Pharmacological Inhibition and Genetic Knockdown of BCL9 Modulate the Cellular Landscape of Cancer-Associated Fibroblasts in the Tumor-Immune Microenvironment of Colorectal Cancer.
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ABSTRACT:
SUBMITTER: Yang M
PROVIDER: S-EPMC8131873 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tumor-associated macrophages (TAMs) are an indispensable part of the tumor microenvironment (TME), and they likely play a negative rather than positive role in cancer treatment. However, the cellular landscape and transcriptional profile regulation of TAMs in the case of tumor gene inactivation or chemical interference remains unclear. The B-cell lymphoma 9/B-cell lymphoma 9-like (BCL9/BCL9L) is a critical transcription co-factor of β-catenin. Suppression of Bcl9 inhibits tumor growth in mouse models of colorectal cancer (CRC). Here, we studied the TAMs of CRC by single-cell sequencing. Bcl9 depletion caused macrophage polarization inhibition from M0 to M2 and changed the CRC TME, which further interferes with the inflammation of M0 and M1. The transcription factor regulating these processes may be related to the Wnt signaling pathway from multiple levels. Furthermore, we also found that the cells delineated from monocyte to NK-like non-functioning cells were significantly different in the BCL9-deprived population. Combining these data, we proposed a TAM-to-NK score to evaluate the dynamic balance in TME of monocyte/TAM cells and NK-like non-functioning cells in The Cancer Genome Atlas (TCGA) clinical samples to verify the clinical significance. We demonstrated that the cell type balance and transcription differences of TAMs regulated by BCL9-driven Wnt signaling affected immune surveillance and inflammation of cancer, ultimately affecting patients' prognosis. We thereby highlighted the potential of targeting Wnt signaling pathway through cancer immunotherapy.
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Project description:Tumor endothelial cells are an important part of the tumor microenvironment, and angiogenesis inhibitory therapy has shown potential in tumor treatment. However, which subtypes of tumor endothelial cells are distributed in tumors, what are the differences between tumor endothelial cells and normal endothelial cells, and what is the mechanism of angiogenesis inhibitory therapy at the histological level, are all need to be resolved urgently. Using single-cell mRNA sequencing, we analyzed 12 CT26 colon cancer samples from mice, and found that knockdown of the downstream factor BCL9 in the Wnt signaling pathway or inhibitor-mediated functional inhibition can modulate tumor endothelial cells at a relatively primitive stage, inhibiting their differentiation into further extracellular matrix construction and angiogenesis functions. Furthermore, we propose a BCL9-endo-Score based on the differential expression of cells related to different states of BCL9 functions. Using published data sets with normal endothelial cells, we found that this score can characterize endothelial cells at different stages of differentiation. Finally, in the The Cancer Genome Atlas (TCGA) pan-cancer database, we found that BCL9-endo-Score can well predict the prognosis of diseases including colon cancer, kidney cancer and breast cancer, and identified the markers of these tumor subtypes, provide a basis for the prognosis prediction of patients with such types of tumor. Our data also contributed knowledge for tumor precision treatment with angiogenesis inhibitory therapy by targeting the Wnt signaling pathway.
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Project description:Colorectal cancer (CRC) is the third most commonly diagnosed cancer, which despite recent advances in treatment, remains incurable due to molecular heterogeneity of tumor cells. The B-cell lymphoma 9 (BCL9) oncogene functions as a transcriptional co-activator of the Wnt/β-catenin pathway, which plays critical roles in CRC pathogenesis. Here we have identified a β-catenin-independent function of BCL9 in a poor-prognosis subtype of CRC tumors characterized by expression of stromal and neural associated genes. In response to spontaneous calcium transients or cellular stress, BCL9 is recruited adjacent to the interchromosomal regions, where it stabilizes the mRNA of calcium signaling and neural associated genes by interacting with paraspeckle proteins. BCL9 subsequently promotes tumor progression and remodeling of the tumor microenvironment (TME) by sustaining the calcium transients and neurotransmitter-dependent communication among CRC cells. These data provide additional insights into the role of BCL9 in tumor pathogenesis and point towards additional avenues for therapeutic intervention.
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Project description:Rationale: Patients with colorectal cancer die mainly due to liver metastases (CRC-LM). Although the tumor microenvironment (TME) plays an important role in tumor development and therapeutic response, our understanding of the individual TME components, especially cancer-associated fibroblasts (CAFs), remains limited. Methods: We analyzed CRC-LM CAFs and cancer cells by single-cell transcriptomics and used bioinformatics for data analysis and integration with related available single-cell and bulk transcriptomic datasets. We validated key findings by RT-qPCR, western blotting, and immunofluorescence. Results: By single-cell transcriptomic analysis of 4,397 CAFs from six CRC-LM samples, we identified two main CAF populations, contractile CAFs and extracellular matrix (ECM)-remodeling/pro-angiogenic CAFs, and four subpopulations with distinct phenotypes. We found that ECM-remodeling/pro-angiogenic CAFs derive from portal resident fibroblasts. They associate with areas of strong desmoplastic reaction and Wnt signaling in low-proliferating tumor cells engulfed in a stiff extracellular matrix. By integrating public single-cell primary liver tumor data, we propose a model to explain how different liver malignancies recruit CAFs of different origins to this organ. Lastly, we found that LTBP2 plays an important role in modulating collagen biosynthesis, ECM organization, and adhesion pathways. We developed fully human antibodies against LTBP2 that depleted LTBP2+ CAFs in vitro. Conclusion: This study complements recent reports on CRC-LM CAF heterogeneity at the single-cell resolution. The number of sequenced CAFs was more than one order of magnitude larger compared to existing data. LTBP2 targeting by antibodies might create opportunities to deplete ECM-remodeling CAFs in CRC-LMs. This might be combined with other therapies, e.g., anti-angiogenic compounds as already done in CRC. Moreover, we showed that in intrahepatic cholangiocarcinoma, in which ECM-remodeling CAF proportion is similar to that of CRC-LM, several genes expressed by ECM-remodeling CAFs, such as LTBP2, were associated with survival.
