bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3458: Investigation of oxidative stress-related gene signature in cancer-associated cachexia
Authors: Jain Sumeet , Shukla Surendra K. , Dasgupta Aneesha , Singh Pankaj K. 
Published: August 2019

Abstract
About eighty percent of pancreatic cancer patients demonstrate excessive loss of skeletal muscles with or without loss of adipose deposits, a condition known as cancer-associated cachexia. Severe complexities related to cancer-associated cachexia contribute to mortality in one-third of pancreatic cancer patients. Multiple factors, including loss of appetite, systemic inflammation, digestive enzymes, and hormonal imbalance may contribute to the development of cancer-associated cachexia. Poor understanding of the molecular mechanism is the key challenge for targeting cancer-associated cachexia. Hence, to facilitate the identification of new targets for ameliorating cancer-induced muscle loss, we undertook genomic studies. We evaluated differentially expressed gene signatures in muscle tissues of cachectic and non-cachectic human pancreatic cancer patients. To better model the mechanisms of cancer cachexia, we also compared the identified gene signatures to that of orthotopic and spontaneous mice models of pancreatic cancer cachexia. We observed significant alterations in multiple genes related to oxidative stress in muscle tissues from human patients with cachexia and mice cachexia models. We targeted oxidative stress regulatory genes by genetic manipulations or targeted oxidative stress with pharmacological approaches to evaluate the impact of oxidative stress in skeletal muscles on cancer-associated cachexia. Our results suggest that targeting the oxidative stress pathway prevents/reverts cancer-associated cachexia. Moreover, inhibition of oxidative stress also abolished cancer cell-conditioned medium-induced atrophy in C2C12-derived myotubes and diminished the expression of atrophy markers. Overall, our studies revealed the potential role of oxidative stress induced by cancer cells in muscle wasting. Future studies to target tumor-induced oxidative stress in muscle fibers may provide new therapeutic approaches to prevent cancer-associated cachexia.
Citation Format: Sumeet Jain, Surendra K. Shukla, Aneesha Dasgupta, Pankaj K. Singh. Investigation of oxidative stress-related gene signature in cancer-associated cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3458.
Abstract 3461: Characterizing the PTEN - p85alpha interaction
Authors: Marshall Jeremy , Mellor Paul , Ruan Xuan , Whitecross Dielle , Moore Stanley , Anderson Deborah 
Published: August 2019

Abstract
Introduction: The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in regulating cell growth and cell survival and is frequently deregulated in cancer cells. p85α regulates the p110α lipid kinase, and also stabilizes and stimulates PTEN, the lipid phosphatase that downregulates this pathway. We set out to identify residues in both PTEN and p85α that mediate their interaction to better understand the regions important in mediating binding.
Experimental Procedures: We previously showed that the BH domain of p85α is sufficient to mediate binding to PTEN. In this work, a deletion analysis and point mutations were used to mutate each of PTEN and the p85α BH domain to identify residues important for binding, determined using a pull-down analysis. Mutations in the p85α BH domain and in PTEN that reduced their interaction were then used as input data and docking software was used to model possible interaction interfaces for the two the proteins. Further mutagenesis and follow-up binding experiments provided support for our model of the PTEN - p85α BH domain complex.
Results: We identified key residues responsible for mediating PTEN - p85α complex formation. Based on these experimental results, a docking model for the PTEN - p85α BH domain complex was developed that is consistent with the known binding interactions for both PTEN and p85α. This model involves extensive side-chain and peptide backbone contacts between both the PASE (R84, Q87, Y88, E91, E99) and C2 (R189, P190, Q219, C250, D252) domains of PTEN and the p85α BH domains with a buried surface area of 1211 Å2 (PTEN - bovine p85α BH) and 1366 Å2 (PTEN - human p85α BH). The p85α BH domain residues that directly contact PTEN in the two docking models were not identical, however both models implicated p85α residues E212, Q221, K225, R228, H234 and W237. The majority of these p85α BH domain residues were confirmed experimentally as important for PTEN binding. We also verified experimentally the importance of PTEN-E91 in mediating interaction with the p85α BH domain.
Conclusions: These results shed new light on the mechanism of PTEN binding and regulation by p85α.
Citation Format: Jeremy Marshall, Paul Mellor, Xuan Ruan, Dielle Whitecross, Stanley Moore, Deborah Anderson. Characterizing the PTEN - p85alpha interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3461.
Abstract 3462: The F-box protein FBXL16 regulates the stability of c-myc oncoprotein
Authors: Morel Marion , Long Weiwen 
Published: August 2019

