TAMI-59. RECIPROCAL IMPACT OF CANCER IMMUNITY AND TUMOR HYPOXIA DURING GLIOBLASTOMA PROGRESSION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi210-vi210
Author(s):  
Anirudh Sattiraju ◽  
Sangjo Kang ◽  
Valerie Marallano ◽  
Concetta Brusco ◽  
Zhihong Chen ◽  
...  
Keyword(s):  
Cytotoxic T Cells ◽  
Tumor Hypoxia ◽  
Gene Signature ◽  
Vascular Supply ◽  
Human Patient ◽  
Fluorescent Reporter ◽  
Mesenchymal Transition ◽  
Underlying Mechanisms ◽  
Immunocompetent Mice

Abstract Tumor hypoxia is linked to poor outcome for glioblastoma (GBM), a highly malignant brain cancer, but the underlying mechanisms and the environmental factors that initiate tumor hypoxia are poorly understood. We tracked tumor hypoxia in GBM in immunocompetent mice with a hypoxia sensitive fluorescent reporter combined with single cell transcriptomics. We found that hypoxic GBM cells are quiescent, immunosuppressive and display a mesenchymal transition, all of which are linked to malignant potency. We also captured in vivo hypoxia gene signature, which is more represented in recurrent GBM and predicts worse outcome. Interestingly, hypoxic GBM cells is a diverse population, consisted of four subclusters, and enriched for immune pathways. Concordantly, our reporter highlighted a distinct geographic pattern of immune cells in hypoxic regions, with phagocytic tumor-associated macrophages (TAMs) and CD8+ cytotoxic T cells (CTLs) congregated in hypoxic cores confined by hypoxic GBM cells in pseudo-palisading patterns. Mechanistically, this is a dynamic temporospatial process, requiring cytokine CCL8. Remarkably, the sequestered TAMs also experience hypoxia, and they are reprogrammed to express immunotolerant markers by factors released from hypoxic GBM cells. Contrary to the conventional viewpoint that hypoxia arises from rapid tumor expansion outstripping vascular supply, we discovered anticancer immunity as an important driving force of tumor hypoxia; attenuating immune responses by implanting GBM in host mice with immunodeficiency or IL1β deletion greatly decreased GBM hypoxia. Analyses of human patient GBM samples highlighted a connection of mesenchymal subtype, immune response, and tumor hypoxia, all contributing to poor survival. Altogether, our study revealed a reciprocal influence of anti-tumor immunity and tumor hypoxia, which has significant ramifications for prognosis and immunotherapy for GBM.

scholarly journals Circular RNA CDR1as Inhibits the Metastasis of Gastric Cancer through Targeting miR-876-5p/GNG7 Axis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Jiajia Jiang ◽  
Rong Li ◽  
Junyi Wang ◽  
Jie Hou ◽  
Hui Qian ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Luciferase Reporter Gene ◽  
Mesenchymal Transition ◽  
Underlying Mechanisms

Circular RNA CDR1as has been demonstrated to participate in various cancer progressions as miRNA sponges. The exact underlying mechanisms of CDR1as on gastric cancer (GC) metastasis remain unknown. Here, we found that CDR1as knockdown facilitated GC cell migration and invasion while its overexpression inhibited the migration and invasion abilities of GC cells in vitro and in vivo. Moreover, epithelial-mesenchymal transition- (EMT-) associated proteins and MMP2 and MMP9 were downregulated by CDR1as. Bioinformatics analysis combined with dual-luciferase reporter gene assays, western blot, RT-qPCR analysis, and functional rescue experiments demonstrated that CDR1as served as a miR-876-5p sponge and upregulated the target gene GNG7 expression to suppress GC metastasis. In summary, our findings indicate that CDR1as suppresses GC metastasis through the CDR1as/miR-876-5p/GNG7 axis.

scholarly journals Human Cancer Cells Express Slug-based Epithelial-Mesenchymal Transition Gene Signature Obtained in Vivo

2011 ◽  
Author(s):  
Jessica Kandel ◽  
Dimitris Anastassiou ◽  
Viktoria Rumjantseva ◽  
Wei-yi Cheng ◽  
Jianzhong Huang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Gene Signature ◽  
Mesenchymal Transition ◽  
Human Cancer Cells

scholarly journals Novel role of lncRNA CHRF in cisplatin resistance of ovarian cancer is mediated by miR-10b induced EMT and STAT3 signaling

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wen-Xi Tan ◽  
Ge Sun ◽  
Meng-Yuan Shangguan ◽  
Zhi Gui ◽  
Yang Bao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cisplatin Resistance ◽  
Gynecological Cancer ◽  
Acquired Resistance ◽  
Tumor Burden ◽  
Human Patient ◽  
Mesenchymal Transition ◽  
Stat3 Signaling

