bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4641: Association between dietary tomato intake and the risk of hepatocellular carcinoma: Findings from a prospective cohort study
Authors: Thomas Claire E. , Luu Hung N. , Wang Renwei , Adams-Haduch Jennifer , Yuan Jian-Min , Jin Aizhen , Koh Woon-Puay
Published: September 2020

Background: Intake of tomato and/or lycopene have been found to be associated with reduced risk of several cancer types, but epidemiological data on risk of hepatocellular carcinoma (HCC) are sparse.

Methods: The associations of tomato and lycopene consumption with risk of HCC were examined in the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese men and women aged 45-74 years at enrollment in 1993-1998 with 25 years of follow-up. Tomato and lycopene consumption was evaluated using a validated semi-quantitative food frequency questionnaire. Incident HCC cases were ascertained through the linkage analysis with the nationwide Singapore cancer registry. Cox proportional hazard regression was used to estimate hazard ratio (HR) and its 95% confidence interval (CI) of HCC with the consumption of tomato and lycopene among all cohort participants, and unconditional logistic regression was used to assess the association among individuals negative for hepatitis B surface antigen (HBsAg).

Results: After a mean follow-up of 17.6 years, 561 incident HCC cases were identified. Higher tomato intake was associated with lower risk of HCC after adjustment for multiple potential confounders (Ptrend<0.001). Compared to the lowest quartile, HRs (95% CIs) of HCC for the 2nd, 3rd, and 4th quartile of tomato intake were 0.70 (0.56-0.88), 0.73 (0.58-0.92), and 0.63 (0.49-0.81). Among HBsAg-negative individuals, the inverse association remained (Ptrend=0.03). There was no association between lycopene intake and HCC risk (Ptrend=0.54).

Conclusion: Tomato intake may offer protection against the development of HCC, particularly among individuals without chronic infection with hepatitis B virus.

Citation Format: Claire E. Thomas, Hung N. Luu, Renwei Wang, Jennifer Adams-Haduch, Jian-Min Yuan, Aizhen Jin, Woon-Puay Koh. Association between dietary tomato intake and the risk of hepatocellular carcinoma: Findings from a prospective cohort study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4641.
Abstract 4645: Lifestyle and dietary oxidative balance scores and risk for incident colorectal cancer among older women: The Iowa Women's Health Study
Authors: Mao Ziling , Prizment Anna E. , Lazovich DeAnn , Gibbs David C. , Bostick Roberd M.
Published: September 2020

Background: Basic science literature strongly supports a role of oxidative stress in colorectal cancer (CRC) etiology; however, in epidemiologic studies, associations of individual lifestyle and dietary anti- and pro-oxidant exposures with CRC have been largely inconsistent. However, recent epidemiologic evidence suggests that the collective effects of these exposures on oxidative balance and CRC risk may be substantial.

Methods: From lifestyle and food frequency questionnaire data from the prospective Iowa Women's Health Study (1986 - 2012), we calculated equal-weight, 4-component lifestyle and 11-component dietary oxidative balance scores (OBS), and investigated their separate and joint associations with incident CRC using multivariable Cox proportional hazards regression.

Results: Of the 34,135 cancer-free women aged 55 to 69 at baseline, 1,635 developed CRC during follow-up. Among participants in the highest lifestyle and dietary OBS quintiles (higher anti-oxidant relative to pro-oxidant exposures) relative to the lowest, the multivariable-adjusted hazard ratios (HRs) were, respectively, 0.63 (95% confidence interval (CI), 0.54-0.73; Ptrend < 0.0001) and 0.77 (95% CI, 0.64-0.94; Ptrend = 0.01. The lowest risk was among those in the highest relative to the lowest joint lifestyle/dietary OBS quintile (HR = 0.47; 95% CI, 0.29-0.76).

Conclusions: Our findings suggest that a predominance of antioxidant over pro-oxidant lifestyle and dietary exposures–especially lifestyle separately and jointly with dietary exposures–may be inversely associated with CRC risk among older women.

Citation Format: Ziling Mao, Anna E. Prizment, DeAnn Lazovich, David C. Gibbs, Roberd M. Bostick. Lifestyle and dietary oxidative balance scores and risk for incident colorectal cancer among older women: The Iowa Women's Health Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4645.
Abstract 4687: Oncogenic role of the transcription factor YY1 and its target Survivin in non-Hodgkin's lymphoma
Authors: Vivarelli Silvia , Falzone Luca , Candido Saverio , Bonavida Benjamin , Libra Massimo
Published: September 2020

Objective

Yin Yang 1 (YY1) is a transcription factor with a dual role in cancer genesis. Hematological malignancies, including non-Hodgkin lymphomas (NHL), are often characterized by a frequent development of resistance to therapy and a high rate of tumor recurrence. Our previous observations showed that YY1 is overexpressed in hematological tumors. The aim of this study was to investigate the functional role of YY1 in anti-cancer therapy induced cell death and to identify YY1 downstream resistant factors.

