Invasion: proteases, adhesion & the invasive front
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.
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.
In one picture
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.
Diagram
top- 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
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