title: Compound genetically engineered mouse models of cancer reveal dual targeting of ALK1 and endoglin as a synergistic opportunity to impinge on angiogenic TGF-β signaling.
abstract: Angiogenesis occurs early in tumor development, sustains primary tumor growth and provides a route for metastatic escape. The TGF-β family receptors modulate angiogenesis via endothelial-cell specific pathways. Here we investigate the interaction of two such receptors, ALK1 and endoglin, in pancreatic neuroendocrine tumors (PanNET). Independently, ALK1 and endoglin deficiencies exhibited genetically divergent phenotypes, while both highly correlate to an endothelial metagene in human and mouse PanNETs. A concurrent deficiency of both receptors synergistically decreased tumor burden to a greater extent than either individual knockdown. Furthermore, the knockout of Gdf2 (BMP9), the primary ligand for ALK1 and endoglin, exhibited a mixed phenotype from each of ALK1 and endoglin deficiencies; overall primary tumor burden decreased, but hepatic metastases increased. Tumors lacking BMP9 display a hyperbranching vasculature, and an increase in vascular mesenchymal-marker expression, which may be implicit in the increase in metastases. Taken together, our work cautions against singular blockade of BMP9 and instead demonstrates the utility of dual blockade of ALK1 and endoglin as a strategy for anti-angiogenic therapy in PanNET.
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden.
authors.forename: Nikolas M
authors.initials: NM
authors.lastname: Eleftheriou
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Sjölund
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bocci
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden.
authors.forename: Eliane
authors.initials: E
authors.lastname: Cortez
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Sara I
authors.initials: SI
authors.lastname: Cunha
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden.
authors.forename: Kristian
authors.initials: K
authors.lastname: Pietras
mesh_terms: D030201:Activin Receptors, Type I / Q000172:deficiency / Q000235:genetics*; D030301:Activin Receptors, Type II; D000818:Animals; D000071063:Endoglin / Q000172:deficiency / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055427:Growth Differentiation Factor 2 / Q000172:deficiency / Q000235:genetics; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D016212:Transforming Growth Factor beta; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse
keywords: ALK1; BMP9; angiogenesis; endoglin; targeted therapy