Experimental Designs

The NHL Raji cell line was used as a cellular model. The expression of YY1 was assessed by q-PCR and WB. YY1 knock-down (KD) was achieved using retroviral shRNA. Viability was measured by both the MTT assay and the Trypan Blue live/dead cell count. Cell death was induced following Vincristine and Doxorubicin treatments. The following analyses were used in this study: the JASPAR database, the Encyclopedia of DNA Elements (ENCODE) and the Cancer Genome Atlas (TCGA) datasets relative to NHL patients have been analyzed to assess the expression levels of YY1 and apoptotic genes, according to tumor stages and patients' clinical-pathological features.

Results

Silencing of YY1 in Raji cells resulted in increased sensitivity to both Vincristine and Doxorubicin treatments and augmented apoptosis. Jaspar analysis identified several potential YY1 transcriptional targets involved in cellular death regulation. As a result of q-PCR screening and validation, Survivin has been identified as a potential YY1 target, as it was significantly downregulated following YY1 KD. Bioinformatic analysis of deposited Chip-Seq databases in ENCODE revealed that YY1 is able to target Survivin transcriptional regulatory regions in different cancer cell lines, as well as in normal B lymphocytes. The TCGA-deposited datasets identified specific clusters of YY1 expression significantly correlated with Survivin.

Conclusions

Our findings demonstrated that (1) YY1 silencing resulted in the sensitization of Raji tumor cells to drug-induced apoptosis (2) q-PCR-mediated screening of putative YY1 targets led to the identification of Survivin as a potential YY1 target, as when YY1 was KD, Survivin levels were strongly downregulated (3) YY1 might be positively regulating Survivin expression (4) Survivin could be a potential target of YY1 in NHL and (5) YY1 and Survivin in NHL may represent two novel diagnostic and prognostic biomarkers to assess patients' response to chemotherapy.

Citation Format: Silvia Vivarelli, Luca Falzone, Saverio Candido, Benjamin Bonavida, Massimo Libra. Oncogenic role of the transcription factor YY1 and its target Survivin in non-Hodgkin's lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4687.
Abstract 470: High-dose TSLP decreases in vivo tumor burden in preclinical models of CRLF2 B-ALL
Authors: Ruiz-Jimenez Caleb , Coats Jacqueline , Stoian Cornelia , Baez Ineavely , Alkashgari Hossam , Paz-Aldana Andy , Choi Hannah , Williams Roland , Gohar Shadi Farzin , Dovat Sinisa , Payne Kimberly
Published: September 2020

B cell acute lymphoblastic leukemia (B-ALL) is the most common cancer in pediatric patients and children of Hispanic ancestry experience higher incidence and mortality rates than others. While cure rates approach 90%, approximately 10% to 20% of patients still relapse. Genomic profiling has identified Ph-like B-ALL as the subtype at highest risk for relapse. Half of all Ph-like B-ALL overexpress the CRLF2 surface protein (CRLF2+ B-ALL). CRLF2 homodimerizes with the IL-7 receptor alpha (IL-7Ra) to comprise a receptor complex that is activated by the cytokine, Thymic Stromal Lymphopoietin (TSLP). TSLP activates the JAK/STAT and PI3/AKT/mTOR pathways which are known to promote cell survival and proliferation. In vitro studies of CRLF2 B-ALL in our laboratory showed that physiological levels (20 pg/ml) of TSLP could activate the TSLP receptor (indicated by STAT5 and ribosomal protein S6 phosphorylation) when stimulated over time. In contrast, we found that supra-physiological levels of TSLP (1 ng/ml or less) induced an initial activation event, but this was followed by a complete shutdown of CRLF2 downstream signaling events that was maintained in the presence of high TSLP. This signal shutdown was correlated with the loss of surface IL-7Ra. The work presented here evaluates the impact of high dose TSLP vs. physiological levels of TSLP on CRLF2 B-ALL in vivo. We make use of novel PDX/xenograft models that expresses human TSLP (hTSLP, mouse TSLP does not activate human CRFL2) created in our lab. Using in vivo bioluminescence analysis of xenografts produced from the MUTZ5 CRLF2 B-ALL cell line, we found that high dose hTSLP induced an 82% decrease in tumor burden (p < 0.0001) as compared to controls with physiological levels of hTSLP. Ongoing studies are evaluating the effect of high dose TSLP on leukemia burden and prolonged survival in a PDX model produced from a Hispanic pediatric patient with CRLF2 B-ALL. Results from these studies will be presented. Taken together, these data suggest that TSLP has promise as a biologic for the treatment of CRLF2 B-ALL.

This work was supported by NIH NCI award R01 CA209829 (KJP & SD).

Citation Format: Caleb Ruiz-Jimenez, Jacqueline Coats, Cornelia Stoian, Ineavely Baez, Hossam Alkashgari, Andy Paz-Aldana, Hannah Choi, Roland Williams, Shadi Farzin Gohar, Sinisa Dovat, Kimberly Payne. High-dose TSLP decreases in vivo tumor burden in preclinical models of CRLF2 B-ALL [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 470.
Abstract 4702: DNA methylation enhances apoptosis resistance of renal cancer cells through the control of mitochondria related gene expression
Authors: Miyakuni Kosuke , Nishida Jun , Ehata Shogo , Miyazono Kohei
Published: September 2020

