WNThigh colon cancer stem cells drive résistance to standard anti-angiogenic therapies

Although chemotherapy combined with the anti-angiogenic, VEGF-blocking antibody bevacizumab is a first-line treatment for metastatic colorectal cancer (CRC) it provides only a modest survival benefit. In this work, we examined potential mechanisms driving bevacizumab resistance in tumors with high levels of Wnt signaling (Wnthi), which make up 37% of CRC cases. We showed that both normal and transformed intestinal stem cells are localized in normoxic zones surrounded by a stable vasculature, while more differentiated intestinal cells are hypoxic and associated with actively sprouting and angiogenic blood vessels. Furthermore, while anti-Vegf treatment efficiently prunes such sprouting blood vessels in Wnthi tumors, stem cell-associated vessels are highly resistant to Vegf deprivation. Analysis of tumors from colon cancer patients confirmed that vessels in WNThi tumors were anti-correlated with active VEGF-signaling. Finally, assessment of transcriptomes from endothelial cell sorted after epithelial activation of Wnt signaling demonstrated increased expression of Sema3F and Apelin. Overexpression of either gene in MC38 cancer cells, normally highly sensitive to Vegfa blockade, switched tumor sensitivity towards resistance. Our work suggests that CRC stem cells actively remodel blood vessels and identifies one of the mechanisms for intrinsic or acquired resistance to anti-VEGF therapies in CRC. Additional studies would enable the development of novel treatments and potential diagnostic tools. Indeed, high WNT activity might represent a negative predictive marker of bevacizumab response. -- Dans 20% des cas de cancer colorectaux (CCR), des metastases sont deja presentes et justifient un traitement par bevacizumab, un anticorps bloquant le VEGF-A. Ce medicament n’augmente cependant que modestement la survie globale des patients. Nous avons investigue les mecanismes potentiels de resistance au bevacizumab dans des modeles de CCR ou la voie de signalisation Wnt est fortement activee (Wnthi) et qui represente 37% des cas. Nous avons observe que les cellules souches intestinales ou cancereuses sont associees a une vascularisation peu dense et un environnement normoxique. Par contre, les cellules intestinales ou cancereuses bien differenciees sont hypoxiques et proches de vaisseaux en constant remaniement et fortement angiogeniques. Apres traitement par anti- Vegf, la presence de cellules souches rendait les vaisseaux sanguins resistants, annulant ainsi l’effet global sur la croissance tumorale. Ces resultats ont ete confirmes dans des echantillons de patients. L’analyse transcriptomique de cellules endotheliales isolees apres l’activation epitheliale de la voie Wnt dans l’intestin a demontre que l’expression de Sema3F et Apelin etaient fortement augmentees. La surexpression de Sema3F et Apelin dans des tumeurs MC38 prealablement sensibles aux anti-Vegf a induit un mecanisme de resistance au traitement. Ce travail suggere donc que les cellules souches cancereuses dans le CCR regulent activement le developpement des vaisseaux sanguins et representent un des mecanismes de resistance aux therapies anti-angiogeniques. Il propose d’utiliser la signature WNT comme biomarqueur predictif pour ce type de traitement.