Kindlin-1 loss disrupts vascular and extracellular matrix organisation to sustain hypoxia in cutaneous squamous cell carcinoma

Kindlin-1, encoded by FERMT1, is an essential integrin co-activator that regulates cell-extracellular matrix (ECM) adhesion, tissue architecture, and microenvironment signalling. Loss-of-function mutations in FERMT1 cause Kindler epidermolysis bullosa, which is strongly associated with aggressive cutaneous squamous cell carcinoma (cSCC). Although Kindlin-1 deficiency promotes hypoxia and invasion, the impacts on ECM-vascular organisation and oxygen homeostasis are not known. Here, using genetic deletion of Kindlin-1 in a murine model of cSCC across 2D cultures, 3D spheroids, and in vivo tumours, combined with collagen and vascular imaging and spatial mixed-effects modelling, we show that Kindlin-1 loss uncouples ECM-vascular regulation, driving hypoxia and tumour progression. Tumours in which Kindlin-1 was deleted displayed a dense but dysfunctional vascular network, with reduced tissue-to-vessel and inter-bifurcation distances, increased vessel alignment, and persistent hypoxia despite increased vascular density. Collagen deposition was reduced and fibres were straighter, indicating a simplified, invasion-permissive matrix. Hypoxia increased Vegfa and Angpt1 expression while reducing Col1a1, and hypoxia-responsive spheroids confirmed greater hypoxia and invasiveness in Kindlin-1-deficient cells. Transcriptomic analysis revealed enrichment of ECM degradation and vascular dysfunction pathways, including upregulation of matrix-remodelling and vascular permeability genes such as Mmp13, Mmp3, and Ptgs2, alongside reduced collagen-associated and vascular homeostasis genes. Spatial modelling further showed disrupted collagen-vascular coupling and an association between hypoxia and reduced vessel diameter, consistent with dysfunctional angiogenesis rather than improved perfusion. These changes arose early and independently of tumour size, establishing impaired integrin activation as a central mechanism linking ECM degradation, vascular dysfunction, and sustained hypoxia in aggressive cSCC.