Many gene alterations have been identified in the onset of renal carcinogenesis. However, molecular alterations might be added to renal cancer cells during the progression. In order to uncover additional molecular alterations, we established highly malignant cancer cells which possess identical background to original cancer cells, and analyzed them in the present study. Since our previous works demonstrated that interaction with cancer microenvironment aids cancer cells with malignant trait through “education” and “selection”, serial orthotopic transplantation was utilized. First, parental human clear cell renal cell carcinoma cells, OS-RC-2, were subjected to serial orthotopic transplantation. Then, novel derivatives were obtained from resulting primary renal tumors. These derivatives formed primary renal tumor faster than parental cells and exhibited increased lung metastasis, suggesting that these derivatives were defined as “highly malignant cancer cells”. Next, we tried to identify the underlying molecular mechanism(s) for renal cancer progression through the characterization of highly malignant cancer cells. Gene expressions in each cell were profiled using RNA-sequencing, and these analyses revealed that expression of several genes associated with mitochondrial functions were dramatically down-regulated in highly malignant cancer cells. Since mitochondrial electron transport chain triggers apoptotic cell death, decrease of these genes may contribute to suppression of apoptosis of highly malignant cancer cells. Cell culture and in vivo experiments demonstrated that mitochondrial dysfunction is responsible for increased survival of renal cancer cells and cancer metastasis. Finally, regulatory mechanism of downregulation of these mitochondria-related genes was analyzed. Bisulfite sequencing analysis revealed that the downregulation may occur by DNA hypermethylation of CpG islands in the promoter regions in renal cancer cells.Taken together, these findings suggested that renal cancer cells acquire additional anti-apoptotic ability through the DNA methylation during the interactions with renal microenvironment, which may in turn lead to the cancer progression and metastasis. We are currently investigating whether the effect of anti-cancer reagent is enhanced in the presence of DNA methylation inhibitors.

Citation Format: Kosuke Miyakuni, Jun Nishida, Shogo Ehata, Kohei Miyazono. DNA methylation enhances apoptosis resistance of renal cancer cells through the control of mitochondria related gene expression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4702.
Abstract 4703: Role of REST in the regulation of MMP24 and estrogen sensitivity in breast cancer
Authors: Vargheese Aditya M. , Cloud Ashley , Gunewardena Sumedha , Shimak Raeann , Kumaraswamy Easwari , Jensen Roy A. , Chennathukuzhi Vargheese M.
Published: September 2020

Breast cancer, the most common malignancy in women, is very difficult to detect and treat due to its heterogeneity. An important subset of breast cancers, Luminal or ER/PR positive tumors, lack REST (repressor element 1 silencing transcription factor) protein but not its mRNA. REST is a tumor suppressor and is known to play a role in regulating neurodegenerative diseases such as Alzheimer's. The loss of REST leads to the dysregulation of its target genes, many of which are involved in tumorigenesis. About 20% of breast cancers show loss of REST expression, yet little to nothing is currently known about the role REST plays in tumor growth. We hypothesized that the loss of REST promotes breast cancer growth by altering cell signaling. Our results show that knockdown of REST in MCF7 cells (ER/PR positive) causes similar gene dysregulation as seen in aggressive forms of breast cancers. Also, Ingenuity Pathway Analysis (IPA®) of our RNA sequencing results showed that REST knockdown leads to significant increase in estrogen receptor signaling in MCF7 cells. Upregulation of estrogen receptor expression has been associated with tumor progression. In addition, REST knockdown led to significant increases in the expression of MMP24 (>20-fold, p<10−85), a matrix modifying enzyme which could play a role in tumor metastasis, as well as KCNK3 (19-fold, p<10−40), a biomarker associated with poor patient survival. Thus, the poor survival of patients with RESTless breast cancers may be related to the activation of its target genes and elevated estrogen receptor signaling. Furthermore, these patients may respond differently to estrogen receptor antagonists compared to those with REST positive breast cancers. Our results will help with the future development of individualized therapies for breast cancer.

Citation Format: Aditya M. Vargheese, Ashley Cloud, Sumedha Gunewardena, Raeann Shimak, Easwari Kumaraswamy, Roy A. Jensen, Vargheese M. Chennathukuzhi. Role of REST in the regulation of MMP24 and estrogen sensitivity in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4703.
Abstract 4729: Identifying genomic drivers of lung adenocarcinoma brain metastases
Authors: Nayyar Naema , Shih David J. , Bihun Ivanna , Dagogo-Jack Ibiayi , Gill Corey M. , Aquilanti Elisa , Bertalan Mia , Kaplan Alexander , D'Andrea Megan R. , Chukwueke Ugonma , Alvarez-Breckenridge Christopher , Lastrapes Matthew , Kuter Ben , Strickland Matthew R. , Martinez-Gutierrez Juan Carlos , Nagabhushan Deepika , De Sauvage Magali , White Michael D. , Castro Brandyn A. , Hoang Kaitlin , Paek Sun Ha , Park Sun Hye , Martinez-Lage Maria , Berghoff Anna S. , Merrill Parker , Gerstner Elizabeth R. , Batchelor Tracy T. , Frosch Matthew P. , Frazier Ryan P. , Borger Darrell R. , Iafrate A John , Santagata Sandro , Preusser Matthias , Cahill Daniel P. , Carter Scott L. , Brastianos Priscilla K.
Published: September 2020

