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// Benoit Langlois 1, 2, 3, 4, * , Falk Saupe 1, 2, 3, 4, * , Tristan Rupp 1, 2, 3, 4 , Christiane Arnold 1, 2, 3, 4 , Michael van der Heyden 1, 2, 3, 4 , Gertraud Orend 1, 2, 3, 4 , Thomas Hussenet 1, 2, 3, 4 1 Inserm U1109, MN3T team, Moliere, Strasbourg, 67200, France 2 Universite de Strasbourg, Strasbourg, 67000, France 3 LabEx Medalis, Universite de Strasbourg, Strasbourg, 67000, France 4 Federation de Medecine Translationnelle de Strasbourg (FMTS), Strasbourg, 67000, France * These authors contributed equally to this work Correspondence to: Gertraud Orend, e-mail: gertraud.orend@inserm.fr Thomas Hussenet, e-mail: hussenetthomas@gmail.com Keywords: Tumor angiogenesis, angiogenic switch, extracellular matrix, matrisome Received: July 23, 2014 Accepted: September 06, 2014 Published: October 07, 2014 ABSTRACT Angiogenesis represents a rate-limiting step during tumor progression. Targeting angiogenesis is already applied in cancer treatment, yet limits of anti-angiogenic therapies have emerged, notably because tumors adapt and recur after treatment. Therefore, there is a strong need to better understand the molecular and cellular mechanisms underlying tumor angiogenesis. Using the RIP1-Tag2 transgenic murine model, we identified 298 genes that are deregulated during the angiogenic switch, revealing an ingression/expansion of specific stromal cell types including endothelial cells and pericytes, but also macrophages and perivascular mesenchymal cells. Canonical TGF-β signaling is up-regulated during the angiogenic switch, especially in tumor-associated macrophages and fibroblasts. The matrisome, comprising extracellular matrix (ECM) and ECM-associated molecules, is significantly enriched, which allowed us to define the AngioMatrix signature as the 110 matrisomal genes induced during the RIP1-Tag2 angiogenic switch. Several AngioMatrix molecules were validated at expression level. Ablation of tenascin-C, one of the most highly induced ECM molecules during the switch, resulted in reduced angiogenesis confirming its important role. In human glioma and colorectal samples, the AngioMatrix signature correlates with the expression of endothelial cell markers, is increased with tumor progression and finally correlates with poor prognosis demonstrating its diagnostic and therapeutic potential.