Intra-Tumoral Metabolic Zonation and Resultant Phenotypic Diversification Are Dictated by Blood Vessel Proximity

Differential exposure of tumor cells to blood-borne and angiocrine factors results in diverse metabolic microenvironments conducive for non-genetic tumor cell diversification. Here, we harnessed a methodology for retrospective sorting of fully functional, stroma-free cancer cells solely on the basis...

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Bibliographic Details
Published in:Cell metabolism 2019-07, Vol.30 (1), p.201-211.e6
Main Authors: Kumar, Saran, Sharife, Husni, Kreisel, Tirzah, Mogilevsky, Maxim, Bar-Lev, Libat, Grunewald, Myriam, Aizenshtein, Elina, Karni, Rotem, Paldor, Iddo, Shlomi, Tomer, Keshet, Eli
Format: Article
Language:English
Subjects:
blood vessels
glioblastoma
metabolic compartmentalization
mTOR pathway
tumor heterogeneity
tumor microenvironment
tumor vasculature
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Summary:Differential exposure of tumor cells to blood-borne and angiocrine factors results in diverse metabolic microenvironments conducive for non-genetic tumor cell diversification. Here, we harnessed a methodology for retrospective sorting of fully functional, stroma-free cancer cells solely on the basis of their relative distance from blood vessels (BVs) to unveil the whole spectrum of genes, metabolites, and biological traits impacted by BV proximity. In both grafted mouse tumors and natural human glioblastoma (GBM), mTOR activity was confined to few cell layers from the nearest perfused vessel. Cancer cells within this perivascular tier are distinguished by intense anabolic metabolism and defy the Warburg principle through exercising extensive oxidative phosphorylation. Functional traits acquired by perivascular cancer cells, namely, enhanced tumorigenicity, superior migratory or invasive capabilities, and, unexpectedly, exceptional chemo- and radioresistance, are all mTOR dependent. Taken together, the study revealed a previously unappreciated graded metabolic zonation directly impacting the acquisition of multiple aggressive tumor traits. [Display omitted] •A methodology for sorting cancer cells based on the distance from blood vessels•Differential exposure to vascular inputs generates multiple metabolic niches•mTOR activity in glioblastoma is restricted to a narrow perivascular tier•Enhanced aggressiveness and chemoresistance of perivascular cells are mTOR dependent Kumar et al. report a previously unappreciated level of metabolic zonation within glioblastoma tumors dictated by the relative distance from blood vessels. This metabolic zonation leads to position-dependent functional heterogeneity. Proximity to perfused vessels endows a “privileged” perivascular tier with a distinctive mTOR-dominated anabolic metabolism, enhanced cancer aggressiveness, and superior resistance to chemo- and radiotherapy.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2019.04.003