Abstract Ovarian Cancer (OC) is a highly lethal gynecological cancer which often progresses through acquired resistance against the administered therapy. Cisplatin is a common therapeutic for the treatment of OC patients and therefore it is critical to understand the mechanisms of resistance against this drug. We studied a paired cell line consisting of parental and cisplatin resistant (CR) derivative ES2 OC cells, and found a number of dysregulated lncRNAs, with CHRF being the most significantly upregulated lncRNA in CR ES2 cells. The findings corroborated in human patient samples and CHRF was significantly elevated in OC patients with resistant disease. CHRF was also found to be elevated in patients with liver metastasis. miR-10b was found to be mechanistically involved in CHRF mediated cisplatin resistance. It induced resistance in not only ES2 but also OVCAR and SKOV3 OC cells. Induction of epithelial-to-mesenchymal-transition (EMT) and activation of STAT3 signaling were determined to be the mechanisms underlying the CHRF-miR-10b axis-mediated cisplatin resistance. Down-regulation of CHRF reversed EMT, STAT3 activation and the resulting cisplatin resistance, which could be attenuated by miR-10b. The results were also validated in an in vivo cisplatin resistance model wherein CR cells were associated with increased tumor burden, CHRF downregulation associated with decreased tumor burden and miR-10b again attenuated the CHRF downregulation effects. Our results support a novel role of lncRNA CHRF in cisplatin resistance of OC and establish CHRF-miR-10b signaling as a putative therapeutic target for sensitizing resistant OC cells.

scholarly journals ROR2 Promotes EMT and Necrosis by Hyperactivating ERK in Melanoma

2021 ◽  
Author(s):  
María Victoria Castro ◽  
Gastón Barbero ◽  
María Belen Villanueva ◽  
Jérémie Nsengimana ◽  
Julia Newton-Bishop ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Orphan Receptor ◽  
Loss Of Function ◽  
Western Blots ◽  
Mesenchymal Transition ◽  
Lung Colonization ◽  
Attractive Therapeutic Target ◽  
Underlying Mechanisms

Abstract PurposeReceptor tyrosine kinase-like orphan receptor 2 (ROR2) has been shown to play opposite roles in the progression of different tumor types. In melanoma, ROR2 was shown to associate with a more invasive phenotype and to contribute to experimental lung colonization. However, the underlying mechanisms regulated by ROR2 have not been elucidated. More importantly, it has not been established whether ROR2 is just a marker or a driver of melanoma aggressiveness. MethodsGain and loss-of-function experiments were applied to study the biological function of ROR2 in melanoma. Transwell assays and Western blots were used to evaluate cell migration and both expression and activation of Epithelial-Mesenchymal Transition (EMT) markers and signaling proteins. The role of ROR2 in vivo was assessed in xenotransplantation experiments.ResultsWe describe that ROR2 promotes EMT by inducing cadherin switch and the upregulation of the transcription factors ZEB1, Twist, Slug, Snail, and HIF1A, together with a mesenchymal phenotype and increased migration. ROR2 association with EMT is also observed in melanoma samples. ROR2 exerts these effects by hyperactivating the MAPK/ERK pathway far above the typical high constitutive activity observed in melanoma. ROR2 also promoted EMT, invasion, and necrosis in xenotransplanted mice. This important role of ROR2 translates into melanoma patient’s prognosis since patients with lymph node metastasis displaying elevated ROR2 levels have reduced overall survival and distant metastasis-free survival.Conclusions These results demonstrate that ROR2 contributes to melanoma progression by hyperactivating ERK and inducing EMT and necrosis. Thus, ROR2 can be an attractive therapeutic target for metastatic melanoma.

SNHG5 inhibits the progression of EMT through the ubiquitin-degradation of MTA2 in oesophageal cancer

2020 ◽  
Author(s):  
Sisi Wei ◽  
Shiping Sun ◽  
Xinliang Zhou ◽  
Cong Zhang ◽  
Xiaoya Li ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Survival Rates ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Underlying Mechanisms ◽  
And Function

