bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 667: Tumor cell dormancy is mediated by an increase in RTK signaling in reversible pancreatic cancer models expressing oncogenic K-Ras and c-Myc
Authors: Rajbhandari Nirakar 
Published: July 2016

Abstract
Recent genetic studies of pancreatic cancer expressing mutant Kras and c-Myc strongly favor targeted therapies against these oncogenic drivers for the successful treatment of advanced staged pancreatic cancer. The potential limitation of these treatments is that they likely leave residual cancer cells that can play a role in tumor recurrence. Our study is focused on understanding the molecular mechanism of the survival of pancreatic cancer cells in the absence of the tumor-driving oncogene in order to successfully eliminate cancer cells and prevent tumor relapse.
Using a reversible c-Myc-induced pancreatic cancer model, we have demonstrated that expression of c-Myc in pancreatic progenitors is sufficient to induce invasive pancreatic cancer, and its expression is required for the maintenance of tumors at primary and metastatic sites. However, despite the complete macroscopic remission of invasive pancreatic tumors at primary and metastatic sites upon downregulation of c-Myc, a few cancer cells survived and remained dormant for a protracted period of time (Lin et al., 2013). In this current study, we have used a reversible Kras-induced pancreatic tumor model and found that cancer cell dormancy is a common attribute in pancreatic cancer following oncogene ablation.
In an effort to identify common, cancer cell-intrinsic molecular pathways that mediate residual disease following the ablation of oncogenic drivers, we performed a genome-wide gene expression analysis (RNA-Seq) of in vivo-derived bulk tumor cells and dormant cancer cells that survived the ablation of c-Myc and oncogenic Kras. Comparison of the gene expression profile of bulk and residual cancer cells revealed that the residual cancer cells have increased receptor tyrosine kinase (RTK)/Akt signaling as a common mechanism for their survival in both c-Myc and Kras-induced tumors. We have experimentally validated the importance of this signaling pathway in cancer cell survival in the absence of oncogenic signaling in both tumor models. In comparison to control mice, we observed a significant slow tumor growth and delayed tumor relapse resulting in longer survival of the tumor bearing mice though a combination of this RTK/Akt pathway inhibition and ablation of Kras or c-Myc. In conclusion, our current study in reversible cancer models highlights the importance for the development of an adjuvant therapeutic strategy targeting this RTK/Akt pathway in addition to oncogenic drivers to effectively eradicate residual cancer cells and to prevent pancreatic cancer recurrence.
Citation Format: Nirakar Rajbhandari. Tumor cell dormancy is mediated by an increase in RTK signaling in reversible pancreatic cancer models expressing oncogenic K-Ras and c-Myc. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 667.
Abstract 672: Differential effects of p53 mutations on cancer invasion and metastasis in a mouse model of colon cancer
Authors: Feng Ying , Sakamoto Naoya , Green Maranne , Greenn Megan , Cho Kathleen R. , Fearon Eric R. 
Published: July 2016

