# Invasion: proteases, adhesion & the invasive front

Source: https://onco.cc/pathways/invasion-ecm-degradation/  
OnCo record `invasion-ecm-degradation` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- 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.
- 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

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Invadopodia
- Friedl & Alexander, Cancer invasion and the microenvironment: plasticity and reciprocity (Cell 2011): https://doi.org/10.1016/j.cell.2011.11.016

## Connected records

- terms: [Cancer-associated fibroblasts (CAFs)](https://onco.cc/terms/cancer-associated-fibroblasts/), [Desmoplasia (tumour stroma)](https://onco.cc/terms/desmoplasia/), [Hallmark: activating invasion and metastasis](https://onco.cc/terms/activating-invasion-metastasis/), [Low-grade serous ovarian cancer (LGSOC)](https://onco.cc/terms/lgsoc/), [Mechanical theory: stiffness, pressure and force as causes](https://onco.cc/terms/mechanical-theory-of-cancer/), [TNM staging](https://onco.cc/terms/tnm-staging/)
- cancers: [Head and neck squamous cell carcinoma](https://onco.cc/cancers/head-and-neck/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [FAPI PET](https://onco.cc/technologies/fapi-pet/), [Fluorescence-guided surgery](https://onco.cc/technologies/fluorescence-guided-surgery/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/), [Single-cell & spatial profiling](https://onco.cc/technologies/single-cell-spatial/), [Targeting tumour mechanics and pressure](https://onco.cc/technologies/mechanobiology-therapy/)
- targets: [FAK (PTK2)](https://onco.cc/targets/fak/), [FAP](https://onco.cc/targets/fap/), [HGF](https://onco.cc/targets/hgf/), [KRAS](https://onco.cc/targets/kras/), [MET](https://onco.cc/targets/met/), [MMP2](https://onco.cc/targets/mmp2/), [Smoothened (hedgehog pathway)](https://onco.cc/targets/smoothened/), [ZEB1](https://onco.cc/targets/zeb1/)
- drugs: [Avutometinib + defactinib](https://onco.cc/drugs/avutometinib-defactinib/), [FAP-2286 (177Lu / 68Ga)](https://onco.cc/drugs/fap-2286/)
- pathways: [Basement membrane & tissue barriers](https://onco.cc/pathways/basement-membrane-tissue-barriers/), [Epithelial-mesenchymal transition & drug efflux](https://onco.cc/pathways/emt/), [Fibroblast activation, desmoplasia & matrix stiffness](https://onco.cc/pathways/caf-activation-desmoplasia/), [Hippo-YAP/TAZ](https://onco.cc/pathways/hippo-yap/), [TGF-β signalling](https://onco.cc/pathways/tgf-beta/), [The metastatic cascade](https://onco.cc/pathways/metastatic-cascade/)
- key papers: [Cancer invasion and the microenvironment: plasticity and reciprocity](https://onco.cc/key-papers/paper-friedl-cell/)

---
JSON: https://onco.cc/api/v1/entities/invasion-ecm-degradation.json