Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis

Abstract Background: PD-L1 immunotherapy remains poorly efficacious in colorectal cancer. The RON receptor tyrosine kinase plays an important role in regulating tumor immunity. Here, we identify patterns of RON and PD-L1 expression and explore the clinical significance of these patterns in colorectal cancer. Methods: Gene expression data were obtained from the Gene Expression Omnibus database (GEO; n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZUSM; n = 381) and were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor cells and the tumor microenvironment of colorectal cancer. Human colorectal cancer cell lines were treated with BMS-777607 to explore the relationship between RON activity and PD-L1 protein expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and western blot. Results: In the GEO cohort, cut-off values for RON and PD-L1 expression of 7.70 and 4.30, respectively, were determined. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 associated with poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and in tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121 (32%), 43 (11%), 91 (24%), and 51 (13.4%), respectively. High expression of RON and high expression of PD-L1 in the tumor cell compartment was significantly correlated (p < 0.001). High expression of RON and PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with poor prognosis. In vitro , BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in colorectal cancer cells. Conclusions: RON, PD-L1 and the crosstalk between these proteins plays an important role in predicting the prognostic value of colorectal cancer. Moreover, phosphorylation of RON upregulates the expression of PD-L1, which provides a novel approach to immunotherapy in colorectal cancer.

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High Expression of LTBP2 Contributes to Poor Prognosis in Patients with Colorectal Cancer

SSRN Electronic Journal ◽

10.2139/ssrn.3244026 ◽

2018 ◽

Author(s):

Ying Huang ◽

Guihua Wang ◽

Chunmei Zhao ◽

Rong Geng ◽

Shu Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Poor Prognosis ◽

High Expression

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Early T Stage Is Associated With Poor Prognosis in Patients With Metastatic Liver Colorectal Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.00716 ◽

2020 ◽

Vol 10 ◽

Author(s):

Lunpo Wu ◽

Jianfei Fu ◽

Yi Chen ◽

Liangjing Wang ◽

Shu Zheng

Keyword(s):

Colorectal Cancer ◽

Poor Prognosis ◽

T Stage ◽

Metastatic Liver

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Recruitment and Expansion of Tregs Cells in the Tumor Environment—How to Target Them?

Cancers ◽

10.3390/cancers13081850 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1850

Author(s):

Justine Cinier ◽

Margaux Hubert ◽

Laurie Besson ◽

Anthony Di Roio ◽

Céline Rodriguez ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Tumor Microenvironment ◽

Poor Prognosis ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Major Function ◽

Normal Tissues ◽

Tumor Environment ◽

Plastic Transformation

Regulatory T cells (Tregs) are present in a large majority of solid tumors and are mainly associated with a poor prognosis, as their major function is to inhibit the antitumor immune response contributing to immunosuppression. In this review, we will investigate the mechanisms involved in the recruitment, amplification and stability of Tregs in the tumor microenvironment (TME). We will also review the strategies currently developed to inhibit Tregs’ deleterious impact in the TME by either inhibiting their recruitment, blocking their expansion, favoring their plastic transformation into other CD4+ T-cell subsets, blocking their suppressive function or depleting them specifically in the TME to avoid severe deleterious effects associated with Treg neutralization/depletion in the periphery and normal tissues.

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MYH9-dependent polarization of ATG9B promotes colorectal cancer metastasis by accelerating focal adhesion assembly

Cell Death and Differentiation ◽

10.1038/s41418-021-00813-z ◽

2021 ◽

Author(s):

Yan Zhong ◽

Ting Long ◽

Chuan-Sha Gu ◽

Jing-Yi Tang ◽

Ling-Fang Gao ◽

...

Keyword(s):

Colorectal Cancer ◽

Focal Adhesion ◽

Poor Prognosis ◽

Cancer Metastasis ◽

Integrin Β1 ◽

Independent Manner ◽

Interacting Protein ◽

Tumour Metastasis ◽

Elevated Expression ◽

Dependent Polarization

AbstractTumour metastasis is a major reason accounting for the poor prognosis of colorectal cancer (CRC), and the discovery of targets in the primary tumours that can predict the risk of CRC metastasis is now urgently needed. In this study, we identified autophagy-related protein 9B (ATG9B) as a key potential target gene for CRC metastasis. High expression of ATG9B in tumour significantly increased the risk of metastasis and poor prognosis of CRC. Mechanistically, we further find that ATG9B promoted CRC invasion mainly through autophagy-independent manner. MYH9 is the pivotal interacting protein for ATG9B functioning, which directly binds to cytoplasmic peptide segments aa368–411 of ATG9B by its head domain. Furthermore, the combination of ATG9B and MYH9 enhance the stability of each other by decreasing their binding to E3 ubiquitin ligase STUB1, therefore preventing them from ubiquitin-mediated degradation, which further amplified the effect of ATG9B and MYH9 in CRC cells. During CRC cell invasion, ATG9B is transported to the cell edge with the assistance of MYH9 and accelerates focal adhesion (FA) assembly through mediating the interaction of endocytosed integrin β1 and Talin-1, which facilitated to integrin β1 activation. Clinically, upregulated expression of ATG9B in human CRC tissue is always accompanied with highly elevated expression of MYH9 and associated with advanced CRC stage and poor prognosis. Taken together, this study highlighted the important role of ATG9B in CRC metastasis by promoting focal adhesion assembly, and ATG9B together with MYH9 can provide a pair of potential therapeutic targets for preventing CRC progression.

