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This study demonstrates that loss of Kindlin-1, a protein that regulates cell adhesion to the extracellular matrix, disrupts the normal coordination between blood vessel formation and tissue structure in cutaneous squamous cell carcinoma. Using mouse models, the researchers found that tumors lacking Kindlin-1 developed dense but dysfunctional blood vessel networks and simplified collagen matrices, resulting in persistent oxygen deprivation (hypoxia) despite increased vessel density. The uncoupling of vascular and matrix organization promotes tumor invasion and progression through sustained hypoxia and activation of tissue-remodeling pathways.
Why it matters
These findings explain why patients with Kindler epidermolysis bullosa, who have mutations in the gene encoding Kindlin-1, develop particularly aggressive skin cancers. Understanding this mechanism could lead to therapeutic strategies targeting the abnormal vascular and matrix remodeling in these tumors, potentially improving outcomes for high-risk patients.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.