Although lung adenocarcinomas frequently metastasize to the brain, treatment options for lung adenocarcinoma brain metastases (BM-LUAD) are limited. We discovered novel candidate drivers of progression by using case-control analyses to compare whole-exome sequencing data from a cohort of 73 BM-LUAD to a control cohort of 503 primary lung adenocarcinomas. We identified MYC, YAP1 and MMP13 as genomic regions with significantly more frequent amplifications in BM-LUAD compared to control cohort. We validated that MYC, YAP1 and MMP13 can drive brain metastases in a patient-derived xenograft mouse model, where incidence of brain metastases was higher in mice injected with tumor cells expressing the candidate drivers compared to tumor cells expressing LacZ. These results indicate that somatic alterations can drive lung adenocarcinomas to metastasize to the brain. These candidate drivers may serve as therapeutic targets in patients with brain metastatic lung adenocarcinomas.

Citation Format: Naema Nayyar, David J. Shih, Ivanna Bihun, Ibiayi Dagogo-Jack, Corey M. Gill, Elisa Aquilanti, Mia Bertalan, Alexander Kaplan, Megan R. D'Andrea, Ugonma Chukwueke, Christopher Alvarez-Breckenridge, Matthew Lastrapes, Ben Kuter, Matthew R. Strickland, Juan Carlos Martinez-Gutierrez, Deepika Nagabhushan, Magali De Sauvage, Michael D. White, Brandyn A. Castro, Kaitlin Hoang, Sun Ha Paek, Sun Hye Park, Maria Martinez-Lage, Anna S. Berghoff, Parker Merrill, Elizabeth R. Gerstner, Tracy T. Batchelor, Matthew P. Frosch, Ryan P. Frazier, Darrell R. Borger, A John Iafrate, Sandro Santagata, Matthias Preusser, Daniel P. Cahill, Scott L. Carter, Priscilla K. Brastianos. Identifying genomic drivers of lung adenocarcinoma brain metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4729.
Abstract 4740: Molecular profiling of adenoid cystic carcinomas
Authors: Ellis Michelle , Swensen Jeff , Stafford Phillip , Gatalica Zoran
Published: September 2020

Introduction: Adenoid cystic carcinomas (AdCC) are uncommon malignant neoplasm that can occur in different locations throughout the body. These tumors are typically characterized by the presence of MYB:NFIB or MYBL1:NFIB fusion, but not in every case.

Methods: We analyzed 107 adenoid cystic carcinomas from various primary sites that were genetically profiled using a large NGS panel (592) genes in genomic DNA and whole transcriptome sequencing. Immunohistochemical staining was performed for PD-L1.

Results: The primary sites included salivary gland (60), lung (15), sino-nasal passages (10), oral cavity (9) breast (5), head, face or neck or other sites (5), skin (1), vulva (1), and unknown primary site (1). Fusions were detected in 87 cases (81%). The two fusions known to be associated with AdCC, MYB:NFIB and MYBL1:NFIB, were detected in 67 specimens (56 MYB:NFIB, 11 MYBL1:NFIB). In addition several fusions of uncertain significance involving these genes were detected (each found in one sample): MYBL1:SGK3, CD274:NFIB, NFIB:AHI1, NFIB:LINC00271 and TOP2B:MYBL1.

No fusions were detected in 20 AdCC; the most common primary sites being salivary glands (14) and lung (4). The most common mutations detected in genomic DNA from these specimens involved NOTCH1 (5 cases), KDM6A (4 cases) ARID1A and TP53 (3 cases each). Two lung primaries were PD-L1 positive, low expression. No pathogenic mutations were detected in 3 cases: 2 salivary gland tumors and 1 oral cavity tumor.

In cases with MYBL1:NFIB fusion, the gene expression of MYB is in the lower 20th percentile (relative to the entire cohort) while MYBL1 expression is in the upper 80th percentile. Conversely in cases with the MYB:NFIB fusions, MYB expression is ectopic resulting in expression in the upper 80th percentile while MYLB1 in the lower 20th percentile.

Conclusion: We detected a classic MYB:NFIB or MYBL1:NFIB fusion in 67 of 107 adenoid cystic carcinomas profiled in this study. There is a strong pattern linking the presence or absence of fusions with the expression of MYB and MYBL1. Thus, fusions are driving high expression of either MYB or MYBL1, but the gene not involved in the fusion shows evidence of reduced expression. We hypothesize that a negative feedback mechanism may result in reduced expression of the other MYB-family gene to maintain homeostasis. From the treatment perspective, rare primary lung AdCC are amenable for I-O therapy based on expression of PD-L1.

Citation Format: Michelle Ellis, Jeff Swensen, Phillip Stafford, Zoran Gatalica. Molecular profiling of adenoid cystic carcinomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4740.
Abstract 475: Preoperativechemoradiation increases levels of immune system modulators in tumor tissue in locally advanced rectal cancer
Authors: Bae SungUk , Kim Shin , Lee Hye Won , Byun Sang Jun , Park Jee Young , Min Hyeonji
Published: September 2020

Purpose: Neoadjuvant chemoradiation therapy (CRT) is a widely and effectively used preoperative treatment strategy in locally advanced rectal cancers. However, little research has been done to characterize the molecular changes caused by neoadjuvant CRT in these cancer tissues. The purpose of this study was to investigate the effects of preoperative CRT on tumor gene expression in Korean patients with colorectal cancer (CRC).