Abstract
Inactivation of the APC (adenomatous polyposis coli) tumor suppressor gene plays an important role in initiating most adenomas and colorectal cancers (CRCs). Somatic mutations in the TP53 tumor suppressor gene and KRAS oncogene are found in roughly 60% and 40% of CRCs, respectively, and contribute to tumor progression. In the vast majority of human CRCs, TP53 missense mutations lead to high levels of mutant p53 protein expression and the loss of the other wild type TP53 allele. To evaluate the role of TP53 missense mutations in CRC progression, we generated a genetically engineered mouse model of colorectal carcinoma, via combined targeting of Apc, Kras, and Trp53 alleles in mouse colon epithelium, focusing on comparing phenotypic effects of the murine equivalent of the human R273H mutation (i.e., murine R270H mutation) or a large deletion mutation of mouse Trp53. Inactivation of one allele Apc and activation of an oncogenic Kras allele in colon epithelium generated serrated and hyperplastic morphologic epithelium and adenomas. The addition of either the R270H missense mutation or the Trp53 null mutation to the Apc and Kras mutations led to markedly shortened survival of the mice, due to the development of multiple colon tumors in each mouse ranging from adenomas to late stage adenocarcinomas. Evidence of invasion into the smooth muscle and serosa area was found in both compound mice with missense or deletion mutations in Trp53, with the Trp53R270H mutant mice displaying an increased prevalence of deeply invasive tumors relative to the mice with deletion of Trp53. Furthermore, we found that the missense mutant Trp53R270H allele in combination with Apc and Kras mutations, but not the null-mutant Trp53 allele, was strongly linked to metastases to lymph nodes and lung. We have developed a useful mouse model of metastatic colon cancer that recapitulates the role of TP53 mutations in cooperating with APC and KRAS mutations in human CRC development and progression. In addition, our findings strongly suggest a powerful role for missense mutant p53 proteins compared to TP53 null mutations in promoting invasion and metastasis in CRC progression.
Citation Format: Ying Feng, Naoya Sakamoto, Maranne Green, Megan Greenn, Kathleen R. Cho, Eric R. Fearon. Differential effects of p53 mutations on cancer invasion and metastasis in a mouse model of colon cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 672.
Abstract 675: Ninjurin1, a target of p53, modulates p53-dependent tumor suppression in vivo
Authors: Yang Hee Jung , Cho Seong Jun , Zhang Jin , Yan Wensheng , Chen Xinbin 
Published: July 2016

Abstract
The nerve injury-induced protein 1 (Ninjurin1, Ninj1), a homophilic adhesion molecule, is involved in nerve regeneration, inflammation and vascular regression. Ninj1 is found to be overexpressed in human cancers including hepatocellular carcinoma and acute lymphoblastic leukemia. However, the role of Ninj1 in tumorigenesis has not been elucidated. Recently, we found that Ninj1 is transcriptionally regulated by p53, which in turn regulates p53 expression through mRNA translation. Thus, the mutual regulation between p53 and Ninj1 represents a novel loop in the p53 pathway. To examine the biological significance of the p53-Ninj1 loop, we generated and monitored 4 cohorts of mice: (i) WT, (ii) Ninj1-het, (iii) p53-null, (iv) Ninj1-het; p53-null. We found that Ninj1-het mice were highly prone to skin lesions. We also found that Ninj1 deficiency shortened the life-span but decreased the incidence of sarcoma in mice without p53. Additionally, we found that Ninj1-het; p53-null mice were prone to hydrocephalus and kidney abnormality. To examine the association of Ninj1 with mutant p53, we generated and characterized Ninj1+/-; p53 R270H/- and p53 R270H/- mice. We found that Ninj1 deficiency shortened the life-span and promoted the frequency and aggressiveness of tumors in p53 R270H/- mice. Together, we conclude that Ninj1 differently regulates the tumor susceptibility in a p53-dependent manner in vivo and that the Ninj1-p53 loop plays a pivotal role in tumor suppression and longevity.
Citation Format: Hee Jung Yang, Seong Jun Cho, Jin Zhang, Wensheng Yan, Xinbin Chen. Ninjurin1, a target of p53, modulates p53-dependent tumor suppression in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 675.
Abstract 687: Critical role and mechanism of WASF3 in HER2/HER3 regulation of breast cancer metastasis
Authors: teng yong , Pi Wenhu , Cowell John 
Published: July 2016