Abstract
F-box proteins are major components of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligases as they are responsible for substrate recognition. In this complex, F-box proteins bind to SKP1 through the F-box motif to bring the ubiquitination machinery and mediate protein ubiquitination of the substrates. So far, 69 F-box proteins are identified in humans, and they fall into 3 families depending on their substrate recognition domains: FBXLs (Leucine-Rich Repeats or LRR), FBXWs (WD repeats) and FBXOs (Other domains). FBXL16 is a poorly studied F-box protein which consists of an N-terminal Proline-rich domain, an F-box motif and a C-terminal domain of Leucine-rich repeats. FBXL16 was first identified as a transcriptional target of E2F1 (Sato et al, 2010) and was then showed as a binding partner of PP2A (Protein Phosphatase 2A) and as a regulator of its phosphatase activity (Honarpour et al, 2014). Interestingly, FBXL16 was shown to be overexpressed in a number of cancers, particularly invasive breast carcinoma (Oncomine) indicating that FBXL16 may play important roles in cancers. In this study, by both knockdown and overexpression experiments, we found that FBXL16 promotes cancer cell migration. To our surprise, we observed that knockdown of FBXL16 in cancer cells resulted in a strong decrease of c-myc protein level. Importantly, we also found that FBXL16 binds to and stabilizes c-myc protein. Mechanistically, FBXL16 overexpression decreased c-myc protein ubiquitination. Taken together, our study demonstrates a positive role of FBXL16 in regulating c-myc protein stability by inhibiting its ubiquitination.
Citation Format: Marion Morel, Weiwen Long. The F-box protein FBXL16 regulates the stability of c-myc oncoprotein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3462.
Abstract 3464: CBAP: A novel rheostat molecule for regulation of TSC GAP activity and mTORC1 signaling in cancer cells
Authors: Yen Jong-Young J. , Chiang Yun-Jung , Liao Wei-Ting , Wang Shih-Hao , Yang-Yen Hsin-Fang 
Published: August 2019

Abstract
The PI3K-mTOR signaling pathway is one of the most frequently dysregulated signaling cascades in cancer. Understanding the molecular wiring of the PI3K-mTOR signaling network and its activation in cancer will improve our understanding of their contribution to cancer pathology and provide novel therapeutic strategies by targeting this network. Our previous works demonstrated that Common receptor Beta chain Associated Protein (CBAP) is required for Jurkat cell leukemogenesis and regulates Akt-dependent TSC2 phosphorylation and lysosomal dissociation of TSC complexes, and in turn enhances mTORC1 signalling and expression of c-MYC and HIF-1a in Jurkat T-ALL leukemic cells. In this report, we tackle the question how TSC/Rheb/mTORC1 pathway is regulated by CBAP via cell-based functional assay, immunoprecipitation and in vitro GTPase assay. Our data revealed that CBAP interacted with TSC2 via tuberin-binding domain and could compete for TSC2 binding with TSC1 and suppressed the GTPase activation activity of TSC1/2 complexes. Akt could also associate with TSC2 complexes and CBAP in both Jurkat and CBAP-knockout Jurkat cells, except that TSC1 could be detected within the complexes only in the absence of CBAP. Moreover, the Rheb-GAP activity of this Akt-associated TSC2 complexes was sensitive to the presence of CBAP and TSC1/2 GAP activity was strongly suppressed by recombinant CBAP proteins in the in vitro reconstituted assay. Finally, a peptide domain of CBAP interacting with TSC2 was mapped and disruption of CBAP-TSC2 interaction by overexpressing this peptide inhibits the Akt/Rheb signal axis and suppresses leukemia cell growth. In summary, our data revealed an important role of the interaction between CBAP and TSC2 proteins in promoting Rheb/mTORC1 signaling activity, and suggested a crucial role of overexpression of CBAP protein in tumor cell proliferation.
Citation Format: Jong-Young J. Yen, Yun-Jung Chiang, Wei-Ting Liao, Shih-Hao Wang, Hsin-Fang Yang-Yen. CBAP: A novel rheostat molecule for regulation of TSC GAP activity and mTORC1 signaling in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3464.
Abstract 3472: The role of mutant p53 R248W in oral squamous cell carcinoma
Authors: Enaka Mayu , Nakanishi Masako , Muragaki Yasuteru 
Published: August 2019

