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Identification of vascular cues contributing to cancer cell stemness and function

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Abstract

Glioblastoma stem cells (GSCs) reside close to blood vessels (BVs) but vascular cues contributing to GSC stemness and the nature of GSC-BVs cross talk are not fully understood. Here, we dissected vascular cues influencing GSC gene expression and function to perfusion-based vascular cues, as well as to those requiring direct GSC-endothelial cell (EC) contacts. In light of our previous finding that perivascular tumor cells are metabolically different from tumor cells residing further downstream, cancer cells residing within a narrow, < 60 µm wide perivascular niche were isolated and confirmed to possess a superior tumor-initiation potential compared with those residing further downstream. To circumvent reliance on marker expression, perivascular GSCs were isolated from the respective locales based on their relative state of quiescence. Combined use of these procedures uncovered a large number of previously unrecognized differentially expressed GSC genes. We show that the unique metabolic milieu of the perivascular niche dominated by the highly restricted zone of mTOR activity is conducive for acquisition of GSC properties, primarily in the regulation of genes implicated in cell cycle control. A complementary role of vascular cues including those requiring direct glioma/EC contacts was revealed using glioma/EC co-cultures. Outstanding in the group of glioma cells impacted by nearby ECs were multiple genes responsible for maintaining GSCs in an undifferentiated state, a large fraction of which also relied on Notch-mediated signaling. Glioma-EC communication was found to be bidirectional, evidenced by extensive Notch-mediated EC reprogramming by contacting tumor cells, primarily metabolic EC reprogramming.

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Acknowledgements

We thank Dr.Sharona Elgavish and the Info-Core Bioinformatics unit of the Hebrew University faculty of Medicine for bioinformatics analysis, all the members of the Keshet lab for their inputs and Dr. Aparna Anand for proof reading the manuscript. This work was supported by the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ), the Israeli Ministry of Science and Technology (MOST) to EK (CA-178) and New Faculty Grant from Indian Institute of Technology Delhi to SK (MI00148).

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  1. Saran Kumar

    Present address: Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India

Authors and Affiliations

  1. Department of Developmental Biology and Cancer Research, Faculty of Medicine, Hadassah Medical School, The Hebrew University, 9112001, Jerusalem, Israel

    Saran Kumar, Libat Bar-Lev, Husni Sharife, Myriam Grunewald, Tamar Licht & Eli Keshet

  2. Department of Biochemistry and Molecular Biology, Hadassah Medical School, The Hebrew University, 9112001, Jerusalem, Israel

    Maxim Mogilevsky

  3. Laboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology, Department of Oncology, KU Leuven, 3000, Leuven, Belgium

    Jermaine Goveia, Federico Taverna & Peter Carmeliet

  4. Department of Neurosurgery, Hadassah University Hospital, Ein-Kerem, 9112001, Jerusalem, Israel

    Iddo Paldor

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Contributions

SK conceived, designed, and performed experiments. LB performed in vitro co-culture experiments and data analysis. MM, HS, MG, and TL assisted in animal studies. FT, JG, and PC analyzed transcriptomics/metabolomics data of co-culture experiments. EK conceived and supervised the study. SK and EK wrote the manuscript.

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Kumar, S., Bar-Lev, L., Sharife, H. et al. Identification of vascular cues contributing to cancer cell stemness and function. Angiogenesis 25, 355–371 (2022). https://doi.org/10.1007/s10456-022-09830-z

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