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Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001341 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001341

Author(s):

Chunxiao Li ◽

Xiaofei Xu ◽

Shuhua Wei ◽

Ping Jiang ◽

Lixiang Xue ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Cancer Cells ◽

Poor Prognosis ◽

Tumor Immunotherapy ◽

Therapeutic Strategies ◽

Preclinical Studies ◽

Future Prospects ◽

Tumor Associated Macrophages

Macrophages are the most important phagocytes in vivo. However, the tumor microenvironment can affect the function and polarization of macrophages and form tumor-associated macrophages (TAMs). Usually, the abundance of TAMs in tumors is closely associated with poor prognosis. Preclinical studies have identified important pathways regulating the infiltration and polarization of TAMs during tumor progression. Furthermore, potential therapeutic strategies targeting TAMs in tumors have been studied, including inhibition of macrophage recruitment to tumors, functional repolarization of TAMs toward an antitumor phenotype, and other therapeutic strategies that elicit macrophage-mediated extracellular phagocytosis and intracellular destruction of cancer cells. Therefore, with the increasing impact of tumor immunotherapy, new antitumor strategies to target TAMs are now being discussed.

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A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients

npj Precision Oncology ◽

10.1038/s41698-021-00142-x ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Xiaoqiang Zhu ◽

Xianglong Tian ◽

Linhua Ji ◽

Xinyu Zhang ◽

Yingying Cao ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Drug Sensitivity ◽

Chemotherapy Resistance ◽

Gene Expression Signature ◽

Prediction Algorithm ◽

Specific Gene ◽

Chemotherapy Response ◽

Rna Seq ◽

Mesenchymal Transition

AbstractStudies have shown that tumor microenvironment (TME) might affect drug sensitivity and the classification of colorectal cancer (CRC). Using TME-specific gene signature to identify CRC subtypes with distinctive clinical relevance has not yet been tested. A total of 18 “bulk” RNA-seq datasets (total n = 2269) and four single-cell RNA-seq datasets were included in this study. We constructed a “Signature associated with FOLFIRI resistant and Microenvironment” (SFM) that could discriminate both TME and drug sensitivity. Further, SFM subtypes were identified using K-means clustering and verified in three independent cohorts. Nearest template prediction algorithm was used to predict drug response. TME estimation was performed by CIBERSORT and microenvironment cell populations-counter (MCP-counter) methods. We identified six SFM subtypes based on SFM signature that discriminated both TME and drug sensitivity. The SFM subtypes were associated with distinct clinicopathological, molecular and phenotypic characteristics, specific enrichments of gene signatures, signaling pathways, prognosis, gut microbiome patterns, and tumor lymphocytes infiltration. Among them, SFM-C and -F were immune suppressive. SFM-F had higher stromal fraction with epithelial-to-mesenchymal transition phenotype, while SFM-C was characterized as microsatellite instability phenotype which was responsive to immunotherapy. SFM-D, -E, and -F were sensitive to FOLFIRI and FOLFOX, while SFM-A, -B, and -C were responsive to EGFR inhibitors. Finally, SFM subtypes had strong prognostic value in which SFM-E and -F had worse survival than other subtypes. SFM subtypes enable the stratification of CRC with potential chemotherapy response thereby providing more precise therapeutic options for these patients.

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Hypoxia and the Tumor Microenvironment

Technology in Cancer Research & Treatment ◽

10.1177/15330338211036304 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110363

Author(s):

Yue Li ◽

Long Zhao ◽

Xiao-Feng Li

Keyword(s):

Immune Response ◽

Cell Proliferation ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Poor Prognosis ◽

Tumor Biology ◽

Metastatic Potential ◽

Tumor Detection ◽

Tumor Aggressiveness

Hypoxia is an important feature of the tumor microenvironment, and is closely associated with cell proliferation, angiogenesis, metabolism and the tumor immune response. All these factors can further promote tumor progression, increase tumor aggressiveness, enhance tumor metastatic potential and lead to poor prognosis. In this review, these effects of hypoxia on tumor biology will be discussed, along with their significance for tumor detection and treatment.

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Transcriptome of Tumor-Infiltrating T Cells in Colorectal Cancer Patients Uncovered a Unique Gene Signature in CD4+ T Cells Associated with Poor Disease-Specific Survival

Vaccines ◽

10.3390/vaccines9040334 ◽

2021 ◽

Vol 9 (4) ◽

pp. 334

Author(s):

Salman M. Toor ◽

Varun Sasidharan Nair ◽

Reem Saleh ◽

Rowaida Z. Taha ◽

Khaled Murshed ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

T Cell Activation ◽

Cd4 T Cells ◽

Poor Prognosis ◽

Gene Signature ◽

The Cancer Genome Atlas ◽

Disease Specific Survival ◽

Unique Gene ◽

Disease Specific

Colorectal cancer (CRC) is influenced by infiltration of immune cell populations in the tumor microenvironment. While elevated levels of cytotoxic T cells are associated with improved prognosis, limited studies have reported associations between CD4+ T cells and disease outcomes. We recently performed transcriptomic profiling and comparative analyses of sorted CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) from bulk tumors of CRC patients with varying disease stages. In this study, we compared the transcriptomes of CD4+ with CD8+ TILs. Functional annotation pathway analyses revealed the downregulation of inflammatory response-related genes, while T cell activation and angiogenesis-related genes were upregulated in CD4+ TILs. The top 200 deregulated genes in CD4+ TILs were aligned with the cancer genome atlas (TCGA) CRC dataset to identify a unique gene signature associated with poor prognosis. Moreover, 69 upregulated and 20 downregulated genes showed similar trends of up/downregulation in the TCGA dataset and were used to calculate “poor prognosis score” (ppScore), which was significantly associated with disease-specific survival. High ppScore patients showed lower expression of Treg-, Th1-, and Th17-related genes, and higher expression of Th2-related genes. Our data highlight the significance of T cells within the TME and identify a unique candidate prognostic gene signature for CD4+ TILs in CRC patients.

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