Abstract A substantial fraction of transcripts are known as long noncoding RNAs (lncRNAs), and these transcripts play pivotal roles in the development of cancer. However, little information has been published regarding the functions of lncRNAs in oesophageal squamous cell carcinoma (ESCC) and the underlying mechanisms. In our previous studies, we demonstrated that small nucleolar RNA host gene 5 (SNHG5), a known lncRNA, is dysregulated in gastric cancer (GC). In this study, we explored the expression and function of SNHG5 in development of ESCC. SNHG5 was found to be downregulated in human ESCC tissues and cell lines, and this downregulation was associated with cancer progression, clinical outcomes and survival rates of ESCC patients. Furthermore, we also found that overexpression of SNHG5 significantly inhibited the proliferation, migration and invasion of ESCC cells in vivo and in vitro. Notably, we found that metastasis-associated protein 2 (MTA2) was pulled down by SNHG5 in ESCC cells using RNA pulldown assay. We also found that SNHG5 reversed the epithelial–mesenchymal transition by interacting with MTA2. In addition, overexpression of SNHG5 downregulated the transcription of MTA2 and caused its ubiquitin-mediated degradation. Thus, overexpression of MTA2 partially abrogated the effect of SNHG5 in ESCC cell lines. Furthermore, we found that MTA2 mRNA expression was significantly elevated in ESCC specimens, and a negative correlation between SNHG5 and MTA2 expression was detected. Overall, this study demonstrated, for the first time, that SNHG5-regulated MTA2 functions as an important player in the progression of ESCC and provide a new potential therapeutic strategy for ESCC.

scholarly journals Disulfiram Sensitizes a Therapeutic-Resistant Glioblastoma to the TGF-β Receptor Inhibitor

2021 ◽  
Vol 22 (19) ◽  
pp. 10496
Author(s):  
Chan-Chuan Liu ◽  
Cheng-Lin Wu ◽  
Meng-Xuan Lin ◽  
Chun-I Sze ◽  
Po-Wu Gean
Keyword(s):  
Mesenchymal Transition ◽  
Aldehyde Dehydrogenases ◽  
Tumor Sphere ◽  
Radiation Resistant ◽  
Β Receptor ◽  
Underlying Mechanisms ◽  
Sphere Formation ◽  
Target Cancer

Despite neurosurgery following radiation and chemotherapy, residual glioblastoma (GBM) cells develop therapeutic resistance (TR) leading to recurrence. The GBM heterogeneity confers TR. Therefore, an effective strategy must target cancer stem cells (CSCs) and other malignant cancer cells. TGF-β and mesenchymal transition are the indicators for poor prognoses. The activity of aldehyde dehydrogenases (ALDHs) is a functional CSC marker. However, the interplay between TGF-β and ALDHs remains unclear. We developed radiation-resistant and radiation-temozolomide-resistant GBM models to investigate the underlying mechanisms conferring TR. Galunisertib is a drug targeting TGF-β receptors. Disulfiram (DSF) is an anti-alcoholism drug which functions by inhibiting ALDHs. The anti-tumor effects of combining DSF and Galunisertib were evaluated by in vitro cell grow, wound healing, Transwell assays, and in vivo orthotopic GBM model. Mesenchymal-like phenotype was facilitated by TGF-β in TR GBM. Additionally, TR activated ALDHs. DSF inhibited TR-induced cell migration and tumor sphere formation. However, DSF did not affect the tumor growth in vivo. Spectacularly, DSF sensitized TR GBM to Galunisertib both in vitro and in vivo. ALDH activity positively correlated with TGF-β-induced mesenchymal properties in TR GBM. CSCs and mesenchymal-like GBM cells targeted together by combining DSF and Galunisertib may be a good therapeutic strategy for recurrent GBM patients.

scholarly journals Loss of Ubiquitin Ligase STUB1 Amplifies IFNγ-R1/JAK1 Signaling and Sensitizes Tumors to IFNγ

2020 ◽  
Author(s):  
Georgi Apriamashvili ◽  
David W. Vredevoogd ◽  
Oscar Krijgsman ◽  
Onno B. Bleijerveld ◽  
Maarten A. Ligtenberg ◽  
...  
Keyword(s):  
T Cells ◽  
Ubiquitin Ligase ◽  
Cytotoxic T Cells ◽  
Gene Signature ◽  
Immune Checkpoint Blockade ◽  
Genome Wide ◽  
A Genome ◽  
Rational Combination ◽  
Clinical Interest

AbstractDespite the success of immune checkpoint blockade (ICB) most patients fail to respond durably, in part owing to reduced interferon gamma (IFNγ) sensitivity. Thus, elevating tumor IFNγ-receptor 1 (IFNγ-R1) expression to enhance IFNγ-mediated cytotoxicity is of potential clinical interest. Here, we show that increased IFNγ-R1 expression sensitizes tumors to IFNγ-mediated killing. To unveil the largely undefined mechanism governing IFNγ-R1 expression, we performed a genome-wide CRISPR/Cas9 screen for suppressors of its cell surface abundance. We uncovered STUB1 as key mediator of proteasomal degradation of the IFNγ-R1/JAK1 complex. STUB1 inactivation amplified IFNγ signaling, thereby sensitizing to cytotoxic T cells, but also inducing PD-L1. STUB1 loss in a rational combination with PD-1 blockade strongly inhibited melanomas in vivo. Clinically corroborating these results, a STUB1-KO gene signature was strongly associated with anti-PD-1 response. These results uncover STUB1 as pivotal regulator of IFNγ tumor signaling and provide a rationale for its inhibition combined with anti-PD-1.