Materials and methods: We included 11 paired human rectal cancer tissues before and after irradiation between August 2016 and December 2017, and performed RNA sequencing analysis. Principal component analysis of CRC demonstrated strong similarity in respective groups of CRC tissues before and after CRT from CRC patients at the transcriptome level.

Results: Volcano plot filtering identified 3325 differentially expressed genes (DEGs) in CRC tissues after CRT, compared to CRC tissues before CRT. Gene set enrichment analysis with DEGs revealed 45 signaling pathways associated with down-regulated target genes, significantly including the mismatch repair signaling pathway. CRT significantly increased tumor mutation burden (TMB) in CRC tissues. Notably, preoperative CRT increased immune signature scores including interferon-gamma, immune cytolytic score, and immune signature.

Conclusion: Neoadjuvant CRT modulates immune-related characteristics of CRC, including increasing TMB and various immune signature scores, suggesting that neoadjuvant CRT has potential to improve responsiveness to immunotherapy.

Citation Format: SungUk Bae, Shin Kim, Hye Won Lee, Sang Jun Byun, Jee Young Park, Hyeonji Min. Preoperativechemoradiation increases levels of immune system modulators in tumor tissue in locally advanced rectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 475.
Abstract 4755: Chemoprevention and pharmacokinetics study using Gasdermin D knock out induced colon cancer model mouse treated with FAS inhibitors
Authors: Orita Hajime , Lee Hyeoncheol , Kobayashi Toshiyuki , Fukunaga Tetsu
Published: September 2020

(Introduction) It is well known that cancer cell harness different metabolic pathway from normal cells more efficiently. Recent studies indicate disorder of lipid metabolism has happen even in the benign cell, and that cause to be malignancy. Our research group focus attention on irregular accumulation of fatty acid in cancer cells. This time, we analysis several studies using Gasdermin D knock out induced colon cancer model mouse treated with FAS inhibitors.

1) metabolism analysis for mouse colon cancer. 2) Colon cancer treatment and chemoprevention by FAS inhibitor 3)Pharmacokinetics status of FAS inhibitor (colon cancer model mouse) Gasdermin D (GSDM D), pylotosis key factor, knockout mouse treat with AOM and DSS. 3month after all mouse has several big tumors (patent in Japan 2016-69775)

(Result) 1) There are Many famous long chain fatty acids in cancer tissue. And also Very Long Chain Fatty Acid (:VLCFA) can detected by this analysis. 2) C75 and Kampo (include Berberine) can decrease tumor number and size. And they has chemoprevention effects, too. 3) Almost 40% FAS activity can reduce by everyday FAS inhibitor treatment.

(Conclusion) AS metabolic disorders seem to induce colon cancer carcinogenesis, this target therapy can work for that prevention and treatment.

Citation Format: Hajime Orita, Hyeoncheol Lee, Toshiyuki Kobayashi, Tetsu Fukunaga. Chemoprevention and pharmacokinetics study using Gasdermin D knock out induced colon cancer model mouse treated with FAS inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4755.
Abstract 4783: Suppression of IL-6-induced metastatic potential by inhibition of mitochondrial fission in ovarian cancer cells
Authors: Lee Juwon , Han Youngjin , Song Yong Sang
Published: September 2020

Ovarian cancer is the fifth most common cause of cancer death among females in the United States. In tumor microenvironment, inflammation has been shown to play a key role, governing malignant properties of cancer cells such as angiogenesis, chemoresistance and metastasis. Interleukin-6 (IL-6) is a pro-inflammatory cytokine, produced in response to injury, infection, and inflammation. IL-6 can regulate growth, differentiation and gene expression of cells. In our previous study, we have shown that IL-6 was found to be present at a high level in malignant ascites when compared to those in benign ascites. Similar to many other oncogenic cytokines, IL-6 has been reported to increase malignant properties of cancer such as metastasis. Mitochondria, energy plants of cells regulating metabolic homeostasis, are structurally dynamic organelles undergoing continuous fission and fusion. In metastatic cancer cells, mitochondrial fission has been shown to be more frequent, than in the primary cancer cells. A key facilitator of mitochondrial fission is a molecule called dynamin-1-related protein 1 (Drp1) and its phosphorylation status can determine the activity of the molecule. Herein, we investigated the effect of the inflammatory cytokine IL-6 on the mitochondrial dynamics and the relationship between the changes in mitochondrial dynamics and metastatic potential of ovarian cancer cells. Treatment of IL-6 on epithelial ovarian cancer (EOC) cell lines (PA-1 and SKOV3) increased the metastatic potential, such as invasion and migration, verified by trans-well invasion and wound healing assays. IL-6 did not change the Drp1 expression at the protein level but modulated the ratio of phospho-Drp1s616 (active form) and phospho-Drp1s637 (inactive form), together with increased fission of mitochondria in the EOC cells. An increase of mitochondrial fission by IL-6 was confirmed through MitoSpy staining. Inhibition of mitochondrial fission by RNAi and a pharmacologic inhibitor attenuated metastatic potential of the EOC cells. Altogether, our study strongly suggests the role of mitochondrial fission in the metastatic potential of EOC cells induced by IL-6. The inhibition of mitochondrial fission could be a potential therapeutic approach suppressing the metastasis of EOC.