Abstract
WASF3 is overexpressed in high-grade breast cancer and promotes invasion and metastasis but does not affect proliferation. The HER2/ERBB2/NEU gene is also frequently overexpressed in breast cancer and has been shown to promote invasion and metastasis in these tumors. Here we show that WASF3 in present in the HER2 immunocomplex and suppression of WASF3 function leads to suppression of invasion even in the presence of HER2 expression. Overexpression of both HER2 and WASF3 in non-metastatic MCF7 breast cancer cells promotes invasion and metastasis more significantly than either gene alone. HER2 forms homodimers as well as heterodimers with other HER family members and we now show that the ability of WASF3 to promote invasion is highly dependent on the HER2/HER3 heterodimer. The engagement of WASF3 with the HER2/HER3 complex facilitates its phospho-activation and transcriptional upregulation, which is facilitated by HER2/HER3 activation of JAK/STAT signaling. In breast cancer cells overexpressing HER2, therefore, WASF3 is specifically required to facilitate the invasion/metastasis response. Targeting WASF3, therefore, could be a potential therapeutic approach to suppress metastasis of HER2-overexpressing breast tumors.
Citation Format: yong teng, Wenhu Pi, John Cowell. Critical role and mechanism of WASF3 in HER2/HER3 regulation of breast cancer metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 687.
Abstract 690: Functional characterization of RPS6KA3 (RSK2) and identification of its naturally occurring mutants in hepatocellular carcinoma
Authors: Chan Lo-Kong , Ho Daniel Wai-Hung , Chiu Yung-Tuen , Kai Alan Ka-Lun , Wong Chun-Ming , Ng. Irene Oi-Lin 
Published: July 2016

Abstract
RPS6KA3 encodes the p90 ribosomal S6 kinase 2 (p90RSK2 or RSK2), a protein kinase to relay the upstream transduction signal of the mitogen-activated protein kinase (MAPK) pathway. Currently, no characterization on RSK2 in human HCC has been performed. We determined the RSK2 mRNA expression in paired human HCC samples and their corresponding non-tumorous livers (n = 22) by real time PCR. RSK2 over-expression (≥2 folds) was found in 38% of the human HCCs and this over-expression was associated with tumor microsatellite formation, a feature of HCC metastasis. The oncogenic and pro-metastatic roles of RSK2 were further assessed and demonstrated in vivo by an orthotopic liver injection model in nude mice with stable shRSK2 knockdown HCC cells. Stable shRSK2 knockdown cells showed a significant reduction in tumor incidence in liver and lung metastasis. By exome-sequencing and targeted sequencing in a cohort of HBV-associated HCC patient samples (n = 111), we found that RSK2 was recurrently mutated in 6.3% of the samples being screened (n = 7). All the RSK2 mutants were confirmed by independent Sanger sequencing. Intriguingly, among the identified somatic RSK2 mutants, half of them introduced pre-mature stop gain to the transcript, which leads to the loss-of function of RSK2 through various mechanisms. Taken together, our data suggested that RSK2 may play differential roles in different subsets of HCC patients. Further characterization will definitely derive novel insights on the functional role of mutant RSK2 and its potential use to stratify HCC patients into different molecular subgroups.
(This study was supported by a RGC GRF fund (17116414), SK Yee Medical Research Fund 2011 and University Development Fund of The University of Hong Kong. Ng is Loke Yew Professor in Pathology)
Citation Format: Lo-Kong Chan, Daniel Wai-Hung Ho, Yung-Tuen Chiu, Alan Ka-Lun Kai, Chun-Ming Wong, Irene Oi-Lin Ng. Functional characterization of RPS6KA3 (RSK2) and identification of its naturally occurring mutants in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 690.
Abstract 700: Regulation of Fn14 expression by EGFRvIII-STAT signaling enhances glioblastoma cell invasion and survival
Authors: Roos Alison , Mayo Zachary , Sonnemann Heather , Pineda Michael , Lambert Gil , Dhruv Harshil D. , Winkles Jeffrey A. , Berens Michael E. , Tran Nhan L. 
Published: July 2016

