scholarly journals Genomic events shaping epithelial-to-mesenchymal trajectories in cancer

2021 ◽  
Author(s):  
Guidantonio Tagliazucchi ◽  
Maria Secrier
Keyword(s):  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Evolutionary Constraints ◽  
Breast Cancers ◽  
Driver Genes ◽  
Mesenchymal Transition ◽  
Therapeutic Value ◽  
Intermediate States ◽  
Mesenchymal Transformation ◽  
Pan Cancer

Abstract The epithelial to mesenchymal transition (EMT) is a key cellular process underlying cancer progression, with multiple intermediate states whose molecular hallmarks remain poorly characterized. To fill this gap, we explored EMT trajectories in 8,778 tumours of epithelial origin and identified three macro-states with prognostic and therapeutic value, attributable to epithelial, hybrid E/M (hEMT) and mesenchymal phenotypes. We show that the hEMT state is remarkably stable and linked with increased aneuploidy, APOBEC mutagenesis and hypoxia. Additionally, we provide an extensive catalogue of genomic events underlying distinct evolutionary constraints on EMT transformation, including novel pan-cancer dependencies of hEMT on driver genes PRRX1, BCOR and CNOT3, as well as links between full mesenchymal transformation and REG3A and SHISA4 mutations in lung and breast cancers, respectively. This study sheds light on the aetiology of the lesser characterised hybrid E/M state in cancer progression and the broader genomic hallmarks shaping the mesenchymal transformation of primary tumours.

scholarly journals Genomic events shaping epithelial-to-mesenchymal trajectories in cancer

2021 ◽  
Author(s):  
Guidantonio Malagoli Tagliazucchi ◽  
Maria Secrier
Keyword(s):  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Evolutionary Constraints ◽  
Breast Cancers ◽  
Driver Genes ◽  
Mesenchymal Transition ◽  
Therapeutic Value ◽  
Intermediate States ◽  
Mesenchymal Transformation ◽  
Pan Cancer

The epithelial to mesenchymal transition (EMT) is a key cellular process underlying cancer progression, with multiple intermediate states whose molecular hallmarks remain poorly characterized. To fill this gap, we explored EMT trajectories in 8,778 tumours of epithelial origin and identified three macro-states with prognostic and therapeutic value, attributable to epithelial, hybrid E/M (hEMT) and mesenchymal phenotypes. We show that the hEMT state is remarkably stable and linked with increased aneuploidy, APOBEC mutagenesis and hypoxia. Additionally, we provide an extensive catalogue of genomic events underlying distinct evolutionary constraints on EMT transformation, including novel pan-cancer dependencies of hEMT on driver genes PRRX1, BCOR and CNOT3, as well as links between full mesenchymal transformation and REG3A and SHISA4 mutations in lung and breast cancers, respectively. This study sheds light on the aetiology of the lesser characterised hybrid E/M state in cancer progression and the broader genomic hallmarks shaping the mesenchymal transformation of primary tumours.

scholarly journals αvβ3 Integrin induces partial EMT independent of TGF-β signaling

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yoshinobu Kariya ◽  
Midori Oyama ◽  
Takato Suzuki ◽  
Yukiko Kariya
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Αvβ3 Integrin ◽  
Poor Survival ◽  
Mesenchymal Transition ◽  
Intermediate States ◽  
Tgf Β1

AbstractEpithelial–mesenchymal transition (EMT) plays a pivotal role for tumor progression. Recent studies have revealed the existence of distinct intermediate states in EMT (partial EMT); however, the mechanisms underlying partial EMT are not fully understood. Here, we demonstrate that αvβ3 integrin induces partial EMT, which is characterized by acquiring mesenchymal phenotypes while retaining epithelial markers. We found αvβ3 integrin to be associated with poor survival in patients with lung adenocarcinoma. Moreover, αvβ3 integrin-induced partial EMT promoted migration, invasion, tumorigenesis, stemness, and metastasis of lung cancer cells in a TGF-β-independent fashion. Additionally, TGF-β1 promoted EMT progression synergistically with αvβ3 integrin, while a TGF-β signaling inhibitor showed no effect on αvβ3 integrin-induced partial EMT. Meanwhile, the microRNA-200 family abolished the αvβ3 integrin-induced partial EMT by suppressing αvβ3 integrin cell surface expression. These findings indicate that αvβ3 integrin is a key inducer of partial EMT, and highlight a new mechanism for cancer progression.

scholarly journals The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1239
Author(s):  
Leila Jahangiri ◽  
Tala Ishola ◽  
Perla Pucci ◽  
Ricky M. Trigg ◽  
Joao Pereira ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Progression ◽  
Regulatory Networks ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Microenvironment ◽  
Repair Capacity ◽  
Mesenchymal Transition ◽  
Cellular Processes

Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.

scholarly journals DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer

2018 ◽  
Vol 115 (51) ◽  
pp. E11978-E11987 ◽  
Author(s):  
Ryoichi Matsunuma ◽  
Doug W. Chan ◽  
Beom-Jun Kim ◽  
Purba Singh ◽  
Airi Han ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Negative Feedback ◽  
Epithelial To Mesenchymal Transition ◽  
Triple Negative ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Multinucleated Cells ◽  
P21 Activated Kinase ◽  
Emt Markers ◽  
Mitotic Defect

A Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomic analysis prioritized dihydropyrimidinase-like-3 (DPYSL3) as a multilevel (RNA/protein/phosphoprotein) expression outlier specific to the claudin-low (CLOW) subset of triple-negative breast cancers. A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive (DPYSL3+) CLOW cell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition (EMT) markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative (DPYSL3−) CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2 (PAK2)-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT.

scholarly journals Sp1-Induced Upregulation of LBX2-AS1 Aggravates The Progression of Glioblastoma By Targeting The miR-491-5p/LIF Axis

2021 ◽  
Author(s):  
Wentao Li ◽  
Ismatullah Soufiany ◽  
Xiao Lyu ◽  
Lin Zhao ◽  
Chenfei Lu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Regulatory Effects

Abstract Background: Mounting evidences have shown the importance of lncRNAs in tumorigenesis and cancer progression. LBX2-AS1 is an oncogenic lncRNA that has been found abnormally expressed in gastric cancer and lung cancer samples. Nevertheless, the biological function of LBX2-AS1 in glioblastoma (GBM) and potential molecular mechanism are largely unclear. Methods: Relative levels of LBX2-AS1 in GBM samples and cell lines were detected by qRT-PCR and FISH. In vivo and in vitro regulatory effects of LBX2-AS1 on cell proliferation, epithelial-to-mesenchymal transition (EMT) and angiogenesis in GBM were examined through xenograft models and functional experiments, respectively. The interaction between Sp1 and LBX2-AS1 was assessed by ChIP. Through bioinformatic analyses, dual-luciferase reporter assay, RIP and Western blot, the regulation of LBX2-AS1 and miR-491-5p on the target gene leukemia Inhibitory factor (LIF) was identified. Results: LBX2-AS1 was upregulated in GBM samples and cell lines, and its transcription was promoted by binding to the transcription factor Sp1. As a lncRNA mainly distributed in the cytoplasm, LBX2-AS1 upregulated LIF, and activated the LIF/STAT3 signaling by exerting the miRNA sponge effect on miR-491-5p, thus promoting cell proliferation, EMT and angiogenesis in GBM. Besides, LBX2-AS1 was unfavorable to the progression of glioma and the survival. Conclusion: Upregulated by Sp1, LBX2-AS1 promotes the progression of GBM by targeting the miR-491-5p/LIF axis. It is suggested that LBX2-AS1 may be a novel diagnostic biomarker and therapeutic target of GBM.

scholarly journals Pan-Cancer Analysis Reveals that the SARS-CoV-2 Receptor ACE2 is a Protective Factor for Cancer Progression

2020 ◽  
Author(s):  
Zhilan Zhang ◽  
Lin Li ◽  
Mengyuan Li ◽  
Xiaosheng Wang
Keyword(s):  
Tumor Progression ◽  
Clinical Outcomes ◽  
Cancer Progression ◽  
Antitumor Immunity ◽  
Protective Factor ◽  
Cancer Genomics ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Oncogenic Pathways ◽  
Pan Cancer

Abstract Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 13 million people and has caused more than 570,000 deaths worldwide as of July 13, 2020. The SARS-CoV-2 human cell receptor ACE2 has recently received extensive attention for its role in SARS-CoV-2 infection. Many studies have also explored the association between ACE2 and cancer. However, a systemic investigation into associations between ACE2 and oncogenic pathways, tumor progression, and clinical outcomes in pan-cancer remains lacking. Methods: Using cancer genomics datasets from the Cancer Genome Atlas (TCGA) program, we performed computational analyses of associations between ACE2 expression and antitumor immunity, immunotherapy response, oncogenic pathways, tumor progression phenotypes, and clinical outcomes in 12 cancer cohorts. We also identified co-expression networks of ACE2 in cancer.Results: ACE2 upregulation was associated with increased antitumor immune signatures and PD-L1 expression, and favorable anti-PD-1/PD-L1/CTLA-4 immunotherapy response. ACE2 expression levels inversely correlated with the activity of cell cycle, mismatch repair, TGF-β, Wnt, VEGF, and Notch signaling pathways. Moreover, ACE2 expression levels had significant inverse correlations with tumor proliferation, stemness, and epithelial-mesenchymal transition (EMT). ACE2 upregulation was associated with favorable survival in pan-cancer and in multiple individual cancer types. Conclusions: ACE2 upregulation was associated with increased antitumor immunity and immunotherapy response, reduced tumor malignancy, and favorable survival in cancer, suggesting that ACE2 is a protective factor for cancer progression. Our data may provide potential clinical implications for treating cancer patients infected with SARS-CoV-2.

scholarly journals Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

2016 ◽  
Vol 113 (48) ◽  
pp. E7749-E7758 ◽  
Author(s):  
Roberto Rangel ◽  
Song-Choon Lee ◽  
Kenneth Hon-Kim Ban ◽  
Liliana Guzman-Rojas ◽  
Michael B. Mann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Breast Cancer Subtype ◽  
Clinical Importance ◽  
Transposon Mutagenesis ◽  
Phosphatase And Tensin Homolog ◽  
Mesenchymal Transition ◽  
Tensin Homolog ◽  
Cancer Subtype

Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressorTRPS1. Down-regulation ofTRPS1in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression ofSERPINE1andSERPINB2and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.

scholarly journals Roles of MicroRNA-34a in Epithelial to Mesenchymal Transition, Competing Endogenous RNA Sponging and Its Therapeutic Potential

2019 ◽  
Vol 20 (4) ◽  
pp. 861 ◽  
Author(s):  
Dongsong Nie ◽  
Jiewen Fu ◽  
Hanchun Chen ◽  
Jingliang Cheng ◽  
Junjiang Fu
Keyword(s):  
Cancer Therapy ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Circular Rna ◽  
Signal Pathways ◽  
Competing Endogenous Rna ◽  
Mesenchymal Transition

MicroRNA-34a (miR-34a), a tumor suppressor, has been reported to be dysregulated in various human cancers. MiR-34a is involves in certain epithelial-mesenchymal transition (EMT)-associated signal pathways to repress tumorigenesis, cancer progression, and metastasis. Due to the particularity of miR-34 family in tumor-associated EMT, the significance of miR-34a is being increasingly recognized. Competing endogenous RNA (ceRNA) is a novel concept involving mRNA, circular RNA, pseudogene transcript, and long noncoding RNA regulating each other’s expressions using microRNA response elements to compete for the binding of microRNAs. Studies showed that miR-34a is efficient for cancer therapy. Here, we provide an overview of the function of miR-34a in tumor-associated EMT. ceRNA hypothesis plays an important role in miR-34a regulation in EMT, cancer progression, and metastasis. Its potential roles and challenges as a microRNA therapeutic candidate are discussed. As the negative effect on cancer progression, miR-34a should play crucial roles in clinical diagnosis and cancer therapy.

scholarly journals Cancer-Associated Stemness and Epithelial-to-Mesenchymal Transition Signatures Related to Breast Invasive Carcinoma Prognostic

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3053
Author(s):  
Iulia-Monica Groza ◽  
Cornelia Braicu ◽  
Ancuta Jurj ◽  
Oana Zanoaga ◽  
Raduly Lajos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Survival Rate ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Options ◽  
Overall Survival Rate ◽  
Cancer Genes ◽  
Mesenchymal Transition ◽  
Oncological Diseases

Breast cancer is one of the most common oncological diseases in women, as its incidence is rapidly growing, rendering it unpredictable and causing more harm than ever before on an annual basis. Alterations of coding and noncoding genes are related to tumorigenesis and breast cancer progression. In this study, several key genes associated with epithelial-to-mesenchymal transition (EMT) and cancer stem cell (CSC) features were identified. EMT and CSCs are two key mechanisms responsible for self-renewal, differentiation, and self-protection, thus contributing to drug resistance. Therefore, understanding of the relationship between these processes may identify a therapeutic vulnerability that can be further exploited in clinical practice, and evaluate its correlation with overall survival rate. To determine expression levels of altered coding and noncoding genes, The Cancer Omics Atlas (TCOA) are used, and these data are overlapped with a list of CSCs and EMT-specific genes downloaded from NCBI. As a result, it is observed that CSCs are reciprocally related to EMT, thus identifying common signatures that allow for predicting the overall survival for breast cancer genes (BRCA). In fact, common CSCs and EMT signatures, represented by ALDH1A1, SFRP1, miR-139, miR-21, and miR-200c, are deemed useful as prognostic biomarkers for BRCA. Therefore, by mapping changes in gene expression across CSCs and EMT, suggesting a cross-talk between these two processes, we have been able to identify either the most common or specific genes or miRNA markers associated with overall survival rate. Thus, a better understanding of these mechanisms will lead to more effective treatment options.

scholarly journals A Perspective on the Development of TGF-β Inhibitors for Cancer Treatment

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 743 ◽  
Author(s):  
Linh Huynh ◽  
Christopher Hipolito ◽  
Peter ten Dijke
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Clinical Status ◽  
Tumor Promoter ◽  
Receptor Interaction ◽  
Type I ◽  
Mesenchymal Transition ◽  
Β Receptor

Transforming growth factor (TGF)-β is a secreted multifunctional cytokine that signals via plasma membrane TGF-β type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-β signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-β can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-β in cancer cells are blocked, TGF-β signaling can act as tumor promoter by its ability to stimulate epithelial-to-mesenchymal transition of cancer cells, by stimulating angiogenesis, and by promoting evasion of immune responses. In this review, we will discuss the rationale and challenges of targeting TGF-β signaling in cancer and summarize the clinical status of TGF-β signaling inhibitors that interfere with TGF−β bioavailability, TGF-β/receptor interaction, or TGF-β receptor kinase function. Moreover, we will discuss targeting of TGF-β signaling modulators and downstream effectors as well as alternative approaches by using promising technologies that may lead to entirely new classes of drugs.

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