Citation Format: Juwon Lee, Youngjin Han, Yong Sang Song. Suppression of IL-6-induced metastatic potential by inhibition of mitochondrial fission in ovarian cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4783.
Abstract 4790: An in situ hybridization assay reveals high mitochondrial DNA copy number in stem cell/proliferative cell compartments
Authors: CHEN JIAYU , Zheng Qizhi , Peiffer Lauren B. , Hicks Jessica L. , Haffner Michael C. , Rosenberg Avi Z. , Levi Moshe , Wang Xiaoxin , Ozbek Busra , Yegnasubramanian Srinivasan , De Marzo Angelo M.
Published: September 2020

Mitochondria are critical regulators of energy production, metabolism and cell death. Warburg observed that in the presence of oxygen, many cancer cells take up abundant amounts of glucose, and excrete the carbon mainly as lactate. Warburg postulated that this aerobic glycolysis was essential and universal in cancer, and was caused by mitochondrial dysfunction. Yet, more recent findings suggest that aerobic glycolysis also occurs in rapidly dividing normal cells to support anabolic reactions needed for cell growth and replication. Furthermore, a number of metabolites generated by the tricarboxylic acid cycle and the electron transport chain are also used for macromolecular synthesis in proliferating cancer and normal cells. This suggests that an increase in mitochondrial activity, especially those functions related to anabolic metabolism, may be required for cancer development and progression. One mechanism to increase mitochondrial function is through mitochondrial biogenesis, which is partly regulated by regulating mitochondrial DNA (mtDNA) copy number.

Alterations in mtDNA sequence and copy number have been implicated in various cancers. Since most prior measurements of mtDNA copy number have been performed using homogenates of complex tissues composed of multiple cell types, very little is known about cell type-specific mtDNA copy number heterogeneity. Here, we validated a quantitative in situ hybridization approach to study mtDNA levels at the single cell level in tissue sections. In hierarchically organized self-renewing tissues, higher levels of mtDNA were observed in stem/proliferative compartments than in differentiated compartments. Also, we found zonal heterogeneity of mtDNA levels in the liver that mirrors the known oxygen tension gradient. In the kidney, we observed markedly lower mtDNA levels in glomeruli and the collecting ducts compared to cortical proximal and distal tubules. This work provides visualization of mtDNA copy number in distinct cell populations in situ for the first time across normal mammalian tissues, and can serve as a foundation for quantifying cell type-specific mtDNA copy number dynamics in any relevant diseases, especially in cancers and their precursor lesions.

Citation Format: JIAYU CHEN, Qizhi Zheng, Lauren B. Peiffer, Jessica L. Hicks, Michael C. Haffner, Avi Z. Rosenberg, Moshe Levi, Xiaoxin Wang, Busra Ozbek, Srinivasan Yegnasubramanian, Angelo M. De Marzo. An in situ hybridization assay reveals high mitochondrial DNA copy number in stem cell/proliferative cell compartments [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4790.
Abstract 4802: Functional analysis of cancer associated mitochondrial genome alterations
Authors: Otto Neil
Published: September 2020

It is well documented that a variety of alterations can occur in the mitochondrial genome during human tumor development. These alterations often correlate with cancer phenotypes like treatment resistance and metastasis. Alterations to the mitochondrial genome may therefore be a biomarker for early detection, prognosis and/or predictor of therapeutic sensitivity. However, a method to easily and quickly create isogenic populations of human cells with mitochondrial genome specific alterations is not available. To combat this, we have developed a technology using transient expression of mitochondria targeted TAL domain nickases and TAL endonucleases (TALENs). This the first reliable method to introduce specific mutations into the mitochondrial genome of mammalian cells. We have efficiently induced mtDNA deletions in zebrafish embryos, human and mouse cell lines. In mouse NIH3T3 fibroblasts, we deleted a mitochondrial genome region corresponding to the same disease sequence seen in the human Kearns-Sayre Syndrome (KSS). The deletion resulted in a measurable phenotype including decreased mitochondria basal respiration, ATP production and maximal respiration. We are expanding this work by engineering targeted and precise mtDNA deletions in conjunction with known cancer initiating nuclear mutations in mammalian cells, as well as systemically in mice. These tools will allow us to determine the effect mitochondrial alterations have on the transformation of cancer cells harboring known cancer causing nuclear mutations. We are also developing an inducible system for expressing mitoTALENs, making it possible to create “conditional” loss of function mutations in mitochondrial genes in human cell lines, including induced pluripotent stem cells (iPSCs). This inducible model system will be highly useful in settings where the mitochondrial deletion may cause a selective disadvantage during early cellular differentiation.

