Publications by authors named "Ju-Seog Lee"

229 Publications

Inhibition of CDK4/6 Overcomes Primary Resistance to PD-1 Blockade in Malignant Mesothelioma.

Ann Thorac Surg 2021 Sep 27. Epub 2021 Sep 27.

Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030. Electronic address:

Background: Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with PD-1 blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remain unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM.

Methods: We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (four responders and four non-responders). We used the TCGA MPM cohort (N=73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model.

Results: Immunogenomic analysis by applying our anti-PD-1 resistance signature to the TCGA cohort revealed that deletion of CDKN2A was highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome by CDK4/6 inhibition, we tested whether CDK4/6 inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived from Cdkn2a(-/-) AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration of CDK4/6 inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth, compared with anti-PD-1 or CDK4/6 inhibitor alone.

Conclusions: We identified a therapeutic target, CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials of CDK4/6 inhibitors in more than 40% of patients with MPM who demonstrate loss of CDKN2A.
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http://dx.doi.org/10.1016/j.athoracsur.2021.08.054DOI Listing
September 2021

An Overview of the Genomic Characterization of Hepatocellular Carcinoma.

J Hepatocell Carcinoma 2021 7;8:1077-1088. Epub 2021 Sep 7.

Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA.

Tumor classifications based on alterations in the genome, epigenome, or proteome have revealed distinct tumor subgroups that are associated with clinical outcomes. Several landmark studies have demonstrated that such classifications can significantly improve patient outcomes by enabling tailoring of therapy to specific alterations in cancer cells. Since cancer cells accumulate numerous alterations in many cancer-related genes, it is a daunting task to find and confirm important cancer-promoting alterations as therapeutic targets or biomarkers that can predict clinical outcomes such as survival and response to treatments. To aid further advances, we provide here an overview of the current understanding of molecular and genomic subtypes of hepatocellular carcinoma (HCC). System-level integration of data from multiple studies and development of new technical platforms for analyzing patient samples hold great promise for the discovery of new targets for treatment and correlated biomarkers, leading to personalized medicine for treatment of HCC patients.
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http://dx.doi.org/10.2147/JHC.S270533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434863PMC
September 2021

Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model.

Ann Surg 2021 Aug 13. Epub 2021 Aug 13.

Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee WI, USA Transplant Center, Froedtert & the Medical College of Wisconsin, and Children's Wisconsin, Milwaukee, WI, USA Department of Surgery, Inha University School of Medicine, Incheon, South Korea Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA Department of Pathology, Mayo Clinic, Rochester, MN, USA Department of Pharmacology, Concordia University, Mequon, WI, USA Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee WI, USA.

Objective: We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death (DCD) model.

Summary Of Background Data: DCD represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation.

Methods: Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control-Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed.

Results: Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis.

Conclusion: Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Subnormothermic RHR has potential applicability to clinical liver transplantation.
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http://dx.doi.org/10.1097/SLA.0000000000005156DOI Listing
August 2021

Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer.

J Immunother Cancer 2021 03;9(3)

Institute of Medical Science & Institute for Cancer Research, Keimyung University, Daegu, Korea (the Republic of)

Background: Neoadjuvant chemoradiation therapy (CRT) is a widely used preoperative treatment strategy for locally advanced rectal cancer (LARC). However, a few studies have evaluated the molecular changes caused by neoadjuvant CRT in these cancer tissues. Here, we aimed to investigate changes in immunotherapy-related immunogenic effects in response to preoperative CRT in LARC.

Methods: We analyzed 60 pairs of human LARC tissues before and after irradiation from three independent LARC cohorts, including a LARC patient RNA sequencing (RNA-seq) dataset from our cohort and GSE15781 and GSE94104 datasets.

Results: Gene ontology analysis showed that preoperative CRT significantly enriched the immune response in LARC tissues. Moreover, gene set enrichment analysis revealed six significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways associated with downregulated genes, including mismatch repair (MMR) genes, in LARC tissues after CRT in all three cohorts. Radiation also induced apoptosis and downregulated various MMR system-related genes in three colorectal cancer cells. One patient with LARC showed a change in microsatellite instability (MSI) status after CRT, as demonstrated by the loss of MMR protein and PCR for MSI. Moreover, CRT significantly increased tumor mutational burden in LARC tissues. CIBERSORT analysis revealed that the proportions of M2 macrophages and CD8 T cells were significantly increased after CRT in both the RNA-seq dataset and GSE94104. Notably, preoperative CRT increased various immune biomarker scores, such as the interferon-γ signature, the cytolytic activity and the immune signature.

Conclusions: Taken together, our findings demonstrated that neoadjuvant CRT modulated the immune-related characteristics of LARC, suggesting that neoadjuvant CRT may enhance the responsiveness of LARC to immunotherapy.
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http://dx.doi.org/10.1136/jitc-2020-001610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949478PMC
March 2021

Nc886, a Novel Suppressor of the Type I Interferon Response Upon Pathogen Intrusion.