Abstract
Glioblastoma Multiforme (GBM) is the most common malignant brain tumor in adults. Most GBM patients succumb to the disease less than one-year post diagnosis due to the highly invasive nature of the tumor, which prevents complete surgical resection and gives rise to tumor recurrence. The invasive phenotype also confers radio-and chemoresistant properties to the tumor cells; therefore, there is a need to develop new therapeutics that target drivers of GBM invasion. Amplification of EGFR is observed in over 50% of GBM tumors, of which half concurrently overexpress the variant EGFRvIII, and expression of both receptors confers a worse prognosis. EGFR and EGFRvIII cooperate to promote tumor progression and invasion, in part, through activation of the JAK/STAT-signaling pathway. Here we report that GBM cells expressing EGFRvIII show increased expression of a previously established mediator of glioma cell invasion and survival, fibroblast growth factor-inducible 14 (Fn14), at the mRNA and protein level. Treatment with STAT3, STAT5, JAK, or Src inhibitors decreased Fn14 mRNA and protein expression. Finally, knockdown of Fn14 levels in the EGFRvIII-expressing glioma cells decreased both cell survival after temozolomide (TMZ) treatment and cell invasion, which suggests that Fn14, in part, mediates the oncogenic phenotypes conferred by EGFRvIII signaling. Since EGFR inhibitors display limited therapeutic efficacy in GBM patients, we hypothesize that Fn14-targeted therapies could potentially limit invasiveness and chemoresistance in EGFRvIII-dependent GBM tumors.
Citation Format: Alison Roos, Zachary Mayo, Heather Sonnemann, Michael Pineda, Gil Lambert, Harshil D. Dhruv, Jeffrey A. Winkles, Michael E. Berens, Nhan L. Tran. Regulation of Fn14 expression by EGFRvIII-STAT signaling enhances glioblastoma cell invasion and survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 700.
Abstract 704: Hyperglycemia stimulates glycolysis and enhances migratory/invasive potential in tongue squamous cell carcinoma
Authors: Wang Anxun , Wang Wei , Zhao Luodan , He Qianting , Sun Jingjing , Liu Zhonghua , Chen Zujian , Zhou Xiaofeng 
Published: July 2016

Abstract
Objective: The aim of this study was to investigate the role of glycolysis (HK2/PKM2) in the development of tongue squamous cell carcinoma (TSCC) and elucidate how hyperglycaemia stimulate HK2 and PKM2 and enhance migration/invasion potential in TSCC.
Methods: A total of 501 patients which diagnosed as TSCC between 1998 and 2004 were enrolled in the retrospective study. The expression of HK2/PKM2 was examined by IHC and the relationship between TSCC and diabetes mellitus (DM) was investigated. We then investigated the role of HK2/PKM2 in the migration and invasion of TSCC and relevant pathways (the SOD2-H2O2 pathway and miR-138 pathway). Finally, we investigated whether hyperglycaemia enhance migratory/invasive potential of TSCC through stimulating glycolysis.
Results: The prevalent rate of TSCC patients with diabetes was 13.97%, which was significantly higher than the incidence rate of DM (11.6%) in China. Cox analysis revealed that the HR for patients with DM vs without DM was 1.32. IHC results confirmed that the up-regulation of PKM2/HK2 expression was correlated with tumor stage, clinical stages, diabetes, lymph node metastasis and associated with reduced overall survival. PKM2/HK2/AKT1 overexpression increased cell migration and invasion, SOD2 activities and intracellular H2O2. The siRNA-based PKM2/HK2 knockdown inhibited cell migration and invasion, reduced activities of SOD2 and intracellular H2O2, and also inhibited tumor growth and lung metastasis in vivo. Luciferase assays revealed that PKM2/AKT1 was directly targeted by miR-138 and miR-138 can reduce the expression of the PKM2/AKT1 gene. High glucose enhanced the migration/invasion ability, miR-138/PKM2/HK2 expression and increased SOD2 activities and intracellular H2O2.
Conclusions: Our results confirm that DM may be a risk factor in the development of TSCC. PKM2/HK2 plays an important role in the progression of TSCC, and may serve as a biomarker or therapeutic target for patients with TSCC. High glucose stimulates glycolysis (PKM2/HK2) and enhances migration/invasion potential in TSCC.
Citation Format: Anxun Wang, Wei Wang, Luodan Zhao, Qianting He, Jingjing Sun, Zhonghua Liu, Zujian Chen, Xiaofeng Zhou. Hyperglycemia stimulates glycolysis and enhances migratory/invasive potential in tongue squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 704.
Abstract 713: Determining the role of tumor-infiltrating B cells in NSCLC
Authors: Centuori Sara M. , Kim Samuel , Gomes Cecil , Putnam Charles , Mount David , Garland Linda , Larsen Brandon , Martinez Jesse D. 
Published: July 2016

