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Fibrotic Response to anti-CSF-1R Treatment Potentiates Glioblastoma Recurrence

ABSTRACT: Treatment of glioblastoma with anti-CSF-1R immunotherapy, radiotherapy, or surgical tumor resection were found to all induce a fibrotic response to treatment, which was highly associated with tumor recurrence. To investigate the drivers of fibrotic treatment response we performed multi-omic analysis of the glioblastoma microenvironment following treatment with anti-CSF-1R immunotherapy. Studies consisted of mass spectrometry proteomic analysis, single cell transcriptomics, and high-dimensional spatial analysis. These data identified a protective spatial niche that supported tumor cell survival following treatment, ultimately leading to tumor recurrence. Therapeutic inhibition of fibrotic treatment response blocked the formation of this niche, and significantly improved survival in anti-CSF-1R preclinical trials

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Glioblastoma Cell

DISEASE(S): Glioblastoma

SUBMITTER: Manfredo Quadroni

LAB HEAD: Johanna Joyce

PROVIDER: PXD041689 | Pride | 2024-08-12

REPOSITORIES: Pride

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Project description:Macrophage polarization between the M2 (repair, pro-tumorigenic) and M1 (inflammatory) phenotypes is seen as a continuum of states. The detailed transcriptional events and signals downstream of CSF-1R that contribute to amplification of the M2 phenotype and suppression of the M1 phenotype are largely unknown. Macrophage CSF-1R pTyr-721 signaling promotes cell motility and enhancement of tumor cell invasion in vitro. Combining analysis of cellular systems for CSF-1R gain-of-function and loss-of-function with bioinformatic analysis of the macrophage CSF-1R pTyr-721-regulated transcriptome, we uncovered miR-21 as a downstream molecular switch controlling macrophage activation and identified ERK1/2 and NF-M-NM-:B as CSF-1R pTyr-721-regulated signaling nodes. We show that CSF-1R pTyr-721 signaling suppresses the proinflammatory phenotype, predominantly by induction of miR-21. Profiling of the miR-21-regulated mRNAs revealed that 80% of the CSF-1-regulated canonical miR-21 targets are pro-inflammatory molecules. Additionally, miR-21 positively regulates M2 marker expression. Moreover, miR-21 feeds back to positively regulate its own expression and to limit CSF-1R-mediated activation of ERK1/2 and NF-M-NM-:B. Consistent with an anti-inflammatory role of miRNA-21, intraperitoneal injection of mice with a miRNA-21 inhibitor increases the recruitment of inflammatory monocytes and enhances the peritoneal monocyte/macrophage response to lipopolysaccharide (LPS). M-bM-^@M-^C These results identify the macrophage miR-21 network as a novel target for controlling macrophage polarization. We performed microarray-based analysis on four mouse macrophage cell lines, two CSF-1R pTyr-721-expressing cell lines (M-/-.WT and M-/-.3ABY721) and two CSF-1R Tyr-721-deficient lines (M-/-.Y721F and M-/-.3AB). Total RNA (two biological replicates) was extracted from CSF-1-starved cells (UR) or from cells constitutively grown in CSF-1 (CONST). Additionally, CSF-1-starved M-/-.WT and M-/-.Y721F cell lines were stimulated with CSF-1 for 0min, 20 min, 60 min and 180 min and used for total RNA extraction. Total RNA preparations with Ribosomal Integrity Numbers (RIN) > 9.5 were used for microarray analysis. A total of 100 ug/cell line/replicate was used for gene expresion analysis on the Affymetrix Mouse Gene ST1.0 chips at the Genomics Core at Einstein, according to manufacturerM-bM-^@M-^Ys instructions. Differential expression analysis was performed using the M-bM-^@M-^XlimmaM-bM-^@M-^Y package of R/Bioconductor to identify significantly differentially expressed mRNAs over time, in response to CSF-1 treatment and to the genotype. CSF1-regulated genes were identified according to the cutoff with both expression folder change > 1.5 and p-value < 0.05.

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Fibrotic Response to anti-CSF-1R Treatment Potentiates Glioblastoma Recurrence

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