Int J Mol Sci 2021 Feb 18;22(4). Epub 2021 Feb 18.

Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea.

Interferons (IFNs) are a crucial component in the innate immune response. Especially the IFN-β signaling operates in most cell types and plays a key role in the first line of defense upon pathogen intrusion. The induction of IFN-β should be tightly controlled, because its hyperactivation can lead to tissue damage or autoimmune diseases. Activation of the IFN-β promoter needs Interferon Regulatory Factor 3 (IRF3), together with Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Activator Protein 1 (AP-1). Here we report that a human noncoding RNA, nc886, is a novel suppressor for the IFN-β signaling and inflammation. Upon treatment with several pathogen-associated molecular patterns and viruses, nc886 suppresses the activation of IRF3 and also inhibits NF-κB and AP-1 via inhibiting Protein Kinase R (PKR). These events lead to decreased expression of IFN-β and resultantly IFN-stimulated genes. nc886's role might be to restrict the IFN-β signaling from hyperactivation. Since nc886 expression is regulated by epigenetic and environmental factors, nc886 might explain why innate immune responses to pathogens are variable depending on biological settings.
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http://dx.doi.org/10.3390/ijms22042003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922379PMC
February 2021

Pathological predictive factors for late recurrence of hepatocellular carcinoma in chronic liver disease.

Liver Int 2021 07 25;41(7):1662-1674. Epub 2021 Mar 25.

Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.

Background & Aims: Late recurrence of hepatocellular carcinoma (HCC) is regarded as de novo HCC from chronic hepatitis. This study investigated clinicopathological and molecular factors to develop a nomogram for predicting late HCC recurrence (>2 years after curative resection).

Methods: The training and validation cohorts included HCC patients with a major aetiology of hepatitis B who underwent curative resection. Clinicopathological features including lobular and porto-periportal inflammatory activity, fibrosis and liver cell change were evaluated. Proteins encoded by genes related to late recurrence were identified using a reverse phase protein array of 95 non-tumourous liver tissues. Immunoexpression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), plasminogen activator inhibitor-1, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and spleen tyrosine kinase (SYK) was measured.

Results: Late recurrence occurred in 74/402 (18%) and 47/243 (19%) in the training and validation cohorts respectively. Cirrhosis, moderate/severe lobular inflammatory activity, and expression of pSTAT3, pERK1/2, and SYK proteins correlated to the gene signature of hepatocyte injury and regeneration were independently associated with late recurrence, with odds ratios (95% confidence intervals) of 2.0 (1.2-3.3), 21.1 (4.3-102.7) and 6.0 (2.1-17.7) respectively (P < .05 for all). A nomogram based on these variables (histological parameters and immunohistochemical marker combinations) showed high reliability in both the training and validation cohorts (Harrell's C index: 0.701 and 0.716; 95% confidence intervals: 0.64-0.76 and 0.64-0.79 respectively).

Conclusions: The combination of pSTAT3, pERK1/2 and SYK immunoexpression with high lobular inflammatory activity and cirrhosis (fibrosis) predicts late HCC recurrence.
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http://dx.doi.org/10.1111/liv.14835DOI Listing
July 2021

Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma.

Gut 2021 Nov 17;70(11):2055-2065. Epub 2020 Dec 17.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Objective: Prognosis of patients with advanced oesophagogastric adenocarcinoma (mEGAC) is poor and molecular determinants of shorter or longer overall survivors are lacking. Our objective was to identify molecular features and develop a prognostic model by profiling the genomic features of patients with mEGAC with widely varying outcomes.

Design: We profiled 40 untreated mEGACs (20 shorter survivors <13 months and 20 longer survivors >36 months) with whole-exome sequencing (WES) and RNA sequencing and performed an integrated analysis of exome, transcriptome, immune profile and pathological phenotypes to identify the molecular determinants, developing an integrated model for prognosis and comparison with The Cancer Genome Atlas (TCGA) cohorts.

Results: alterations were exclusively observed in shorter survivors together with high level of intratumour heterogeneity and complex clonal architectures, whereas the APOBEC mutational signatures were significantly enriched in longer survivors. Notably, the loss of heterozygosity in chromosome 4 (Chr4) was associated with shorter survival and 'cold' immune phenotype characterised by decreased B, CD8, natural killer cells and interferon-gamma responses. Unsupervised transcriptomic clustering revealed a shorter survivor subtype with distinct expression features (eg, upregulated druggable targets and ). An integrated model was then built based on clinical variables and the identified molecular determinants, which significantly segregated shorter and longer survivors. All the above features and the integrated model have been validated independently in multiple TCGA cohorts.