Abstract
TP53 is the most commonly mutated gene in oral squamous cell carcinoma (OSCC). It is known that mutant p53 has not only loss of function but gain of function. Cytokeratin 17 (K17) has been shown to promote tumorigenesis and aggressiveness in OSCCs and other various carcinomas. Although p53 reportedly induces K17 transcription by irradiation, the molecular interaction between p53 and K17 in OSCCs remains unknown. To address this issue, we investigated the relationship between p53 and K17 using SAS cells with nonsense mutation and Ca9-22 cells with R248W mutation in the TP53 gene. Western blot and immunohistochemistry showed higher K17 expression in SAS cells and virtually no K17 expression in Ca9-22 cells, suggesting negative correlation between p53 and K17 expression. ChIP analysis revealed that p53 bound specifically to the tentative p53 binding site in the promoter region of the K17 gene. Unexpectedly, however, overexpression of wild-type (wt) p53 did not suppress K17 expression in SAS cells, whereas knock down of mutant (mt) p53 significantly upregulated K17 expression in Ca9-22 cells, raising a possibility that only R248W mtp53 suppresses K17 expression. Furthermore, overexpression of wtp53 and R248Q mtp53 did not suppressed K17 expression in Ca9-22 cells with knock down of p53, whereas R248W mtp53 overexpression clearly showed suppression of K17. Taken together, R248W mtp53 acts as a direct transcriptional repressor of K17 in OSCCs, reducing aggressiveness of the carcinoma cells.
Citation Format: Mayu Enaka, Masako Nakanishi, Yasuteru Muragaki. The role of mutant p53 R248W in oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3472.
Abstract 3473: Comprehensive genetic screening in hereditary colorectal cancer
Authors: Rohlin Anna , Eiengård Frida , Mårtensson Emma , Zagoras Theofanis , Gebre-Medhin Samuel , Nordling Margareta 
Published: August 2019