Citation Format: Neil Otto. Functional analysis of cancer associated mitochondrial genome alterations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4802.
Abstract 4815: Differential expression profiling of long noncoding RNA establishes UCA1 as a hallmark of renal medullary carcinoma
Authors: Msaouel Pavlos , Malouf Gabriel G. , Su Xiaoping , Yao Hui , Tripathi Durga N. , Gao Jianjun , Rao Priya , Bertocchio Jean-Philippe , Karam Jose , Wood Christopher G. , Walker Cheryl L. , Genovese Giannicola , Tannir Nizar M.
Published: September 2020

Renal medullary carcinoma (RMC) is a rare but highly lethal renal cell carcinoma (RCC) that predominantly afflicts young African Americans with sickle cell hemoglobinopathies. There are currently no approved targeted therapies for RMC and the median survival from diagnosis is 13 months despite best available treatments. New biomarkers and therapeutic targets are therefore urgently needed for this very aggressive disease. No studies to date have profiled the long noncoding RNA landscape of RMC. We performed RNA sequencing in untreated primary tumor samples obtained from 11 patients with RMC. The lncRNA expression profile of RMC was compared to that of adjacent normal kidney (n = 6 patients with RMC), upper tract urothelial carcinoma (UTUC), and closely related RCCs including collecting duct carcinoma (CDC), clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal cell carcinoma (chRCC). We performed principal component analyses as well as hierarchical clustering of the lncRNA expression levels using the Pearson correlation coefficient as the distance metric and the ward's linkage rule. The read counts of each lncRNA were fitted using a negative binomial model and a Wald test was used in DESeq2 to compare expression levels. The false discovery rate (FDR) was controlled using the Benjamini and Hochberg method. We found that the lncRNA signature of RMC is clearly distinct from that of ccRCC, pRCC, and chRCC, but substantially overlaps with CDC. Urothelial cancer associated 1 (UCA1) was the highest upregulated lncRNA (305-fold increase, FDR < 0.001) in RMC compared with adjacent normal kidney. This dramatic upregulation of UCA1 was similar to that seen in UTUC and not found in any of the other RCCs, including CDC. UCA1 is known to be associated with chemotherapy resistance and was previously considered to be highly specific for urothelial carcinoma. Our findings now suggest that UCA1 is also a hallmark of RMC. Future studies will focus on elucidating the functional consequences of UCA1 expression in RMC pathobiology.

Citation Format: Pavlos Msaouel, Gabriel G. Malouf, Xiaoping Su, Hui Yao, Durga N. Tripathi, Jianjun Gao, Priya Rao, Jean-Philippe Bertocchio, Jose Karam, Christopher G. Wood, Cheryl L. Walker, Giannicola Genovese, Nizar M. Tannir. Differential expression profiling of long noncoding RNA establishes UCA1 as a hallmark of renal medullary carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4815.
Abstract 4827: N6-Methyladenosine modification of LINC00901 promotes pancreatic cancer progression
Authors: Peng Wan-Xin , Yang Liu , Mo Yin-Yuan
Published: September 2020

N6-methyladenosine (m6A) is one of the most prevalent modifications of mRNAs in eukaryotes. Numerous recent studies have indicated that m6A plays the critical role in multiple physiologic functions and disease processes by regulation of mRNA processing, splicing, translation, and stability. Although the majority of RNA methylation studies focus on mRNAs, little is known whether long-coding RNAs (lncRNAs) are also subject to m6A modification. Therefore, this study aims to identify m6A modified lncRNAs and their functional role in pancreatic cancer. We performed methylated RNA immunoprecipitation (MeRIP) profiling against a focused group of lncRNAs and identified five lncRNA candidates, among which the highly enriched lncRNA was LINC00901. RNA dot blot, m6A RNA methylation quantification detection and in vivo RNA pulldown combined with m6A RNA methylation Western Blot confirmed the m6A modification of LINC00901. Of note, the analysis of TCGA datasets indicated that the high level of LINC00901 is associated with the poor overall survival (OS) of pancreatic ductal adenocarcinoma (PDAC) patients. Consistent with this result, we showed that LINC00901 promotes pancreatic cancer cell growth. Importantly, we identified that YTHDF1 serves as a “reader” of the m6A modified LINC00901 and furthermore, ectopic expression of YTHDF1 causes downregulation of LINC00901, suggesting a role for m6A modification in regulation of LINC00901 expression. Experiments are underway to determine how LINC00901 promotes pancreatic cancer cell growth.

Citation Format: Wan-Xin Peng, Liu Yang, Yin-Yuan Mo. N6-Methyladenosine modification of LINC00901 promotes pancreatic cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4827.
Abstract 4861: Loss of YAP1 activates Wnt/beta-Catenin signaling in prostate cancer
Authors: Cheng Siyuan , Yang Shu , Prieto-Dominguez Nestor , Connelly Zachary M. , Shi Yingli , Yu Xiuping
Published: September 2020

