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Glioma stem cell regulator S100A4 modulates gbm immune landscape

Gallup, Thomas and Nirala, Bikesh and Abdelfatta, Nourhan and Squatrito, Massimo and George, Joshy and Baskin, David and Yun, Kyuson (2018) Glioma stem cell regulator S100A4 modulates gbm immune landscape. Neuro-Oncology, 20 (S6). Art. No. STEM-04. ISSN 1522-8517. https://resolver.caltech.edu/CaltechAUTHORS:20190322-091103097

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Abstract

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is virtually incurable. Immunotherapy is a promising new approach to treat GBM as it harnesses one’s own immune system to recognize and kill aberrant cancer cells. Unfortunately ongoing trials with immunotherapies show disappointing results in most glioma patients. GBM has highly immune-suppressive microenvironment. Consistently, mesenchymal subtype, the subtype with worst prognosis, has a strong immune signature. We recently reported that S100A4 is necessary for human and mouse glioma initiating cell (GIC) self-renewal and tumor growth, and that S100A4 is a master regulator of mesenchymal transition in GBM. Importantly, we report that S100A4 regulates expression of cytokines that affect TAM infiltration and polarization towards tumor-promoting phenotype. Consistently, TCGA and IVY-GAP data analyses indicate that S100A4 expression is strongly correlated with GBM patient survival, the mesenchymal subtype, and tumor-promoting TAM (tumor-associated macrophage) and MDSC (myeloid-derived suppressor cell) marker expression (such as CD163, CD204/MSR1, IL10, CD11b, S100A8, and S100A9). S100A4 expression and TAM marker expression strikingly overlap in perivascular and perinecrotic regions, previously reported niches for GICs. Interestingly there is no correlation between S100A4 expression and markers of microglia. Through single cell RNA-sequencing analyses of human GBM samples, we now have evidence that S100A4 is expressed in both glioma cells and infiltrating myeloid cells. When S100a4 is knocked down in mouse glioma cells and transplanted into syngeneic mice, tumor promoting myeloid cell numbers are significantly reduced. We are currently testing the role of S100A4 in bone marrow derived myeloid cells and elucidating the molecular mechanism of S100A4 function. Our unpublished observations strongly suggest that S100A4 is a critical regulator of GBM immune landscape and may be key node that links GICs, mesenchymal transition, and the myeloid cell infiltration.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1093/neuonc/noy148.1011DOIArticle
Additional Information:© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model). Published: 05 November 2018.
Subject Keywords:cytokine phenotype stem cells glioblastoma adult glioma immune system immunotherapy interleukin-10 macrophage-1 antigen macrophages microglia myeloid cells sequence analysis, rna bone marrow brain mice neoplasms tumor growth tumor cells, malignant the cancer genome atlas project myeloid-derived suppressor cells s100 calcium-binding protein a4
Issue or Number:S6
Record Number:CaltechAUTHORS:20190322-091103097
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190322-091103097
Official Citation:Thomas Gallup, Bikesh Nirala, Nourhan Abdelfatta, Massimo Squatrito, Joshy George, David Baskin, Kyuson Yun, STEM-04. GLIOMA STEM CELL REGULATOR S100A4 MODULATES GBM IMMUNE LANDSCAPE, Neuro-Oncology, Volume 20, Issue suppl_6, November 2018, Page vi244, https://doi.org/10.1093/neuonc/noy148.1011
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94041
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:22 Mar 2019 16:28
Last Modified:03 Oct 2019 21:00

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