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BMP9 signaling promotes the normalization of tumor blood vessels

Oncogene volume 39, pages 2996–3014 (2020)Cite this article

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Abstract

The presence of an immature tumor vascular network contributes to cancer dissemination and the development of resistance to therapies. Strategies to normalize the tumor vasculature are therefore of significant therapeutic interest for cancer treatments. VEGF inhibitors are used clinically to normalize tumor blood vessels. However, the time frame and dosage of these inhibitors required to achieve normalization is rather narrow, and there is a need to identify additional signaling targets to attain vascular normalization. In addition to VEGF, the endothelial-specific receptor Alk1 plays a critical role in vascular development and promotes vascular remodeling and maturation. Therefore, we sought to evaluate the effects of the Alk1 ligand BMP9 on tumor vascular formation. BMP9 overexpression in Lewis Lung Carcinoma (LLC) tumors significantly delayed tumor growth. Blood vessels in BMP9-overexpressing LLC tumors displayed markers of vascular maturation and were characterized by increased perivascular cell coverage. Tumor vasculature normalization was associated with decreased permeability and increased perfusion. These changes in vascular function in BMP9-overexpressing LLC tumors resulted in significant alterations of the tumor microenvironment, characterized by a decrease in hypoxia and an increase in immune infiltration. In conclusion, we show that BMP9 promotes vascular normalization in LLC tumors that leads to changes in the microenvironment.

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Fig. 1: BMP9 overexpression inhibits tumor growth in mice.
Fig. 2: BMP9 overexpression increases vascular density, blood vessels maturation, pericyte coverage and perfusion in LLC tumors.
Fig. 3: Endothelial expression of Alk1 is required for BMP9-induced tumor growth inhibition.
Fig. 4: BMP9 overexpression in tumor cells modulates the angiogenic phenotype of ECs.
Fig. 5: BMP9 overexpression stabilizes endothelial junctions.
Fig. 6: BMP9 inhibits tumor vascular permeability in LLC tumors.
Fig. 7: BMP9-induced vascular normalization alters the tumor micro-environment.
Fig. 8: Vascular normalization in BMP9-overexpressing LLC tumors results in increased immune cell infiltration.

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Acknowledgements

We thank Dr. Paul S. Oh for kindly providing the Alk1ΔEC mice and Manuel Buscarlet for assistance with data analysis. This work was supported by an operating grant from the Cancer Research Society, and an operating grant from the Canadian Institutes of Health Research (363450). CV was supported by a post-doctoral research award from Fonds de recherche – Santé (FRQS). NA was supported by the Department of Ophthalmology of Université de Montréal Research Fund Award (FROUM), Suzanne–Veronneau–Troutmann Award (SVT) and a FRQS scholarship. CA is recipient of a Montreal Diabetes Research Center PhD Award. SL is an FRQS Research Scholar Emeritus. BL is recipient of a New Investigator Award from the Heart and Stroke Foundation of Canada.

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  1. Centre de Recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada

    Claire Viallard, Cindy Audiger, Natalija Popovic, Naoufal Akla, Kevin Lanthier, Isaac Legault-Navarrete, Heather Melichar, Santiago Costantino, Sylvie Lesage & Bruno Larrivée

  2. Département de Biologie Moléculaire, Université de Montréal, Montréal, QC, Canada

    Claire Viallard, Natalija Popovic, Kevin Lanthier & Bruno Larrivée

  3. Département de Microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada

    Cindy Audiger & Sylvie Lesage

  4. Département de Biochimie, Université de Montréal, Montréal, QC, Canada

    Naoufal Akla

  5. Département de Médecine, Université de Montréal, Montréal, QC, Canada

    Heather Melichar

  6. Département d’Ophtalmologie, Université de Montréal, Montréal, QC, Canada

    Santiago Costantino & Bruno Larrivée

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Viallard, C., Audiger, C., Popovic, N. et al. BMP9 signaling promotes the normalization of tumor blood vessels. Oncogene 39, 2996–3014 (2020). https://doi.org/10.1038/s41388-020-1200-0

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