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  • Harada, Kazuto  (5)
  • Wang, Ying  (5)
  • Medicine  (5)
  • 1
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    Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
    BMJ ; 2020
    In:  Gut Vol. 69, No. 1 ( 2020-01), p. 18-31
    Details
    In: Gut, BMJ, Vol. 69, No. 1 ( 2020-01), p. 18-31
    Abstract: 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 CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C , 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.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2018-318070
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
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  • 2
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    Abstract 1071: Overexpression of SHH and GLI1 contributes to poor prognosis and peritoneal metastases in gastric adenocarcinoma
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1071-1071
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1071-1071
    Abstract: Background: The prognosis of gastric adenocarcinoma (GAC) patients with metastases is very poor. Understanding of molecular biology is limited. Hedgehog (Hh) signaling plays an important role in many tumor types and expression of Shh/Gli-1, two major molecules in Hh pathway has been documented in GAC. However, their clinical impact on GAC patients particularly in peritoneal metastasis remains elusive. Methods: Expression of Gli1 and Shh were examined using IHC in tissue microarrays containing more than 500 cases of GAC tissues with clinical annotation. The prognostic variables were determined using univariate and multivariate Cox regression analyses. GAC cell lines, patient-derived peritoneal metastatic cells and novel PDX metastatic model were used to determine the functional role of Shh/Gli-1 in vitro and in vivo. Genetic knockout Gli-1 using LentiCRISPR/Cas9 and Hh inhibitor GDC0449 as well as BET inhibitor were used to test their antitumor activities in GAC cell line and patient-derived cells. Cell proliferation, colony formation, invasion, tumor sphere assays and immunofluorescence were performed to evaluate their functionality and effects of targeted therapy. Results: Both Gli1 and Shh expression are significantly overexpressed in GAC tissue. Among 519 GAC cases, 80.76% and 87.02% were positive for nuclear Gli-1 and cytoplasmic Shh expression respectively, while the strong nuclear expression rate for Gli-1 is 69.56% and 50.10% for Shh. In the univariate Cox analysis, the overall survival was shorter for patients with high Gli-1 (p=0.018) or high Shh expression (p=0.038). In the multivariate cox analysis for both markers, only Gli-1 remained as an independently prognostic for short survival. We also observed high Gli-1 nuclear expression correlated with the presence of lymph node metastasis (p=0.032). Gli1 was highly expressed in most human malignant ascites cells. Interestingly, Gli-1 was significantly upregulated in mouse PDX-ascites cells compared to primary mice tumors. Genetic knockdown Gli-1 or pharmacologically inhibition of Gli-1 by GDC0449 Hh inhibitor or BET inhibitor JQ1 decreased Gli-1 and restored E-cadherin expression and significantly suppressed malignant cell properties and reduced population of cancer stem cells (ALDH1+ or CD133+) in patients' derived metastatic cells. Conclusions: These findings indicate that overexpression of Gli1 and Shh plays an important role in progression of peritoneal metastases of GAC. Targeting Gli1/Hh signaling may provide novel therapeutic strategies for GAC patients with peritoneal metastases. Keywords:Hh pathway, Gli1, Shh, Gastric cancer, metastasis Citation Format: Yan Xu, Yuan Li, Bovey Liu, Melissa Pool Pizzi, Yongxi Song, Kazuto Harada, Ailing Scott, Lang Ma, Jiankang Jin, Xiaochuan Dong, Ying Wang, Brian D. Badgwell, Jeannelyn S. Estrella, Roy-Chowdhuri Sinchita, Fatemeh G. Amlashi, Zhenning Wang, Shumei Song, Jaffer A. Ajani. Overexpression of SHH and GLI1 contributes to poor prognosis and peritoneal metastases in gastric adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1071.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-1071
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
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    YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition
    BMJ ; 2021
    In:  Gut Vol. 70, No. 1 ( 2021-01), p. 55-66
    Details
    In: Gut, BMJ, Vol. 70, No. 1 ( 2021-01), p. 55-66
    Abstract: 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 ( YAP1 ) 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 high 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 high 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.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2019-319748
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 1492637-4
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  • 4
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    YAP1-Mediated CDK6 Activation Confers Radiation Resistance in Esophageal Cancer – Rationale for the Combination of YAP1 and CDK4/6 Inhibitors in Esophageal Cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 7 ( 2019-04-01), p. 2264-2277
