scholarly journals Cooperation between oncogenic Ras and p53 stimulates JAK/STAT non-cell autonomously to promote Ras tumor radioresistance

2020 ◽  
Author(s):  
Yong-Li Dong ◽  
Ganghadara P Valdka ◽  
Jin-Yu (Jim) Lu ◽  
Vakil Ahmad ◽  
Thomas J. Klein ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cellular Response ◽  
Cell Communication ◽  
Genotoxic Stress ◽  
Tumor Resistance ◽  
Therapy Outcomes ◽  
Oncogenic Ras ◽  
Tumor Tissues ◽  
Underlying Mechanisms ◽  
Cell Cell

AbstractOncogenic RAS mutations are associated with tumor resistance to radiation therapy. The underlying mechanisms remain unclear. Emergent cell-cell interactions in the tumor microenvironment (TME) profoundly influence therapy outcomes. The nature of these interactions and their role in Ras tumor radioresistance remain unclear. We used Drosophila oncogenic Ras tissues and human Ras cancer cell radiation models to address these questions. We discovered that cellular response to genotoxic stress cooperates with oncogenic Ras to activate JAK/STAT non-cell autonomously in the TME. JAK/STAT accelerates the growth of the less-damaged Ras tumor cells, leading to rapid tumor recurrence. Specifically, p53 is heterogeneously activated in Ras tumor tissues in response to irradiation. This mosaicism allows high p53-expressing Ras clones to stimulate JAK/STAT cytokines, which activate JAK/STAT in the nearby low p53-expressing surviving Ras clones, leading to robust tumor re-establishment. Blocking any part of this cell-cell communication loop re-sensitizes Ras tumor cells to irradiation. This finding suggests that coupling STAT inhibitors to radiotherapy might improve clinical outcomes for Ras cancer patients.

scholarly journals Cooperation between oncogenic Ras and wild-type p53 stimulates STAT non-cell autonomously to promote tumor radioresistance

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yong-Li Dong ◽  
Gangadhara P. Vadla ◽  
Jin-Yu (Jim) Lu ◽  
Vakil Ahmad ◽  
Thomas J. Klein ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Cellular Response ◽  
Cell Communication ◽  
Genotoxic Stress ◽  
Tumor Resistance ◽  
Wild Type ◽  
Therapy Outcomes ◽  
Oncogenic Ras ◽  
Tumor Tissues ◽  
Cell Cell

AbstractOncogenic RAS mutations are associated with tumor resistance to radiation therapy. Cell-cell interactions in the tumor microenvironment (TME) profoundly influence therapy outcomes. However, the nature of these interactions and their role in Ras tumor radioresistance remain unclear. Here we use Drosophila oncogenic Ras tissues and human Ras cancer cell radiation models to address these questions. We discover that cellular response to genotoxic stress cooperates with oncogenic Ras to activate JAK/STAT non-cell autonomously in the TME. Specifically, p53 is heterogeneously activated in Ras tumor tissues in response to irradiation. This mosaicism allows high p53-expressing Ras clones to stimulate JAK/STAT cytokines, which activate JAK/STAT in the nearby low p53-expressing surviving Ras clones, leading to robust tumor re-establishment. Blocking any part of this cell-cell communication loop re-sensitizes Ras tumor cells to irradiation. These findings suggest that coupling STAT inhibitors to radiotherapy might improve clinical outcomes for Ras cancer patients.

scholarly journals m6A-mediated Cell-cell Communication Controls Planarian Regeneration

2021 ◽  
Author(s):  
Guanshen Cui ◽  
Jia-Yi Zhou ◽  
Xin-Yang Ge ◽  
Bao-Fa Sun ◽  
Ge-Ge Song ◽  
...  
Keyword(s):  
Adult Stem Cells ◽  
Cell Communication ◽  
Whole Body ◽  
Regulatory Subunit ◽  
Cell Renewal ◽  
Specific Expression ◽  
Unique Type ◽  
Planarian Regeneration ◽  
Underlying Mechanisms ◽  
Cell Cell