scholarly journals A Novel Six Metastasis-Related Prognostic Gene Signature for Patients With Osteosarcoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Di Zheng ◽  
Kezhou Xia ◽  
Ling Yu ◽  
Changtian Gong ◽  
Yubo Shi ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Epithelial To Mesenchymal Transition ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Gene Signature ◽  
Suppressor Gene ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Osteosarcoma is the most common malignant bone tumor, and although there has been significant progress in its management, metastases often herald incurable disease. Here we defined genes differentially expressed between primary and metastatic osteosarcoma as metastasis-related genes (MRGs) and used them to construct a novel six-MRG prognostic signature for overall survival of patients with osteosarcoma. Validation in internal and external datasets confirmed satisfactory accuracy and generalizability of the prognostic model, and a nomogram based on the signature and clinical variables was constructed to aid clinical decision-making. Of the six MRGs, FHIT is a well-documented tumor suppressor gene that is poorly defined in osteosarcoma. Consistent with tumor suppressor function, FHIT was downregulated in osteosarcoma cells and human osteosarcoma samples. FHIT overexpression inhibited osteosarcoma proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, FHIT overexpression upregulate the epithelial marker E-cadherin while repressing the mesenchymal markers N-cadherin and vimentin. Our six-MRG signature represents a novel and clinically useful prognostic biomarker for patients with osteosarcoma, and FHIT might represent a therapeutic target by reversing epithelial to mesenchymal transition.

scholarly journals JianPi JieDu Recipe Inhibits Epithelial-to-Mesenchymal Transition in Colorectal Cancer through TGF-β/Smad Mediated Snail/E-Cadherin Expression

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Xuan Liu ◽  
Qing Ji ◽  
Wanli Deng ◽  
Ni Chai ◽  
Yuanyuan Feng ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Mesenchymal Transition ◽  
New Findings ◽  
Smad Signaling Pathway ◽  
Underlying Mechanisms ◽  
E Cadherin

JPJD was an ideal alternative traditional Chinese medicine compound in the prevention and treatment of CRC, but its underlying mechanisms has not been fully elucidated. In this study, we demonstrated in vitro that TGF-β-induced EMT promoted the invasion and metastasis of CRC cells, reduced the expression of E-cadherin, and elevated the expression of Vimentin. However, JPJD could inhibit the invasive and migratory ability of TGF-β-stimulated CRC cells in a concentration-dependent manner through increasing the expression of E-cadherin and repressing the expression of Vimentin, as well as the inhibition of TGF-β/Smad signaling pathway. Meanwhile, JPJD reduced the transcriptional activities of EMT-associated factors Snail and E-cadherin during the initiation of TGF-β-induced EMT. In vivo, the results demonstrated that JPJD can significantly inhibit the liver and lung metastasis of orthotopic CRC tumor in nude mice, as well as significantly prolonging the survival time of tumor-bearing in a dose-dependent manner. Additionally, JPJD can upregulate the expression of E-cadherin and Smad2/3 in the cytoplasm and downregulate the expression of Vimentin, p-Smad2/3, and Snail in the orthotopic CRC tumor tissues. In conclusions, our new findings provided evidence that JPJD could inhibit TGF-β-induced EMT in CRC through TGF-β/Smad mediated Snail/E-cadherin expression.

scholarly journals LncRNA FBXL19-AS1 promotes breast cancer cells proliferation and invasion via acting as a molecular sponge to miR-718

2019 ◽  
Vol 39 (4) ◽  
Author(s):  
Zhenmin Ding ◽  
Pengcheng Ye ◽  
Xiaohu Yang ◽  
Hongmiao Cai
Keyword(s):  
Breast Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Potential Therapeutic Target ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
Non Coding Rnas ◽  
Underlying Mechanisms ◽  
Proliferation And Invasion

Abstract Long non-coding RNAs (lncRNAs) have been suggested to serve vital roles in tumor initiation and progression. However, the expression and underlying mechanisms of lncRNA FBXL19-AS1 in breast cancer (BC) remain unclear. In the present study, we found that FBXL19-AS1 expression was significantly up-regulated and correlated with advanced clinical features and poor overall survival of BC patients. Functionally, FBXL19-AS1 inhibition suppressed BC cells proliferation, invasion, and epithelial–mesenchymal transition (EMT) processes in vitro and reduced tumor growth in vivo. In addition, we found that FBXL19-AS1 might function as a ceRNA to sponge miR-718, and miR-718 could rescue the effects of FBXL19-AS1 on BC cells progression. Therefore, these findings suggested that FBXL19-AS1 might serve as an oncogenic lncRNA and promoted BC progression by sponging miR-718, indicating FBXL19-AS1 could serve as a potential therapeutic target for BC treatment.

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