Abstract
High-penetrant pathogenic variants in established genes associated with hereditary colorectal cancer (CRC) explain the disease in approximately 5-6% of cases. In as much as 20%-30% of all, including sporadic CRC cases, genetic factors are thought to play a significant role. Dependent on technical as well as limitations due to interpretation challenges, the high-penetrant pathogenic variants are gathered in the exonic regions of the genes. Contributions of pathogenic variants in genes, not traditionally associated with hereditary CRC have also recently been recognized. It is crucial for the patients to get a correct molecular diagnosis that allows for adequate follow-up since the majority of the syndromes include predisposition also for tumors in other organs. A comprehensive panel including high-penetrant susceptibility genes as well as genes not generally associated with hereditary CRC was used for the analyses. Sequencing of 50 kb upstream and downstream of all genes including intronic regions were performed. All SNVs and CNVs in exons were thoroughly evaluated concerning pathogenicity and also intronic and intragenic sequences were screened for the presence of possibly pathogenic variants. In addition, cDNA were analysed to detect variants in splice-sites as well as aberrations causing other effects on mRNA level. The study included 206 patients referred to the Cancer Genetics Counselling Clinic in Gothenburg, Sweden. The spectra of pathogenic variants in well-known high-penetrance predisposition genes as well as the contribution of pathogenic variants in low-penetrant genes were determined. The contribution of pathogenic variants also in “non-CRC” genes was examined. The findings include identification of previously unreported variants and putative causative variants in unexplained patients with hereditary CRC. An attempt to identify putative genetic variants that could explain the variability in cancer risk among carriers of specific variants in high-penetrance genes was also made.
Citation Format: Anna Rohlin, Frida Eiengård, Emma Mårtensson, Theofanis Zagoras, Samuel Gebre-Medhin, Margareta Nordling. Comprehensive genetic screening in hereditary colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3473.
Abstract 3483: The African-specific S47 variant of the p53 tumor suppressor gene alters cell metabolism
Authors: Gnanapradeepan Keerthana , Basu Subhasree , Kung Che-Pei , Barnoud Thibaut , Good Madeline , Quinn William , Lee Joyce , Wellen Kathryn , Schug Zachary , Baur Joseph , George Donna , Murphy Maureen 
Published: August 2019

Abstract
The TP53 gene, often referred to as the guardian of the genome, is the most frequently mutated gene in human cancer. This gene encodes the tumor suppressor p53, a master regulator of various processes such as programmed cell death, growth arrest and senescence. However, there is increasing evidence that highlights the role of p53 in tumor suppression with regards to maintaining metabolic homeostasis. Our lab has identified a polymorphic variant of p53 that encodes a serine residue instead of a proline at amino acid 47 (hereafter S47). This variant is most prevalent in African and African-American individuals, and mice and humans carrying this variant have increased cancer risk and impaired response to therapy. Using both mouse models and human cells, we have found that S47 cells have significantly altered metabolism compared to the WT counterpart. Specifically, S47 mice have increased weight and increased lean content compared to WT mice. These mice also show increased fitness in treadmill studies. Analyses of cell metabolism in S47 murine and human cells indicate that S47 cells show increased glycolysis and glycolytic flux, along with increased oxygen consumption rate on a Seahorse analyzer. The combined data support the premise that the S47 variant confers increased cancer risk but also increased metabolic fitness; the latter may explain the high rate of this variant in certain regions of Africa. By clearly elucidating the roles of WT p53 and the S47 variant in the context of metabolism, we hope to uncover new therapeutic avenues and ultimately enable more personalized medicine approaches for individuals who carry this variant.
Citation Format: Keerthana Gnanapradeepan, Subhasree Basu, Che-Pei Kung, Thibaut Barnoud, Madeline Good, William Quinn, Joyce Lee, Kathryn Wellen, Zachary Schug, Joseph Baur, Donna George, Maureen Murphy. The African-specific S47 variant of the p53 tumor suppressor gene alters cell metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3483.
Abstract 3484: Ras recruits oncogenic serine protease hepsin to disrupt mammary epithelial integrity
Authors: Tervonen Topi A. , Pant Shishir M. , Belitskin Denis , Englund Johanna , Närhi Katja , Verschuren Emmy , Kovanen Panu , Klefström Juha 
Published: August 2019

