-high), and collective invasion led by leader cells (keratin-14+ in breast cancer) or by CAFs that generate tracks and pull via N-cadherin/E-cadherin heterotypic junctions. Perineural and lymphovascular invasion are histological markers of the process; stiff, aligned collagen (TACS-3) promotes it. Broad-spectrum MMP inhibitors (marimastat, prinomastat) failed in phase 3 with musculoskeletal toxicity and because MMPs also produce anti-angiogenic fragments. Current approaches: FAK inhibitors (defactinib, approved with avutometinib in KRAS-mutant low-grade serous ovarian cancer; also reduce stromal density), integrin antagonists (cilengitide failed in GBM), uPAR-targeted CAR-T for senescent cells, and RHO/ROCK inhibitors.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Invadopodia","links":[{"label":"Friedl & Alexander, Cancer invasion and the microenvironment: plasticity and reciprocity (Cell 2011)","url":"https://doi.org/10.1016/j.cell.2011.11.016"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":["lgsoc","pancreatic","head-and-neck"],"sections":[],"technologies":["fluorescence-guided-surgery","robotic-surgery","mechanobiology-therapy","fapi-pet","single-cell-spatial","histopathology-ihc"],"targets":["fap","kras","met","smoothened","fak"],"drugs":["avutometinib-defactinib","fap-2286"],"companies":[],"institutions":[],"pathways":["emt","basement-membrane-tissue-barriers","tgf-beta","hippo-yap","caf-activation-desmoplasia","metastatic-cascade"],"terms":["desmoplasia","cancer-associated-fibroblasts","tnm-staging","activating-invasion-metastasis"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-friedl-cell"],"journals":[],"dependsOn":[],"notes":[],"analogy":"A climber in a collapsing tunnel: grip the wall (integrins), chip away the rock ahead (MMPs), and haul forward (myosin). Some climbers squeeze through cracks without chipping (amoeboid). Often a guide (a fibroblast) has already carved the passage.","nodes":[{"id":"cue","label":"TGF-β, HGF, hypoxia, stiffness","x":12,"y":12},{"id":"emt","label":"EMT programme (ZEB1, SNAIL)","x":40,"y":12},{"id":"int","label":"Integrins → FAK / SRC","x":68,"y":12},{"id":"inv","label":"Invadopodia, MT1-MMP","x":68,"y":42},{"id":"mmp","label":"MMP2/9, uPA → ECM breach","x":92,"y":55},{"id":"rho","label":"RHO-ROCK contraction","x":40,"y":42},{"id":"amoe","label":"Amoeboid squeezing","x":12,"y":42},{"id":"coll","label":"Collective invasion (leaders)","x":40,"y":75},{"id":"caf","label":"CAF tracks","x":12,"y":75,"targetId":"fap"},{"id":"front","label":"Invasive front → vessels","x":72,"y":82}],"edges":[{"from":"cue","to":"emt","type":"activates"},{"from":"emt","to":"int","type":"activates"},{"from":"int","to":"inv","type":"activates"},{"from":"inv","to":"mmp","type":"activates"},{"from":"cue","to":"rho","type":"activates"},{"from":"rho","to":"amoe","type":"activates"},{"from":"emt","to":"coll","type":"activates"},{"from":"caf","to":"coll","type":"activates"},{"from":"mmp","to":"front","type":"activates"},{"from":"coll","to":"front","type":"activates"},{"from":"amoe","to":"front","type":"activates"}],"interventions":["FAK inhibitor defactinib with avutometinib (approved 2025, KRAS-mutant low-grade serous ovarian cancer); FAK inhibition also softens stroma","Broad MMP inhibitors and the integrin antagonist cilengitide failed in phase 3; lesson retained in the failure museum","Surgery and radiotherapy margins are the practical answer to local invasion; perineural and lymphovascular invasion