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posted on 2023-10-04, 07:20 authored by Merel van Gogh, Jesus F. Glaus Garzon, Dilara Sahin, Lucia Knopfova, Petr Benes, Onur Boyman, Igor Jurisica, Lubor Borsig c-Myb upregulation in MC38 tumor cells modulates genes involved in immune responses. A, Gene Ontology enrichment analysis of genes significantly dysregulated between tumor cells from mice on Dox- and Ctrl-chow using Enrichr tool (https://maayanlab.cloud/Enrichr). Sorted CD45−GFP+ tumor cells from subcutaneous MC38T/O tumors in C57BL/6J mice, after 21 days were analyzed by RNA-seq (n = 4). B, Using the list of 87 dysregulated genes as input to pathDIP (https://ophid.utoronto.ca/pathDIP), we identified significantly enriched pathways (Supplementary Table S3). Here we highlight pathway-gene associations for the top 10% significantly enriched pathways (i.e., more than 35 of the input DEGs present; listed in Supplementary Table S4). Similar pathways are grouped and color-coded (both pathway name and edge color that connects to corresponding DEGs). Number of gene–pathway associations (i.e., node degree) is reflected by node color shade from green (low degree; only a few pathways or a few genes) through red (high degree; many pathways or many genes). The node degree for genes ranges from 0 (MS4A7, KDM1B) to 90 (CD74, PTPRC, ITGB2), and for pathways from 35 (hematopoietic cell lineage, VEGFA-VEGFR2 Signaling, T-cell activation, costimulation by the CD28 family, TLR signaling, macrophage markers, T-cell antigen receptor pathway during Staphylococcus aureus infection, C-type lectin receptor signaling, RANKL/RANK Signaling) to 71 (chemokine signaling).
Funding
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
Swiss Cancer Research Foundation (Swiss Cancer Research)
History
ARTICLE ABSTRACT
The transcription factor c-Myb is overexpressed in many different types of solid tumors, including colorectal cancer. However, its exact role in tumorigenesis is unclear. In this study, we show that tumor-intrinsic c-Myb expression in mouse models of colon cancer and melanoma suppresses tumor growth. Although no differences in proliferation, apoptosis, and angiogenesis of tumors were evident in tumors with distinct levels of c-Myb expression, we observed changes in intratumoral immune cell infiltrates. MC38 tumors with upregulated c-Myb expression showed increased numbers of CD103+ dendritic cells and eosinophils, but decreased tumor-associated macrophages (TAM). Concomitantly, an increase in the number of activated cytotoxic CD8+ T cells upon c-Myb upregulation was observed, which correlated with a pro-inflammatory tumor microenvironment and increased numbers of M1 polarized TAMs. Mechanistically, c-Myb upregulation in immunogenic MC38 colon cancer cells resulted in enhanced expression of immunomodulatory genes, including those encoding β2-microglobulin and IFNβ, and decreased expression of the gene encoding the chemokine receptor CCR2. The increased numbers of activated cytotoxic CD8+ T cells contributed to tumor growth attenuation. In poorly immunogenic CT26, LLC, and B16-BL6 tumor cells, c-Myb upregulation did not affect the immunomodulatory gene expression. Despite this, c-Myb upregulation led to reduced B16-BL6 tumor growth but it did not affect tumor growth of CT26 and LLC tumors. Altogether, we postulate that c-Myb functions as a tumor suppressor in a tumor cell–type specific manner and modulates antitumor immunity.
