bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4322: Exosomal delivery of stroma-derived miR-145 inhibits pancreatic cancer cell proliferation
Authors: Han Song , Belsare Sayali , Zhang DongYu , Beveridge Mark , Rinaldi Carlos , Trevino Jose G. , Schmittgen Thomas D. , Hughes Steven J. 
Published: July 2017

Abstract
We previously reported that within the pancreatic ductal adenocarcinoma (PDAC) microenvironment, miR-145 and miR-199a are exclusively expressed in tumor-associated stroma (TAS) cells, but these miRNAs are present in PDAC cells following co-culture with TAS cells. We hypothesized that miRNAs function as paracrine signals via exosomal exchange between TAS cells and adjacent PDAC cells.
Primary cultures of human TAS and PDAC cells were employed. Membrane-bound microparticles were isolated from TAS conditioned, serum-free culture media by sequential ultracentrifugation followed by ultrafiltration. Exosomes and microvesicles were then assayed for particle size distribution using nanoparticle tracking analysis and electronic microscopy. miRNA expression levels were determined using quantitative PCR. miRNA transfection was performed with RNAiMax reagents. Cell viability was measured by Alamar Blue. Statistics were performed using Prism 6 software.
Following transfection of human TAS cells with cel-miR-39, a nonhuman miRNA, we demonstrated that miRNA exchanges occurred between TAS cells and neighboring PDAC cells via a process that is not dependent upon cell-cell contact. We next confirmed the presence and enrichment of miR-145-5p in TAS-cell-derived exosomes (8-fold higher concentrations in exosomes than parental cells, p&lt;0.05). Feeding of TAS-derived exosomes or transfection of miR-145-5p mimics into PDAC cells led to dose-dependent decreases in PDAC cell viability (p&lt;0.05).
Taken together, our data suggest that stroma derived exosomes deliver miRNAs to adjacent PDAC cells and may function as tumor-suppressing paracrine signals in the case of miR-145. This finding provides a potential explanation for the observation that stroma depletion paradoxically accelerates PDAC progression in murine models.
Citation Format: Song Han, Sayali Belsare, DongYu Zhang, Mark Beveridge, Carlos Rinaldi, Jose G. Trevino, Thomas D. Schmittgen, Steven J. Hughes. Exosomal delivery of stroma-derived miR-145 inhibits pancreatic cancer cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4322. doi:10.1158/1538-7445.AM2017-4322
Abstract 4574: Combinatorial strategies of folate receptor-targeted chemotherapy guided by improved understanding of tumor microenvironment and immunomodulation
Authors: Lu Yingjuan , Wheeler Leroy W. , Cross Vicky A. , Westrick Elaine M. , Lloyd Alex M. , Johnson Theresa P. , Parker Nikki L. , Leamon Christopher P. 
Published: July 2017

Abstract
Inflammation disorder is a major component of cancer progression and drug resistance. Tumor microenvironment due to its complex nature presents physical and physiological barriers to both chemotherapy and immunotherapy. On the other hand, the folate receptor (FR) family includes two cysteine-rich GPI-anchored membrane glycoproteins (FRα/β) that are capable of bringing folate-linked small-molecule drugs (SMDCs) into the cell cytosol via endocytosis. Consequently, both receptor isoforms have been considered promising therapeutic targets due to frequent overexpression of FRα by cancer cells of epithelial origins and FRβ by tumor-associated macrophages (TAMs). TAMs are strongly immunosuppressive and high TAM frequency has been correlated with poor patient prognosis and treatment outcome.
While a folate-targeted chemotherapy can be very powerful for sensitive tumor types, resistance does regularly occur in FR-positive tumors for reasons that are largely unknown. Moreover, there seems to be considerable disconnect between a drug candidate’s in-vitro activity and in-vivo efficacy. Using syngeneic mouse models that represent different tumor immune microenvironments (M109, Renca, 4T1-Cl2), we investigated the immunomodulatory properties of SMDCs and devised combinatorial strategies with standard-of-care (SOC) agents to break the tumor-induced immune tolerance. Our results indicated that a successful treatment goes beyond targeting the cancer cells themselves; instead, it requires a good match between our compound and a “sensitive” tumor microenvironment. We found that within “TAM-rich” solid tumors, an effective SMDC may be one with dual mechanisms of action that affect both FRα-positive tumor cells and FRβ-positive TAMs. Moreover, the process of choosing partner drugs, such as immune checkpoint inhibitors and inhibitors of myeloid-derived suppressor cells, should be guided by the immunomodulatory properties of both SMDCs and SOC agents to overcome the frequently observed chemo- and immuno-resistance.
Citation Format: Yingjuan Lu, Leroy W. Wheeler, Vicky A. Cross, Elaine M. Westrick, Alex M. Lloyd, Theresa P. Johnson, Nikki L. Parker, Christopher P. Leamon. Combinatorial strategies of folate receptor-targeted chemotherapy guided by improved understanding of tumor microenvironment and immunomodulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4574. doi:10.1158/1538-7445.AM2017-4574
Abstract 4888: Human PGBD5 DNA transposase promotes site-specific oncogenic mutations in rhabdoid tumors
Authors: Henssen Anton G. , Koche Richard , Zhuang Jiali , Jiang Eileen , Reed Casie , Eisenberg Amy , Still Eric , Rodríguez-Fos Elias , Gonzalez Santiago , Puiggròs Montserrat , Blackford Andrew N. , Mason Christopher E. , Stanchina Elisa de , Gönen Mithat , Emde Anne-Katrin , Shah Minita , Arora Kanika , Reeves Catherine , Socci Nicholas D. , Perlman Elizabeth , Antonescu Cristina R. , Roberts Charles W. , Steen Hanno , Mullen Elizabeth , Jackson Stephen P. , Torrents David , Weng Zhiping , Armstrong Scott A. , Kentsis Alex 
Published: July 2017