Regeneration is the regrowth of damaged tissues or organs, a vital mechanism responding to damages from primitive organisms to higher mammals. Planarian possesses active whole-body regenerative capability owning to its vast reservoir of adult stem cells, neoblasts, thus provides an ideal model to delineate the underlying mechanisms for regeneration. N6-methyladenosine (m6A) regulates stem cell renewal and differentiation. However, how m6A controls regeneration at whole-organism level remains largely unknown. Here, we demonstrate that the depletion of m6A methyltransferase regulatory subunit wtap abolishes planarian regeneration, through regulating cell-cell communication and cell cycle. scRNA-Seq analysis unveils that the wtap knockdown induces a unique type of neural progenitor-like cells (NP-like cells), characterized by specific expression of the cell-cell communication ligand grn. Intriguingly, the depletion of m6A-modified transcripts grn/cdk9 (or cdk7) axis rescues the defective regeneration of planarian without wtap. Overall, our study reveals an indispensable role of m6A-dependent cell-cell communication essential for whole-organism regeneration.

scholarly journals Hypoxia Contributes to Poor Prognosis in Primary IDH-wt GBM by Inducing Tumor Cells MES-Like Transformation Trend and Inhibiting Immune Cells Activity

2021 ◽  
Vol 11 ◽  
Author(s):  
Zujian Xiong ◽  
Hongwei Liu ◽  
Chenqi He ◽  
Xuejun Li
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Immune Cells ◽  
Cell Activity ◽  
Cell Communication ◽  
Gene Set Enrichment Analysis ◽  
Rna Seq ◽  
Cell Cell

AimsTo reveal the influence of hypoxia on tumor cells and immune cells in primary IDH-wt glioblastoma patients.MethodsSingle-cell RNA-seq data and bulk RNA-seq data were acquired from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, respectively. Hypoxia status and subtypes of tumor cells were identified based on single-sample Gene Set Enrichment Analysis (ssGSEA). Regulon network analysis of different subtypes under different conditions was conducted by SCENIC. Within tumor microenvironment, biological process activity analysis and cell–cell communication network were conducted to uncover the inner links between each cell subtype under different hypoxia status.ResultsDifferent types of tumor cell in GBM possessed different hypoxia status, and MES-like subtype was under a more severe hypoxia condition than other subtypes. Hypoxia also induced MES-like signature gene expression within each tumor cell, which could stimulate tumor cell proliferation and invasion by regulating cell–cell communication. Additionally, hypoxia inhibited immune cell activity in the tumor microenvironment by inducing macrophage phenotype polarization and upregulating immune-inhibited cell–cell interaction within immune cells. Interactions between tumor cells and immune cells under hypoxia status also promoted tumor progression.ConclusionsHypoxia was a poor prognostic marker for primary IDH-wt GBM patients. Meanwhile, it could induce tumor cells’ MES-like transformation trend and inhibit antitumor function of immune cells.

scholarly journals Development of a Cx46 targeting strategy for cancer stem cells

2018 ◽  
Author(s):  
Erin E. Mulkearns-Hubert ◽  
Luke A. Torre-Healy ◽  
Daniel J. Silver ◽  
Jennifer T. Eurich ◽  
Emily Serbinowski ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Gap Junction ◽  
Tumor Cells ◽  
Cell Communication ◽  
Standard Of Care ◽  
Specific Cell ◽  
Critical Function ◽  
Targeting Strategy ◽  
Cell Cell

SummaryGap junction-mediated cell-cell communication enables tumor cells to synchronize the execution of complex processes. Despite the connexin family of gap junction proteins being considered tumor suppressors, we previously found that glioblastoma cancer stem cells (CSCs) express higher levels of Cx46 compared to non-stem tumor cells, and this was necessary and sufficient for CSC maintenance. To develop a Cx46 targeting strategy, we utilized point mutants to disrupt specific functions of Cx46 and found that gap junction coupling was the critical function of Cx46 for CSCs. Based on this finding, we screened a clinically relevant library of small molecules and identified clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuated proliferation, self-renewal, and tumor growth and synergized with temozolomide to induce apoptosis. These data suggest that combining clofazimine with standard-of-care therapies may target glioblastoma CSCs. Furthermore, these results demonstrate the importance of targeting cell-cell communication as an anti-cancer therapy.

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