Abstract
Type II transmembrane serine protease hepsin is overexpressed and redistributed in clinical breast cancer samples, although the HPN gene is not a frequent target of cancer-specific genetic alterations. Here, we sought to identify cancer relevant upstream factors responsible for oncogenic deregulation of hepsin. We explored the effects of ectopic expression of major oncogenes and tumor suppressors on hepsin protein expression levels in non-malignant mammary epithelial cells, finding that HrasV12, KrasV12, ectopic wild-type Kras, endogenous mutant KrasD12 and E2F-1 induce the expression of active form of hepsin. Oncogenic Ras proteins also reduced expression levels of cognate hepsin inhibitor, HAI-1. Concomitantly, oncogenic Ras expression led to disappearance of desmoplakin and desmoglein 2 from desmosomal junctions, which correlated with mislocalization of hepsin from its predominant localization in desmosomes to cytosol. To explore the effects of mutated Ras expressed at endogenous levels we used lung tumors derived from lox-stop-lox (LSL)-KrasD12; p53-/- and LSL-KrasV12 mammary epithelial structures in ex vivo 3D cultures. In both cases, hepsin was highly expressed and predominantly localized to cytosol. Knockdown of hepsin by shRNA rescued HrasV12-induced epithelial integrity defects in mammary epithelial 3D culture and furthermore, MEK and ERK inhibitors prevented HrasV12-induced hepsin deregulation as well as desmosomal and basement membrane defects. Critical pathways downstream of MAPK pathway are being studied and will be discussed. These findings suggest a critical role for hepsin in mediating Ras-MAPK-mediated disruption of epithelial integrity during tumorigenesis.
Citation Format: Topi A. Tervonen, Shishir M. Pant, Denis Belitskin, Johanna Englund, Katja Närhi, Emmy Verschuren, Panu Kovanen, Juha Klefström. Ras recruits oncogenic serine protease hepsin to disrupt mammary epithelial integrity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3484.
Abstract 3492: A targeted semi-conductor based next-generation sequencing (NGS) test to characterize microsatellite instability in FFPE tumor samples
Authors: Kraltcheva Anelia , El-Difrawy Sameh , Kamat Asha , Au-Young Janice , Cawley Simon , Sadis Seth 
Published: August 2019

Abstract
Microsatellite instability (MSI) arises from defects in the mismatch repair (MMR) system and is associated with hypermutability of short DNA sequence repeats. Defects in MMR are observed in diverse cancer types but are common in colorectal, gastric and endometrial cancers. MSI testing is increasingly important for patient management. For example, in diverse cancer types, MSI is associated with favorable response to immune checkpoint inhibitors. The mainstay of MSI testing has been PCR/fragment analysis or IHC to monitor loss of expression of MMR proteins. Although generally robust, these methods are single biomarker tests that may consume limited biopsy samples. For this reason, MSI testing has been recently incorporated into NGS tests. However, targeted amplicon based NGS tests for MSI that consume limited sample input and provide fast turn-around time remain an unmet need. Herein, we describe a targeted NGS-based method to assess MSI that leverages Ion AmpliSeq™ or Ion AmpliSeq™ HD multiplex PCR and Ion GeneStudio™ S5 next-generation sequencing. The test is comprised of diverse microsatellite markers including mono- and di-nucleotide repeats that range from 10 to 40 bp. A novel algorithm was developed that leverages the unique signal processing properties inherent in semi-conductor sequencing and workflows were developed for tumor only samples as well as paired tumor-normal samples. The test provides results for individual microsatellites and generates an MSI score for the sample. The performance of the assay was verified over a large cohort of colorectal, gastric and endometrial cancer samples with MSI status independently assigned by orthogonal on-market tests. The MSI panel can be used by itself or integrated into larger targeted sequencing panels. MSI tests that leverage the inherent advantages of targeted semiconductor sequencing, low sample input and fast turn-around time, will support expanded research opportunities into the association of MSI with other targeted alterations and help elucidate the interaction of MSI, DNA repair defects, and the response to immune checkpoint inhibition.
Citation Format: Anelia Kraltcheva, Sameh El-Difrawy, Asha Kamat, Janice Au-Young, Simon Cawley, Seth Sadis. A targeted semi-conductor based next-generation sequencing (NGS) test to characterize microsatellite instability in FFPE tumor samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3492.