Abstract
Recent studies in human non-small cell lung cancer (NSCLC) have shown that upregulation of B cell-associated genes strongly correlate with early stage patient survival. After analyzing a gene expression database of lung tumors we showed that CD79A, a pan-B cell marker, had the strongest predictive value, suggesting that B cells are playing a crucial role in NSCLC immunity. In order to evaluate this we first examined where this genetic signature was originating from. We observed that patients with high levels of B cell-related genes also showed high numbers of CD79A+ B cells intimately associated with the tumor, but not being expressed by tumor cells themselves. A closer look at tumor-infiltrating B cells (TIL-B cells) by IHC and flow cytometry of fresh patient tumor samples has confirmed their presence and allowed us to begin elucidating their phenotype. Interestingly, we have found that not all early stage patients have detectable levels of TIL-B cells, but in those that do, TIL-B cells represent a marked proportion of the lymphocytic infiltration. Further evaluation of T cell populations in the same samples indicate that T cell numbers remain relatively consistent but that the numbers of B-cells, especially CD79A+ B-cells, does vary from patient to patient. These data indicate that CD79A+ TIL-B cells are contributing to the generation of an efficient immune response in some but not all patients, and are greatly influencing disease survivability. This information may allow us to stratify patients into low and high risk groups based on the presence or absence of TIL-B cells, respectively.
Citation Format: Sara M. Centuori, Samuel Kim, Cecil Gomes, Charles Putnam, David Mount, Linda Garland, Brandon Larsen, Jesse D. Martinez. Determining the role of tumor-infiltrating B cells in NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 713.
Abstract 715: Adipose tissues derived exosomal microRNAs and their variants in ovarian cancer progression
Authors: Au Yeung Chi Lam , Tsuruga Tetsushi , Co Ngai Na , Yeung Tsz-Lun , Leung Cecilia S. , Wong Kwong K. , Mok Samuel C. 
Published: July 2016

Abstract
Most ovarian cancers are diagnosed at an advanced stage when the tumor is widely metastatic. The 5-year survival drops to 50% for the cancer cases that spread beyond the pelvis to the omentum. However, the mechanisms underlying the effect of omental adipose tissue on ovarian cancer progression are poorly understood. Recent studies showed that exosomes also contain non-coding RNAs such as microRNAs (miRNAs). Thus, we hypothesize that the transfer of microRNAs and their variants from ovarian cancer-associated omental adipose tissues to ovarian cancer cells via exosomes may contribute to the nearby microenvironment for ovarian cancer metastasis and cancer progression.
Ion Torrent next generation sequencing was performed on miRNAs isolated and enriched from exosomes and cell lysates of ovarian cancer cell lines (OVCA), the epithelial component of microdissected omental ovarian cancer tissues (CT), normal omental adipose tissues (OMN) and ovarian cancer-associated omental adipose tissues (OMT). By integrating the miRNA expression profiles, 65 miRNAs were expressed at significant higher levels in OMT-derived exosomes compared with those in OMN-derived exosomes and OVCA-derived exosomes. A set of miRNAs (miR-32a, miR-221 and miR320a), which had been implicated in controlling cell growth and chemoresistance, was identified. Also, the Ion Torrent results were validated and exosomal transfer of OMT-derived miRNAs was confirmed in vitro. The exosomal communication between adipose tissues and ovarian cancer cells in the omental tumor microenvironment is verified. The transferable miRNAs and their variants may remain functional in the recipient ovarian cancer cells and confer more aggressive phenotypes in these cells.
Citation Format: Chi Lam Au Yeung, Tetsushi Tsuruga, Ngai Na Co, Tsz-Lun Yeung, Cecilia S. Leung, Kwong K. Wong, Samuel C. Mok. Adipose tissues derived exosomal microRNAs and their variants in ovarian cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 715.