Single-cell heterogeneity of EGFR and CDK4 co-amplification is linked to immune infiltration in glioblastoma

Kacper A Walentynowicz; Dalit Engelhardt; Simona Cristea; Shreya Yadav; Ugoma Onubogu; Roberto Salatino; Melanie Maerken; Cristina Vincentelli; Aashna Jhaveri; Jacob Geisberg; Thomas O McDonald; Franziska Michor; Michalina Janiszewska

doi:10.1016/j.celrep.2023.112235

Single-cell heterogeneity of EGFR and CDK4 co-amplification is linked to immune infiltration in glioblastoma

Cell Rep. 2023 Mar 28;42(3):112235. doi: 10.1016/j.celrep.2023.112235. Epub 2023 Mar 14.

Affiliations

¹ Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technologies, Jupiter, FL, USA; Department of Molecular Medicine, Scripps Research, Jupiter, FL, USA.
² Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
³ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Department of Medical Oncology, Harvard Medical School, Boston, MA, USA.
⁴ Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technologies, Jupiter, FL, USA; Department of Molecular Medicine, Scripps Research, Jupiter, FL, USA; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA, USA.
⁵ Department of Pathology, Mount Sinai Medical Center, Miami Beach, FL, USA.
⁶ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA; The Ludwig Center at Harvard, Boston, MA, USA. Electronic address: michor@jimmy.harvard.edu.
⁸ Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technologies, Jupiter, FL, USA; Department of Molecular Medicine, Scripps Research, Jupiter, FL, USA; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: mjaniszewska@ufl.edu.

Abstract

Glioblastoma (GBM) is the most aggressive brain tumor, with a median survival of ∼15 months. Targeted approaches have not been successful in this tumor type due to the large extent of intratumor heterogeneity. Mosaic amplification of oncogenes suggests that multiple genetically distinct clones are present in each tumor. To uncover the relationships between genetically diverse subpopulations of GBM cells and their native tumor microenvironment, we employ highly multiplexed spatial protein profiling coupled with single-cell spatial mapping of fluorescence in situ hybridization (FISH) for EGFR, CDK4, and PDGFRA. Single-cell FISH analysis of a total of 35,843 single nuclei reveals that tumors in which amplifications of EGFR and CDK4 more frequently co-occur in the same cell exhibit higher infiltration of CD163⁺ immunosuppressive macrophages. Our results suggest that high-throughput assessment of genomic alterations at the single-cell level could provide a measure for predicting the immune state of GBM.

Keywords: CDK4; CP: Cancer; EGFR; genetic heterogeneity; glioblastoma; tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain Neoplasms* / metabolism
Cyclin-Dependent Kinase 4 / genetics
Cyclin-Dependent Kinase 4 / metabolism
ErbB Receptors / genetics
ErbB Receptors / metabolism
Gene Amplification
Glioblastoma* / pathology
Humans
In Situ Hybridization, Fluorescence
Oncogenes
Tumor Microenvironment

Substances

ErbB Receptors
CDK4 protein, human
Cyclin-Dependent Kinase 4
EGFR protein, human

Single-cell heterogeneity of EGFR and CDK4 co-amplification is linked to immune infiltration in glioblastoma

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Abstract

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