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Topographic mapping of the glioblastoma proteome reveals a triple-axis model of intra-tumoral heterogeneity
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Topographic mapping of the glioblastoma proteome reveals a triple-axis model of intra-tumoral heterogeneity
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Journal Article
Topographic mapping of the glioblastoma proteome reveals a triple-axis model of intra-tumoral heterogeneity
2022
Overview
Glioblastoma is an aggressive form of brain cancer with well-established patterns of intra-tumoral heterogeneity implicated in treatment resistance and progression. While regional and single cell transcriptomic variations of glioblastoma have been recently resolved, downstream phenotype-level proteomic programs have yet to be assigned across glioblastoma’s hallmark histomorphologic niches. Here, we leverage mass spectrometry to spatially align abundance levels of 4,794 proteins to distinct histologic patterns across 20 patients and propose diverse molecular programs operational within these regional tumor compartments. Using machine learning, we overlay concordant transcriptional information, and define two distinct proteogenomic programs, MYC- and KRAS-axis hereon, that cooperate with hypoxia to produce a tri-dimensional model of intra-tumoral heterogeneity. Moreover, we highlight differential drug sensitivities and relative chemoresistance in glioblastoma cell lines with enhanced KRAS programs. Importantly, these pharmacological differences are less pronounced in transcriptional glioblastoma subgroups suggesting that this model may provide insights for targeting heterogeneity and overcoming therapy resistance.
Gioblastoma tumours consist of different niches defined by histology. Here, the authors use proteomics and machine learning to assign protein expression programs to these niches, and reveal that KRAS and hypoxia are associated with drug resistance.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 82/51
/ 82/58
/ Antineoplastic Agents - therapeutic use
/ Brain Neoplasms - drug therapy
/ Drug Resistance, Neoplasm - genetics
/ Gene Expression Regulation, Neoplastic
/ Humanities and Social Sciences
/ Humans
/ Hypoxia
/ Laser Capture Microdissection
/ Neoplasm Proteins - classification
/ Neoplasm Proteins - genetics
/ Neoplasm Proteins - metabolism
/ Proteins
/ Proto-Oncogene Proteins c-myc - genetics
/ Proto-Oncogene Proteins c-myc - metabolism
/ Proto-Oncogene Proteins p21(ras) - genetics
/ Proto-Oncogene Proteins p21(ras) - metabolism
/ Science
/ Tumors