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Project description:To define differences in tumor microenvironment (TME) immune phenotypes between right and left colorectal cancers (CRCs) and explore their therapeutic implications. Gene expression profiling and clinical characteristics of patients with CRC were retrieved from The Cancer Genome Atlas data portal. Immune cell infiltration was estimated based on single-sample gene set enrichment analysis. CRCs tissue microarrays (TMAs) containing 90 consecutive cases of surgical samples were used for validation. Expression of CD8A and VEGFA was confirmed by immunohistochemistry (IHC) analysis with TMAs, and overall survival (OS) was analyzed. Expression profiling data demonstrated that CRC immune microenvironment from right side tumor was characterized as increased infiltration of immune cells with enhanced cytotoxic function, based on higher cytotoxic activity scores (CYT) and interferon-γ signatures. Expression of VEGFA, which could be neutralized by bevacizumab, was associated with decreased levels of activated CD8+ T-cells, Th1 cells, and PRF1 expression on the right side, but not on the left side. IHC analysis of TMAs further confirmed an inverse correlation between CD8A and VEGFA expression, and revealed a favorable OS for patients with CD8AHiVEGFALo disease among right-side CRCs. For the left side, higher CD56bright natural killer cell infiltration and active 4-1BB/IFN-ɑ signaling, which could providing a favorable condition for cetuximab-mediated antibody-dependent cell-mediated cytotoxicity effect, was present in a cohort with extended OS. In the TME, features of immune phenotype sidedness were identified, providing an implication for differential responses to bevacizumab/cetuximab treatment. In addition, a new avenue for innovative experimental design and combinational immunotherapy to treat CRC patients was suggested.
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Project description:Colorectal cancer (CRC) is the third most commonly diagnosed cancer, which despite recent advances in treatment, remains incurable due to molecular heterogeneity of tumor cells. The B-cell lymphoma 9 (BCL9) oncogene functions as a transcriptional co-activator of the Wnt/β-catenin pathway, which plays critical roles in CRC pathogenesis. Here we have identified a β-catenin-independent function of BCL9 in a poor-prognosis subtype of CRC tumors characterized by expression of stromal and neural associated genes. In response to spontaneous calcium transients or cellular stress, BCL9 is recruited adjacent to the interchromosomal regions, where it stabilizes the mRNA of calcium signaling and neural associated genes by interacting with paraspeckle proteins. BCL9 subsequently promotes tumor progression and remodeling of the tumor microenvironment (TME) by sustaining the calcium transients and neurotransmitter-dependent communication among CRC cells. These data provide additional insights into the role of BCL9 in tumor pathogenesis and point towards additional avenues for therapeutic intervention.
2019-11-16 | GSE140488 | GEO
Project description:BackgroundsBladder cancer (BLCA) is one of the most prevalent cancers of the genitourinary system, the clinical outcomes of patients with BLCA are bad, and the morbidity rate is high. One of the key components of the tumor microenvironment (TME) is cancer-associated fibroblasts (CAFs) which are critically involved in BLCA tumorigenesis. Previous studies have shown the involvement of CAFs in tumor growth, cancer progression, immune evasion, angiogenesis, and chemoresistance in several cancers such as breast, colon, pancreatic, ovarian, and prostate cancers. However, only a few studies have shown the role of CAFs in the occurrence and development of BLCA.MethodsWe have retrieved and merged the data on RNA-sequencing of patients with BLCA from databases including "the Cancer Genome Atlas" and "Gene Expression Omnibus." Next, we compared the differences in CAFs-related genes (CRGs) expression between normal and BLCA tissues. Based on CRGs expression, we randomly divided patients into two groups. Next, we determined the correlation between CAFs subtypes and differentially expressed CRGs (DECRGs) between the two subtypes. Furthermore, the "Gene Ontology" and "Kyoto Encyclopedia of Genes and Genomes pathway" enrichment analyses were conducted to determine the functional characteristics between the DECRGs and clinicopathology.ResultsWe identified five genes (POF1B, ARMCX1, ALDOC, C19orf33, and KRT13) using multivariate COX regression and "Least Absolute Shrinkage and Selection Operator (LASSO) COX regression analysis" for developing a prognostic model and calculating the CRGs-risk score. The TME, mutation, CSC index, and drug sensitivity were also analyzed.ConclusionWe constructed a novel five- CRGs prognostic model, which sheds light on the roles of CAFs in BLCA.
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