drive adjuvant decisions","Anti-stromal strategies (FAP theranostics, Hedgehog paradox) reshape the tracks"]},"route":"/pathways/invasion-ecm-degradation/","neighbours":{"term":[{"id":"cancer-associated-fibroblasts","kind":"term","name":"Cancer-associated fibroblasts (CAFs)","route":"/terms/cancer-associated-fibroblasts/"},{"id":"desmoplasia","kind":"term","name":"Desmoplasia (tumour stroma)","route":"/terms/desmoplasia/"},{"id":"activating-invasion-metastasis","kind":"term","name":"Hallmark: activating invasion and metastasis","route":"/terms/activating-invasion-metastasis/"},{"id":"lgsoc","kind":"term","name":"Low-grade serous ovarian cancer (LGSOC)","route":"/terms/lgsoc/"},{"id":"mechanical-theory-of-cancer","kind":"term","name":"Mechanical theory: stiffness, pressure and force as causes","route":"/terms/mechanical-theory-of-cancer/"},{"id":"tnm-staging","kind":"term","name":"TNM staging","route":"/terms/tnm-staging/"}],"cancer":[{"id":"head-and-neck","kind":"cancer","name":"Head and neck squamous cell carcinoma","route":"/cancers/head-and-neck/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"technology":[{"id":"fapi-pet","kind":"technology","name":"FAPI PET","route":"/technologies/fapi-pet/"},{"id":"fluorescence-guided-surgery","kind":"technology","name":"Fluorescence-guided surgery","route":"/technologies/fluorescence-guided-surgery/"},{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"},{"id":"robotic-surgery","kind":"technology","name":"Robotic & minimally invasive surgery","route":"/technologies/robotic-surgery/"},{"id":"single-cell-spatial","kind":"technology","name":"Single-cell & spatial profiling","route":"/technologies/single-cell-spatial/"},{"id":"mechanobiology-therapy","kind":"technology","name":"Targeting tumour mechanics and pressure","route":"/technologies/mechanobiology-therapy/"}],"target":[{"id":"fak","kind":"target","name":"FAK (PTK2)","route":"/targets/fak/"},{"id":"fap","kind":"target","name":"FAP","route":"/targets/fap/"},{"id":"hgf","kind":"target","name":"HGF","route":"/targets/hgf/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"met","kind":"target","name":"MET","route":"/targets/met/"},{"id":"mmp2","kind":"target","name":"MMP2","route":"/targets/mmp2/"},{"id":"smoothened","kind":"target","name":"Smoothened (hedgehog pathway)","route":"/targets/smoothened/"},{"id":"zeb1","kind":"target","name":"ZEB1","route":"/targets/zeb1/"}],"drug":[{"id":"avutometinib-defactinib","kind":"drug","name":"Avutometinib + defactinib","route":"/drugs/avutometinib-defactinib/"},{"id":"fap-2286","kind":"drug","name":"FAP-2286 (177Lu / 68Ga)","route":"/drugs/fap-2286/"}],"pathway":[{"id":"basement-membrane-tissue-barriers","kind":"pathway","name":"Basement membrane & tissue barriers","route":"/pathways/basement-membrane-tissue-barriers/"},{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"caf-activation-desmoplasia","kind":"pathway","name":"Fibroblast activation, desmoplasia & matrix stiffness","route":"/pathways/caf-activation-desmoplasia/"},{"id":"hippo-yap","kind":"pathway","name":"Hippo-YAP/TAZ","route":"/pathways/hippo-yap/"},{"id":"tgf-beta","kind":"pathway","name":"TGF-β signalling","route":"/pathways/tgf-beta/"},{"id":"metastatic-cascade","kind":"pathway","name":"The metastatic cascade","route":"/pathways/metastatic-cascade/"}],"paper":[{"id":"paper-friedl-cell","kind":"paper","name":"Cancer invasion and the microenvironment: plasticity and reciprocity","route":"/key-papers/paper-friedl-cell/"}]}}