Conclusion: This study discovered novel molecular features prognosticating overall survival in patients with mEGAC and identified potential novel targets in shorter survivors.
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http://dx.doi.org/10.1136/gutjnl-2020-322707DOI Listing
November 2021

Pan-cancer methylation analysis reveals an inverse correlation of tumor immunogenicity with methylation aberrancy.

Cancer Immunol Immunother 2021 Jun 24;70(6):1605-1617. Epub 2020 Nov 24.

Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Tumor immunogenicity is driven by various genomic and transcriptomic factors but the association with the overall status of methylation aberrancy is not well established. We analyzed The Cancer Genome Atlas pan-cancer database to investigate whether the overall methylation aberrancy links to the immune evasion of tumor. We created the definitions of hypermethylation burden, hypomethylation burden and methylation burden to establish the values that represent the degree of methylation aberrancy from human methylation 450 K array data. Both hypermethylation burden and hypomethylation burden significantly correlated with global methylation level as well as methylation subtypes defined in previous literatures. Then we evaluated whether methylation burden correlates with tumor immunogenicity and found that methylation burden showed a significant negative correlation with cytolytic activity score, which represent cytotoxic T cell activity, in pan-cancer (Spearman rho = - 0.37, p < 0.001) and 30 of 33 individual cancer types. Furthermore, this correlation was independent of mutation burden and chromosomal instability in multivariate regression analysis. We validated the findings in the external cohorts and outcomes of patients who were treated with immune checkpoint inhibitors, which showed that high methylation burden group had significantly poor progression-free survival (Hazard ratio 1.74, p = 0.038). Overall, the degree of methylation aberrancy negatively correlated with tumor immunogenicity. These findings emphasize the importance of methylation aberrancy for tumors to evade immune surveillance and warrant further development of methylation biomarker.
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http://dx.doi.org/10.1007/s00262-020-02796-1DOI Listing
June 2021

Genomic profiling of multifocal intrahepatic cholangiocarcinoma reveals intraindividual concordance of genetic alterations.

Carcinogenesis 2021 04;42(3):436-441

Department of Surgical Oncology, Houston, TX, USA.

In multifocal intrahepatic cholangiocarcinoma (IHC), intrahepatic metastases (IM) represent a contraindication to surgical resection, whereas satellite nodules (SN) do not. However, no consensus criteria exist to distinguish IM from SN. The purpose of this study was to determine genetic alterations and clonal relationships in surgically resected multifocal IHC. Next-generation sequencing of 34 spatially separated IHC tumors was performed using a targeted panel of 201 cancer-associated genes. Proposed definitions in the literature were applied of SN located in the same liver segment and ≤2 cm from the primary tumor; and IM located in a different liver segment and/or >2 cm from the primary tumor. Somatic point mutations concordant across tumors from individual patients included BAP1, SMARCA4 and IDH1. Small insertions and deletions (indels) present at the same genome positions among all tumors from individuals included indels in DNA repair genes, CHEK1, ERCC5, ATR and MSH6. Copy number alterations were also similar between all tumors in each patient. In this cohort of multifocal IHC, genomic profiles were concordant across all tumors in each patient, suggesting a common progenitor cell origin, regardless of the location of tumors in the liver. The decision to perform surgery should not be based upon a perceived distinction between IM and SN.
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http://dx.doi.org/10.1093/carcin/bgaa124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052956PMC
April 2021

Comprehensive Molecular Characterization of Adenocarcinoma of the Gastroesophageal Junction Between Esophageal and Gastric Adenocarcinomas.

Ann Surg 2020 Oct 19. Epub 2020 Oct 19.

Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.

Objective: To investigate the molecular characteristics of AGEJ compared with EAC and gastric adenocarcinoma.

Summary Of Background Data: Classification of AGEJ based on differential molecular characteristics between EAC and gastric adenocarcinoma has been long-standing controversy but rarely conducted due to anatomical ambiguity and epidemiologic difference.

Methods: The molecular classification model with Bayesian compound covariate predictor was developed based on differential mRNA expression of EAC (N = 78) and GCFB (N = 102) from the Cancer Genome Atlas (TCGA) cohort. AGEJ/cardia (N = 48) in TCGA cohort and AGEJ/upper third GC (N = 46 pairs) in Seoul National University cohort were classified into the EAC-like or GCFB-like groups whose genomic, transcriptomic, and proteomic characteristics were compared.

Results: AGEJ in both cohorts was similarly classified as EAC-like (31.2%) or GCFB-like (68.8%) based on the 400-gene classifier. The GCFB-like group showed significantly activated phosphoinositide 3-kinase-AKT signaling with decreased expression of ERBB2. The EAC-like group presented significantly different alternative splicing including the skipped exon of RPS24, a significantly higher copy number amplification including ERBB2 amplification, and increased protein expression of ERBB2 and EGFR compared with GCFB-like group. High-throughput 3D drug test using independent cell lines revealed that the EAC-like group showed a significantly better response to lapatinib than the GCFB-like group (P = 0.015).