Abstract
Genomic rearrangements are a hallmark of childhood solid tumors, but their mutational causes remain poorly understood. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as an enzymatically active human DNA transposase expressed in the majority of rhabdoid tumors, a lethal childhood cancer. Using assembly-based whole-genome DNA sequencing, we observed previously unknown somatic genomic rearrangements in primary human rhabdoid tumors. These rearrangements were characterized by deletions and inversions involving PGBD5-specific signal (PSS) sequences at their breakpoints, with some recurrently targeting tumor suppressor genes, leading to their inactivation. PGBD5 was found to be physically associated with human genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. We found that ectopic expression of PGBD5 in primary human cells was sufficient to promote penetrant cell transformation in vitro and in immunodeficient mice in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain, as well as end-joining DNA repair, and induced distinct structural rearrangements, involving PSS-associated breakpoints, similar to those found in primary human rhabdoid tumors. Thus, PGBD5 defines a distinct class of oncogenic mutators and induces site-specific somatic DNA rearrangements in human cancer.
Citation Format: Anton G. Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Elias Rodríguez-Fos, Santiago Gonzalez, Montserrat Puiggròs, Andrew N. Blackford, Christopher E. Mason, Elisa de Stanchina, Mithat Gönen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D. Socci, Elizabeth Perlman, Cristina R. Antonescu, Charles W. Roberts, Hanno Steen, Elizabeth Mullen, Stephen P. Jackson, David Torrents, Zhiping Weng, Scott A. Armstrong, Alex Kentsis. Human PGBD5 DNA transposase promotes site-specific oncogenic mutations in rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4888. doi:10.1158/1538-7445.AM2017-4888
Abstract 5079: Inhibition of HDAC2, but not HDAC1, abrogates triple negative breast cancer progression and metastasis
Authors: Burks Hope E. , Elliott Steven , Hoang Van T. , Matossian Margarite D. , Burow Bridgette Collins , Burow Matthew E. 
Published: July 2017

Abstract
Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with higher rates of metastasis and recurrence than other classified subtypes. The decreased survival rates seen in TNBC can be attributed in part to the lack of targeted therapeutics. HDAC inhibitors (HDACi) have emerged as a potential adjuvant therapy for patients with triple negative disease. Previously, our lab has identified Panobinostat, a pan-DAC inhibitor, as a successful therapy for the reversal of the metastatic phenotype in TNBC. However, this therapy lacks specificity and may have increased side effects as a result. In this study, we aim to dissect the necessary HDACs responsible for driving and maintaining the metastatic phenotype of TNBC, with the goal of informing specific HDAC targeted therapies. Here we show that Romidepsin, an HDAC 1 and 2 specific inhibitor, is capable of recapitulating aspects of Panobinostat treatment in TNBC both in vitro and in a patient derived xenograft model in vivo. To parse the necessity and role of HDAC1 and HDAC2 individually, we created knockdown cell lines and analyzed them for changes in gene expression changes and their respective associated biological processes, including proliferation, migration, mammosphere formation, tumor growth and metastasis. We found that HDAC2 knockdown was able to significantly repress migration and proliferation in TNBC cells and their associated gene expression signatures in vitro. Furthermore, HDAC2 knockdown resulted in decreased tumor growth and metastasis an in vivo mouse model. These results illustrate the efficacy of Romidepsin in inhibition of oncogenic processes and implicate HDAC2 as a potential target for therapeutic intervention in TNBC.
Citation Format: Hope E. Burks, Steven Elliott, Van T. Hoang, Margarite D. Matossian, Bridgette Collins Burow, Matthew E. Burow. Inhibition of HDAC2, but not HDAC1, abrogates triple negative breast cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5079. doi:10.1158/1538-7445.AM2017-5079
Abstract 5797: Semaphorin 5A preserves epithelial phenotype in pancreatic cancer cells by regulating cross-talk between Wnt and TGF-β signaling
Authors: Saxena Sugandha , Purohit Abhilasha , Batra Surinder K. , Singh Rakesh K. 
Published: July 2017