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 7 ( 2019-04-01), p. 2264-2277
    Abstract: Esophageal cancer is a lethal disease that is often resistant to therapy. Alterations of YAP1 and CDK6 are frequent in esophageal cancer. Deregulation of both molecules may be responsible for therapy resistance. Experimental Design: Expressions of YAP1 and CDK6 were examined in esophageal cancer cells and tissues using immunoblotting and immunohistochemistry. YAP1 expression was induced in esophageal cancer cells to examine YAP1-mediated CDK6 activation and its association with radiation resistance. Pharmacologic and genetic inhibitions of YAP1 and CDK6 were performed to dissect the mechanisms and assess the antitumor effects in vitro and in vivo. Results: YAP1 expression was positively associated with CDK6 expression in resistant esophageal cancer tissues and cell lines. YAP1 overexpression upregulated CDK6 expression and transcription, and promoted radiation resistance, whereas treatment with the YAP1 inhibitor, CA3, strongly suppressed YAP1 and CDK6 overexpression, reduced Rb phosphorylation, as well as sensitized radiation-resistant/YAP1high esophageal cancer cells to irradiation. CDK4/6 inhibitor, LEE011, and knock down of CDK6 dramatically inhibited expression of YAP1 and sensitized resistant esophageal cancer cells to irradiation indicating a positive feed-forward regulation of YAP1 by CDK6. In addition, suppression of both the YAP1 and CDK6 pathways by the combination of CA3 and LEE011 significantly reduced esophageal cancer cell growth and cancer stem cell population (ALDH1+ and CD133+), sensitized cells to irradiation, and showed a strong antitumor effect in vivo against radiation-resistant esophageal cancer cells. Conclusions: Our results document that a positive crosstalk between the YAP1 and CDK6 pathways plays an important role in conferring radiation resistance to esophageal cancer cells. Targeting both YAP1 and CDK6 pathways could be a novel therapeutic strategy to overcome resistance in esophageal cancer.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-1029
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 5
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    Abstract 288: Genomic profiling of metastatic gastric adenocarcinoma
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 288-288
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 288-288
    Abstract: Objectives: Metastatic gastric adenocarcinoma (mGAC) is highly resistant to therapy and is incurable. Particularly, peritoneal carcinomatosis leads to severe morbidities and short survival. The genome wide approaches have been conducted in primary GAC and have uncovered useful information. However, detailed understanding of mGAC is limited. Thus, we aimed to characterize the genomic landscape of mGAC. Methods: Thirty-four malignant ascites specimens were prospectively collected from at The University of Texas MD Anderson Cancer Center (Houston, USA) from February 2016. 25 specimens had whole exome sequencing and 30 specimens had RNA sequencing. Results: The top highly mutated genes in mGAC were TP53, ATM, SYNE2, TTN, CDH11, FAT4/3, KMT2C, FGF23, NCOR1, RP1, CYP2A, and ADAMTS8/9. Compared with mutations in primary GAC (TCGA and TMUCIH), mutations in mGAC shared only 13.7% with TCGA and 10.9% with TMUCIH data. The commonly shared mutations in all three sets were TP53, ATM, FAT4, CDH1, SYNE1, PLEC, PRKDC, and ZFHX3, while unique mutations in mGAC were TTN, SYNE2, ZNF503, PUS7L, PPP2R5C, NBPF12, MROH1, IFNL1, and COL18A1. Furthermore, RNA- sequencing revealed two frequent fusions; 36.7% of samples with C15orf57-CBX3 (t(15;7)) fusion and 10% with SLC35A1-TSHZ2 (t(6;20)). We explored gene signatures in C15orf57-CBX3 fusion subgroup and C15orf57-CBX3 non-fusion subgroup. Gene set enrichment analysis revealed that C15orf57-CBX3 fusion group had enrichment of immune-response related genes, while non-fusion subgroup had enrichment of genes related to the segregation of chromatid, DNA replication, and histone exchange. The clustering analysis of RNA expression using the top 2000 genes with most median absolute deviation identified two subgroups that correlated either with C15orf57-CBX3 fusion or mutations. Conclusions: We have identified a novel genomic landscape of mGAC, such as unique mutation and fusions. Further studies are needed to gain insights into the mechanism of progression and resistance phenotype of mGAC. Citation Format: Kazuto Harada, Shumei Song, Yan Xu, Brain D. Bagewell, Melissa P. Pizzi, Jiankang Jin, Ying Wang, Ailing W. Scott, Lang Ma, Fatemeh G. Amlashi, Makoto Kobayashi, Jody V. Vykoukal, Cristina Ivan, Jeannelyn S. Estrella, Sinchita R. Chowdhuri, George A. Calin, Samir Hanash, Ju-Seog Lee, Bin Liu, Jaffer A. Ajani. Genomic profiling of metastatic gastric adenocarcinoma [abstract]. In: Proceedings of the American As sociation for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 288.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-288
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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