Prostate cancer (PCa) is the most common non-cutaneous cancer among American men. In 2019, 174,650 new patients will be diagnosed from this disease. Most patients with localized PCa could be treated successfully. However, when PCa develops into castrate-resistant prostate cancer (CRPCa), the five-year survival rate drops below 30%. Neuroendocrine prostate cancer (NEPCa) is an aggressive subtype of PCa observed in 20%-30% CRPCa patients. Understanding how NEPCa progressed from prostate adenocarcinoma could reveal novel therapeutic targets. Previous studies indicate that activation of Wnt/beta-Catenin signaling promotes the progression to CRPCa with an increased NE differentiation. Additionally, animal studies suggest that Wnt/beta-Catenin signaling is active in NEPCa. Here we explored the mechanisms that promote Wnt/beta-Catenin signaling in NEPCa. Using TRAMP mice, which develop NEPCa after castration, we assessed the expression of Wnt-related genes and found that after androgen deprivation, the expression of Wnt7A is increased in prostate derived from both wild type and TRAMP mice but the expression of DKK1, a Wnt inhibitor, is decreased in wild type prostate but not in TRAMP prostate. The elevated expression of Wnt7a in combination with the lack of induction of Dkk1 in TRAMP tumors provides a mechanism to activate Wnt/beta-Catenin signaling in these tumors. Furthermore, we found the expression of YES-associated Protein (YAP1), a key transcriptional coactivator of Hippo pathway, is lost in NEPCa, in contrast to the elevated expression of YAP1 in high-grade prostate adenocarcinoma. YAP1 knockdown activated Wnt/beta-Catenin activity in PCa PC3 and 22Rv1 cells, indicating that the loss of YAP1 expression provides another mechanism to activate Wnt/beta-Catenin signaling, promoting NEPCa phenotype in PCa cells. Funding: This study is supported by: FWCC/Foundation Legacy Funds, DOD New Investigator Award, The Office of Research SEED awards, NIH R01 AND R03.

Citation Format: Siyuan Cheng, Shu Yang, Nestor Prieto-Dominguez, Zachary M. Connelly, Yingli Shi, Xiuping Yu. Loss of YAP1 activates Wnt/beta-Catenin signaling in prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4861.
Abstract 4867: Using a fragment based approach for the identification of TEAD S3 pocket binders
Authors: Delarbre Laure , Venier Olivier , Valtingojer Iris , Houtmann Jacques , Lowinski Maryse , Parent Annick , Bégassat Françoise , Lasbleiz Angelique , Seys Catherine , Bombart Philippe , Debussche Laurent , Rak Alexey
Published: September 2020

YAP1 and TEAD are transcriptional regulators involved in organ size control and cell proliferation. Aberrant activation of YAP1 has been reported for multiple tumor types and inhibiting the interaction of YAP1 with its partner protein TEAD is thought to be a means of targeting aberrant YAP1 activity. In order to identify small molecule inhibitors of YAP1 interaction with TEAD, we have performed a fragment-based-screening looking for ligands binding to TEAD at its interface with YAP1 (TEAD pocket S3). We have employed three techniques for fragment screening (NMR, SPR, DSF) and have cross tested positive hits identified by one technique with the respective orthogonal method. Using this strategy on Sanofi proprietary fragment libraries, three different fragment series have been identified. X-Ray co-structures with TEAD have been obtained for all three fragment series confirming binding to the S3 pocket of TEAD. Binding mode determination by X-Ray crystallography has set the stage for subsequent fragment optimization.

Citation Format: Laure Delarbre, Olivier Venier, Iris Valtingojer, Jacques Houtmann, Maryse Lowinski, Annick Parent, Françoise Bégassat, Angelique Lasbleiz, Catherine Seys, Philippe Bombart, Laurent Debussche, Alexey Rak. Using a fragment based approach for the identification of TEAD S3 pocket binders [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4867.
Abstract 4868: In vitro and in cellulo mass spectrometry study of TEAD1 palmitoylation
Authors: Buzy Armelle , Guichard Olivier , Zacchayus Jean-Luc , Venier Olivier , Courtin Olivier , Valtingojer Iris , Debussche Laurent , Mikol Vincent , Guillemot Jean-Claude
Published: September 2020

The HIPPO pathway plays an important role in cancer progression and one of its essential components are the transcription factor proteins from the TEAD family. The TEAD family consists of 4 different family members (TEAD1-TEAD4) who modulate gene expression through the interaction with co-activator proteins such as YAP1 and TAZ. Recent studies have shown that TEADs are partially palmitoylated. Activity and stability of TEAD proteins are regulated by this modification. Here, we attempt to better understand the palmitoylation status of TEAD proteins in cells. In a first step, we have developed LC/MS/MS-based assays for the detection of palmitoylated TEAD peptides using recombinant TEAD1 protein. Subsequently, we have set out to analyze endogenous TEAD proteins using YAP1 activated malignant mesothelioma H2052 tumor cells. H2052 tumor cells express preferentially TEAD1 protein. TEAD1 was immunoprecipitated from H2052 tumor cells and subjected to peptidic digest and LC/MS/MS analysis. Peptide mapping permitted to confirm the expected site of palmitoylation (cysteine 359 of TEAD1). In addition, novel sites of both palmitoylation and myristoylation were detected on the lysine residue 336 of TEAD1. While these hydrophobic peptides could not be recovered after in-gel digestion of immunoprecipitation enriched TEAD1 of H2052 cells, digestion performed directly on immunoprecipitation beads allowed us to recover those peptides and hence to confirm the existence of TEAD lysine-myristoylation and lysine-palmitoylation in cells. In this study, we show the development of an MS-based strategy to characterize post translational modifications directly on endogenous TEAD1 proteins present in H2052 tumor cells.

Citation Format: Armelle Buzy, Olivier Guichard, Jean-Luc Zacchayus, Olivier Venier, Olivier Courtin, Iris Valtingojer, Laurent Debussche, Vincent Mikol, Jean-Claude Guillemot. In vitro and in cellulo mass spectrometry study of TEAD1 palmitoylation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4868.