Conclusions: AGEJ was the combined entity of the EAC-like and GCFB-like groups with consistently different molecular characteristics in both Seoul National University and TCGA cohorts. The EAC-like group with a high Bayesian compound covariate predictor score could be effectively targeted by dual inhibition of ERBB2 and EGFR.
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http://dx.doi.org/10.1097/SLA.0000000000004303DOI Listing
October 2020

Notch activity characterizes a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features.

J Hepatol 2021 03 8;74(3):613-626. Epub 2020 Oct 8.

Department of Medicine, Columbia University, New York, NY, USA. Electronic address:

Background & Aims: The hepatocyte Notch pathway is a pathogenic factor in non-alcoholic steatohepatitis (NASH)-associated fibrosis, but its role in hepatocellular carcinoma (HCC) is less well defined. Herein, we aimed to characterize the molecular and clinical features of Notch-active human HCC, and to investigate the mechanisms by which Notch affects NASH-driven HCC.

Methods: Using a 14-gene Notch score, we stratified human HCCs from multiple comprehensively profiled datasets. We performed gene set enrichment analyses to compare Notch-active HCCs with published HCC subtype signatures. Next, we sorted Notch-active hepatocytes from Notch reporter mice for RNA sequencing and characterized Notch-active tumors in an HCC model combining a carcinogen and a NASH-inducing diet. We used genetic mouse models to manipulate hepatocyte Notch to investigate the sufficiency and necessity of Notch in NASH-driven tumorigenesis.

Results: Notch-active signatures were found in ~30% of human HCCs that transcriptionally resemble cholangiocarcinoma-like HCC, exhibiting a lack of activating CTNNB1 (β-catenin) mutations and a generally poor prognosis. Endogenous Notch activation in hepatocytes is associated with repressed β-catenin signaling and hepatic metabolic functions, in lieu of increased interactions with the extracellular matrix in NASH. Constitutive hepatocyte Notch activation is sufficient to induce β-catenin-inactive HCC in mice with NASH. Notch and β-catenin show a pattern of mutual exclusivity in carcinogen-induced HCC; in this mouse model, chronic blockade of Notch led to β-catenin-dependent tumor development.

Conclusions: Notch activity characterizes a distinct HCC molecular subtype with unique histology and prognosis. Sustained Notch signaling in chronic liver diseases can drive tumor formation without acquiring specific genomic driver mutations.

Lay Summary: The Notch signaling pathway is known to be involved in the pathogenesis of liver fibrosis. However, its role in liver cancer has not been well defined. Herein, we show that Notch activity is increased in a subset of liver cancers and is associated with poor outcomes. We also used a mouse model to show that aberrant Notch activity can drive cancer progression in obese mice.
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http://dx.doi.org/10.1016/j.jhep.2020.09.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897246PMC
March 2021

Low Expression is Associated with Poor Prognosis in Hepatocellular Carcinoma.

Cells 2020 09 1;9(9). Epub 2020 Sep 1.

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

AT-rich interactive domain 1A () is one of the most frequently mutated genes in hepatocellular carcinoma (HCC), but its clinical significance is not clarified. We aimed to evaluate the clinical significance of low expression in HCC. By analyzing the gene expression data of liver from -knockout mice, hepatic -specific gene expression signature was identified ( < 0.05 and 0.5-fold difference). From this signature, a prediction model was developed to identify tissues lacking activity and was applied to gene expression data from three independent cohorts of HCC patients to stratify patients according to activity. The molecular features associated with loss of were analyzed using The Cancer Genome Atlas (TCGA) multi-platform data, and Ingenuity Pathway Analysis (IPA) was done to uncover potential signaling pathways associated with loss. inactivation was clinically associated with poor prognosis in all three independent cohorts and was consistently related to poor prognosis subtypes of previously reported gene signatures (highly proliferative, hepatic stem cell, silence of Hippo pathway, and high recurrence signatures). Immune activity, indicated by significantly lower IFNG6 and cytolytic activity scores and enrichment of regulatory T-cell composition, was lower in the -low subtype than -high subtype. Ingenuity pathway analysis revealed that direct upstream transcription regulators of the signature were genes associated with cell cycle, including group, and while tumor suppressors such as and were significantly inhibited. plays an important role in immune activity and regulating multiple genes involved in HCC development. Low- subtype was associated with poor clinical outcome and suggests the possibility of as a prognostic biomarker in HCC patients.
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http://dx.doi.org/10.3390/cells9092002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564185PMC
September 2020

Silence of Hippo Pathway Associates with Pro-Tumoral Immunosuppression: Potential Therapeutic Target of Glioblastomas.

Cells 2020 07 23;9(8). Epub 2020 Jul 23.

Department of Systems Biology, Division of Cancer Medicine, Unit 950, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.

The critical role of the Hippo pathway has been recently investigated in various cancers, but little is known about its role in glioblastoma (GBM). In order to evaluate the clinical relevance of the Hippo pathway in GBM, we generated a core gene expression signature from four different previously-established silence of Hippo pathway (SOH) signatures. Based on a newly generated core SOH signature, a SOH and active Hippo pathway (AH) was predicted in GBM samples from The Cancer Genome Atlas (TCGA) and validated in a separate cohort. A comparative analysis was performed on multi-panel genomic datasets from TCGA and the possible association of SOH with immune activity and epithelial mesenchymal transition was also evaluated. The SOH signature was associated with poor prognosis in GBM in both cohorts. Expression levels of and , the most reliable and well-known downstream targets of , were markedly increased in the SOH subgroup of GBM patients. SOH signature was strongly associated with a high immune signature score and mesenchymal features. Genes differentially expressed between SOH and AH groups revealed many markers for inhibitory immune checkpoints and M2-polarized macrophages were upregulated in the SOH subgroup, suggesting that SOH may induce the resistance of cancer cells to host immune response in GBM. In summary, SOH is significantly associated with the poor prognosis of GBM patients and is possibly mediated by pro-tumoral immunosuppression.
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http://dx.doi.org/10.3390/cells9081761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464204PMC
July 2020

Anti-inflammatory Roles of Glucocorticoids Are Mediated by Foxp3 Regulatory T Cells via a miR-342-Dependent Mechanism.

Immunity 2020 09 23;53(3):581-596.e5. Epub 2020 Jul 23.

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. Electronic address:

Glucocorticoids (GC) are the mainstay treatment option for inflammatory conditions. Despite the broad usage of GC, the mechanisms by which GC exerts its effects remain elusive. Here, utilizing murine autoimmune and allergic inflammation models, we report that Foxp3 regulatory T (Treg) cells are irreplaceable GC target cells in vivo. Dexamethasone (Dex) administered in the absence of Treg cells completely lost its ability to control inflammation, and the lack of glucocorticoid receptor in Treg cells alone resulted in the loss of therapeutic ability of Dex. Mechanistically, Dex induced miR-342-3p specifically in Treg cells and miR-342-3p directly targeted the mTORC2 component, Rictor. Altering miRNA-342-3p or Rictor expression in Treg cells dysregulated metabolic programming in Treg cells, controlling their regulatory functions in vivo. Our results uncover a previously unknown contribution of Treg cells during glucocorticoid-mediated treatment of inflammation and the underlying mechanisms operated via the Dex-miR-342-Rictor axis.
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http://dx.doi.org/10.1016/j.immuni.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793548PMC
September 2020

NRG1/ERBB3 Pathway Activation Induces Acquired Resistance to XPO1 Inhibitors.

Mol Cancer Ther 2020 08 4;19(8):1727-1735. Epub 2020 Jun 4.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

XPO1 inhibitors have shown promise in cancer treatment, but mechanisms of resistance to these drugs are not well understood. In this study, we established selective inhibitors of nuclear export (SINE)-resistant ovarian cancer cell lines from mouse tumors and determined the mechanisms of adaptive XPO1 inhibitor resistance using protein and genomic arrays. Pathway analyses revealed upregulation of the NRG1/ERBB3 pathway in SINE-resistant cells. Depletion of ERBB3 using siRNAs restored the antitumor effect of SINE and Furthermore, exogenous NRG1 decreased the antitumor effect of SINE in ovarian cancer cell lines with high ERBB3 expression, but not in those with low expression. These results suggest that NRG1 and ERBB3 expression is a potential biomarker of response to SINE treatment. The antitumor effect of SINE was reduced by exogenous NRG1 in an ERBB3-dependent manner. These findings suggest that NRG1 and ERBB3 are effective biomarkers that should be evaluated in future clinical trials and are relevant therapeutic targets for the treatment of SINE-resistant cancers.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415525PMC
August 2020

YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition.

Gut 2021 01 27;70(1):55-66. Epub 2020 Apr 27.

Department of Gastrointestinal Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA

Objective: Peritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The yes-associated protein 1 () oncogene has emerged in many tumour types, but its clinical significance in PC is unclear. Here, we investigated the role of YAP1 in PC and its potential as a therapeutic target.

Methods: Patient-derived PC cells, patient-derived xenograft (PDX) and patient-derived orthotopic (PDO) models were used to study the function of YAP1 in vitro and in vivo. Immunofluorescence and immunohistochemical staining, RNA sequencing (RNA-Seq) and single-cell RNA-Seq (sc-RNA-Seq) were used to elucidate the expression of YAP1 and PC cell heterogeneity. LentiCRISPR/Cas9 knockout of YAP1 and a YAP1 inhibitor were used to dissect its role in PC metastases.

Results: YAP1 was highly upregulated in PC tumour cells, conferred cancer stem cell (CSC) properties and appeared to be a metastatic driver. Dual staining of YAP1/EpCAM and sc-RNA-Seq revealed that PC tumour cells were highly heterogeneous, YAP1 PC cells had CSC-like properties and easily formed PDX/PDO tumours but also formed PC in mice, while genetic knockout YAP1 significantly slowed tumour growth and eliminated PC in PDO model. Additionally, pharmacologic inhibition of YAP1 specifically reduced CSC-like properties and suppressed tumour growth in YAP1 PC cells especially in combination with cytotoxics in vivo PDX model.

Conclusions: YAP1 is essential for PC that is attenuated by YAP1 inhibition. Our data provide a strong rationale to target YAP1 in clinic for GAC patients with PC.
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http://dx.doi.org/10.1136/gutjnl-2019-319748DOI Listing
January 2021

A Regulatory Noncoding RNA, nc886, Suppresses Esophageal Cancer by Inhibiting the AKT Pathway and Cell Cycle Progression.

Cells 2020 03 26;9(4). Epub 2020 Mar 26.

Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea.

nc886 is a regulatory non-coding RNA (ncRNA) whose expression is frequently silenced in malignancies. In the case of esophageal squamous cell carcinoma (ESCC), nc886 silencing is associated with shorter survival of patients, suggesting nc886's tumor suppressor role in ESCC. However, this observation has not been complemented by an in-detail study about nc886's impact on gene expression and cellular phenotypes. Here we have shown that nc886 inhibits AKT, a key protein in a renowned pro-survival pathway in cancer. nc886-silenced cells (nc886 cells) have activated AKT and altered expression of cell cycle genes. nc886 cells tend to have lower expression of CDKN2A and CDKN2C, both of which are inhibitors for cyclin-dependent kinase (CDK), and higher expression of CDK4 than nc886-expressing cells. As a result, nc886 cells are hyperactive in the progression of the G1 to S cell cycle phase, proliferate faster, and are more sensitive to palbociclib, which is a cancer therapeutic drug that targets CDK4/6. Experimentally by nc886 expression and knockdown, we have determined the AKT target genes and cell cycle genes that are controlled by nc886 (nc886-associated gene sets). These gene sets, in combination with pathologic staging and nc886 expression levels, are a vastly superior predictor for the survival of 108 ESCC patients. In summary, our study has elucidated in ESCC how nc886 inhibits cell proliferation to explain its tumor suppressor role and identified gene sets that are of future clinical utility, by predicting patient survival and responsiveness to a therapeutic drug.
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http://dx.doi.org/10.3390/cells9040801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226379PMC
March 2020

Genomic Signature of the Standardized Uptake Value in F-Fluorodeoxyglucose Positron Emission Tomography in Breast Cancer.

Cancers (Basel) 2020 Feb 20;12(2). Epub 2020 Feb 20.

Genome Editing Research Center, KRIBB, Daejeon 34141, Korea.

The standardized uptake value (SUV), an indicator of the degree of glucose uptake in F-fluorodeoxyglucose positron emission tomography (FDG-PET), has been used for predicting the clinical behavior of malignant tumors. However, its characteristics have been insufficiently explored at the genomics level. Here, we aim to identify genomic signatures reflecting prognostic SUV characteristics in breast cancer (BRC). Through integrative genomic profiling of 3710 BRC patients, including 254 patients who underwent preoperative FDG-PET, we identified an SUV signature, which showed independent clinical utility for predicting BRC prognosis (hazard ratio [HR] 1.27, 95% confidence interval [CI] = 1.12 to 1.45, = 2.23 × 10). The risk subgroups classified by the signature exhibited mutually exclusive mutation patterns of and and showed significantly different responsiveness to immunotherapy. Experimental assays revealed that a signaling axis defined by - and its downstream effectors in glycolysis-gluconeogenesis, including , might be important mediators in the FDG-PET process. Our molecular characterizations support an understanding of glucose metabolism and poor prognosis in BRC with a high SUV, utilizable in clinical practice to assist other diagnostic tools.
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http://dx.doi.org/10.3390/cancers12020497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072341PMC
February 2020

Genomic Perspective on Mouse Liver Cancer Models.

Cancers (Basel) 2019 Oct 25;11(11). Epub 2019 Oct 25.

Department of Systems Biology, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Selecting the most appropriate mouse model that best recapitulates human hepatocellular carcinoma (HCC) allows translation of preclinical mouse studies into clinical studies. In the era of cancer genomics, comprehensive and integrative analysis of the human HCC genome has allowed categorization of HCC according to molecular subtypes. Despite the variety of mouse models that are available for preclinical research, there is a lack of evidence for mouse models that closely resemble human HCC. Therefore, it is necessary to identify the accurate mouse models that represent human HCC based on molecular subtype as well as histologic aggressiveness. In this review, we summarize the mouse models integrated with human HCC genomic data to provide information regarding the models that recapitulates the distinct aspect of HCC biology and prognosis based on molecular subtypes.
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http://dx.doi.org/10.3390/cancers11111648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895968PMC
October 2019

PAC-5 Gene Expression Signature for Predicting Prognosis of Patients with Pancreatic Adenocarcinoma.

Cancers (Basel) 2019 Nov 7;11(11). Epub 2019 Nov 7.

Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea.

Pancreatic adenocarcinoma (PAC) is one of the most aggressive malignancies. Intratumoural molecular heterogeneity impedes improvement of the overall survival rate. Current pathological staging system is not sufficient to accurately predict prognostic outcomes. Thus, accurate prognostic model for patient survival and treatment decision is demanded. Using differentially expressed gene analysis between normal pancreas and PAC tissues, the cancer-specific genes were identified. A prognostic gene expression model was computed by LASSO regression analysis. The PAC-5 signature (LAMA3, E2F7, IFI44, SLC12A2, and LRIG1) that had significant prognostic value in the overall dataset was established, independently of the pathological stage. We provided evidence that the PAC-5 signature further refined the selection of the PAC patients who might benefit from postoperative therapies. SLC12A2 and LRIG1 interacted with the proteins that were implicated in resistance of EGFR kinase inhibitor. DNA methylation was significantly involved in the gene regulations of the PAC-5 signature. The PAC-5 signature provides new possibilities for improving the personalised therapeutic strategies. We suggest that the PAC-5 genes might be potential drug targets for PAC.
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http://dx.doi.org/10.3390/cancers11111749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896100PMC
November 2019

Identification of prognostic biomarker in predicting hepatocarcinogenesis from cirrhotic liver using protein and gene signatures.

Exp Mol Pathol 2019 12 30;111:104319. Epub 2019 Oct 30.

Department of Systems Biology, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Introduction: Cirrhosis primes the liver for hepatocellular carcinoma (HCC) development. However, biomarkers that predict HCC in cirrhosis patients are lacking. Thus, we aimed to identify a biomarker directly from protein analysis and relate it with transcriptomic data to validate in larger cohorts.

Material And Method: Forty-six patients who underwent hepatectomy for HCC that arose from cirrhotic liver were enrolled. Reverse-phase protein array and microarray data of these patients were analyzed. Clinical validation was performed in two independent cohorts and functional validation using cell and tissue microarray (TMA).

Results: Systematic analysis performed after selecting 20 proteins from 201 proteins with AUROC >70 effectively categorized patients into high (n = 20) or low (n = 26) risk HCC groups. Proteome-derived late recurrence (PDLR)-gene signature comprising 298 genes that significantly differed between high and low risk groups predicted HCC well in a cohort of 216 cirrhosis patients and also de novo HCC recurrence in a cohort of 259 patients who underwent hepatectomy. Among 20 proteins that were selected for analysis, caveolin-1 (CAV1) was the most dominant protein that categorized the patients into high and low risk groups (P < .001). In a multivariate analysis, compared with other clinical variables, the PDLR-gene signature remained as a significant predictor of HCC (HR 1.904, P = .01). In vitro experiments revealed that compared with mock-transduced immortalized liver cells, CAV1-transduced cells showed significantly increased proliferation (P < .001) and colony formation in soft agar (P < .033). TMA with immunohistochemistry showed that tissues with CAV1 expression were more likely to develop HCC than tissues without CAV1 expression (P = .047).

Conclusion: CAV1 expression predicts HCC development, making it a potential biomarker and target for preventive therapy.
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http://dx.doi.org/10.1016/j.yexmp.2019.104319DOI Listing
December 2019

Clinical and biological significance of expression in endometrial cancer.

Cancer Biol Ther 2020 22;21(2):147-156. Epub 2019 Oct 22.

Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The objective of this study was to examine the clinical significance of expression and the therapeutic efficacy of its silencing in endometrial cancer. expression in clinical samples was evaluated using a tissue microarray and correlated with clinical outcomes. The biological roles of EZH2 were assayed and . Gene expression was examined to reveal the molecular mechanism underlying the roles of EZH2 in endometrial cancer. We found that overexpression was significantly correlated with disease-free and overall survival of patients with endometrial cancer. silencing resulted in decreased cell viability and invasiveness, and increased apoptosis. In addition, silencing enhanced the cytotoxicity of taxanes and cisplatin in Hec-1A and Ishikawa endometrial cancer cells. silencing using small-interfering RNA (siRNA) incorporated into chitosan nanoparticles (siRNA/CN) induced a significant anti-tumor effect compared with that observed in controls (66.6% reduction in Hec-1A cells and 63.2% reduction in Ishikawa cells, < .05 for both). Moreover, siRNA/CN in combination with taxanes produced more robust anti-tumor effects versus those induced by monotherapies (77.0% for Hec-1A cells and 57.7% for Ishikawa cells, < .05 for both). These results were associated with decreased angiogenesis and cell proliferation, and enhanced apoptosis. Genomic analyses revealed that silencing decreased the expression levels of many genes associated with tumor growth, including . Collectively, these results support as an attractive target for the therapeutic management of endometrial cancer.
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http://dx.doi.org/10.1080/15384047.2019.1672455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012102PMC
March 2021

A prognostic index based on an eleven gene signature to predict systemic recurrences in colorectal cancer.

Exp Mol Med 2019 10 2;51(10):1-12. Epub 2019 Oct 2.

Department of Cancer Research, Institute of Innovative Cancer Research and Asan Institute for Life Sciences, Asan Medical Center, Seoul, 05505, Korea.

Approximately half of colorectal cancer (CRC) patients experience disease recurrence and metastasis, and these individuals frequently fail to respond to treatment due to their clinical and biological diversity. Here, we aimed to identify a prognostic signature consisting of a small gene group for precisely predicting CRC heterogeneity. We performed transcriptomic profiling using RNA-seq data generated from the primary tissue samples of 130 CRC patients. A prognostic index (PI) based on recurrence-associated genes was developed and validated in two larger independent CRC patient cohorts (n = 795). The association between the PI and prognosis of CRC patients was evaluated using Kaplan-Meier plots, log-rank tests, a Cox regression analysis and a RT-PCR analysis. Transcriptomic profiling in 130 CRC patients identified two distinct subtypes associated with systemic recurrence. Pathway enrichment and RT-PCR analyses revealed an eleven gene signature incorporated into the PI system, which was a significant prognostic indicator of CRC. Multivariate and subset analyses showed that PI was an independent risk factor (HR = 1.812, 95% CI = 1.342-2.448, P < 0.001) with predictive value to identify low-risk stage II patients who responded the worst to adjuvant chemotherapy. Finally, a comparative analysis with previously reported Consensus Molecular Subgroup (CMS), high-risk patients classified by the PI revealed a distinct molecular property similar to CMS4, associated with a poor prognosis. This novel PI predictor based on an eleven gene signature likely represents a surrogate diagnostic tool for identifying high-risk CRC patients and for predicting the worst responding patients for adjuvant chemotherapy.
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http://dx.doi.org/10.1038/s12276-019-0319-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802642PMC
October 2019

Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response.

Gut 2020 01 6;69(1):18-31. Epub 2019 Jun 6.

Epidemiology, UT MDACC, Houston, Texas, USA.

Objective: Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC's development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets.

Design: We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs.

Results: We identified distinct alterations in PC versus primary GACs, such as more frequent mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in and , higher level of 'clock-like' mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: 'mesenchymal-like' and 'epithelial-like' with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive 'mesenchymal-like' subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-β as potential therapeutic immune targets.

Conclusions: We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.
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http://dx.doi.org/10.1136/gutjnl-2018-318070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943252PMC
January 2020

Mechanism mediated by a noncoding RNA, nc886, in the cytotoxicity of a DNA-reactive compound.

Proc Natl Acad Sci U S A 2019 04 4;116(17):8289-8294. Epub 2019 Apr 4.

Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, 10408 Goyang, Korea;

DNA-reactive compounds are harnessed for cancer chemotherapy. Their genotoxic effects are considered to be the main mechanism for the cytotoxicity to date. Because this mechanism preferentially affects actively proliferating cells, it is postulated that the cytotoxicity is specific to cancer cells. Nonetheless, they do harm normal quiescent cells, suggesting that there are other cytotoxic mechanisms to be uncovered. By employing doxorubicin as a representative DNA-reactive compound, we have discovered a cytotoxic mechanism that involves a cellular noncoding RNA (ncRNA) nc886 and protein kinase R (PKR) that is a proapoptotic protein. nc886 is transcribed by RNA polymerase III (Pol III), binds to PKR, and prevents it from aberrant activation in most normal cells. We have shown here that doxorubicin evicts Pol III from DNA and, thereby, shuts down nc886 transcription. Consequently, the instantaneous depletion of nc886 provokes PKR and leads to apoptosis. In a short-pulse treatment of doxorubicin, these events are the main cause of cytotoxicity preceding the DNA damage response in a 3D culture system as well as the monolayer cultures. By identifying nc886 as a molecular signal for PKR to sense doxorubicin, we have provided an explanation for the conundrum why DNA-damaging drugs can be cytotoxic to quiescent cells that have the competent nc886/PKR pathway.
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http://dx.doi.org/10.1073/pnas.1814510116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486756PMC
April 2019
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