Abstract
Pancreatic cancer (PC) is one of the deadliest forms of cancers. In spite of recent advances, minimal progress has been made in our understanding of PC progression, metastasis, and treatment of PC patients with advanced disease. Striking similarity between the process of cancer metastasis and guidance of neuronal cells to their target sites has generated interest in pharmacologically targeting guidance cue molecules for treatment of metastasis. Among the guidance cue family members, Semaphorin5A (SEMA5A), was found to be involved in organ-specific homing during PC metastasis. With an interest to delineate the function of SEMA5A in PC, we generated SEMA5A knockdown in metastatic PC cell lines. Knock down of SEMA5A expression resulted in loss of cellular differentiation and epithelial phenotype with higher motility as compared to vector control cells. This observation is in accordance with our previous finding that SEMA5A expression was higher in well-differentiated tumors in comparison with undifferentiated pancreatic tumors. Loss of SEMA5A increased TGF-β2 production, decreased expression of E-cadherin, and nuclear translocation of β-catenin. Furthermore, we observed higher Wnt activity and increased expression of the transcription factor SNAIL in SEMA5A knockdown cells in comparison with vector control cells. Higher Wnt signaling along with increased TGF-β2 production explains the loss of differentiation and epithelial markers. Moreover, we observed that non canonical TGF-β2/AKT mediated inhibition of GSK3-β is responsible for increased stability of β-catenin and SNAIL, thereby activating Wnt signaling in SEMA5A knockdown cells. Our observations demonstrate that SEMA5A has a potential role in maintaining the epithelial phenotype in PC cells by keeping cross-talk between Wnt and TGF-β signaling under check.
Citation Format: Sugandha Saxena, Abhilasha Purohit, Surinder K. Batra, Rakesh K. Singh. Semaphorin 5A preserves epithelial phenotype in pancreatic cancer cells by regulating cross-talk between Wnt and TGF-β signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5797. doi:10.1158/1538-7445.AM2017-5797
Abstract 5947: The NCI Best Practices for Biospecimen Resources: 2016 revised recommendations
Authors: Rao Abhi , Vaught Jim , Guan Ping , Weil Carol , Moore Helen M. 
Published: July 2017

Abstract
Improved biospecimen handling practices are increasingly important for cancer research as advanced molecular analysis becomes routine in clinical trials and more frequently available in standard of care medicine. Biospecimens and associated clinical data collected in a consistent, established fashion can greatly facilitate cancer biomarker validation and development and validation of clinical diagnostic assays. In order to establish a set of guidelines to improve the quality of biospecimen-related research, the NCI’s Biorepositories and Biospecimen Research Branch developed the NCI Best Practices for Biospecimen Resources which includes technical recommendations on biospecimen handling as well as ethical and regulatory best practices. The 3rd, 2016 revised version of these Best Practices focused on updating technical and operational best practices with recommendations based on more recent research, guidance and standards for collecting, processing and storing biospecimens; revised informatics best practices; and updated ethical, legal and policy sections describing new developments on return of research results, informed consent for genomics research, data sharing, and community engagement. These Best Practices aim to help patients by improving the reproducibility of cancer research data. The NCI Best Practices are also foundational to the NIH Precision Medicine Initiative, part of which aims to establish the world’s largest research biobank that will support studies that utilize biospecimens from a cohort of one million individuals in the United States.
Citation Format: Abhi Rao, Jim Vaught, Ping Guan, Carol Weil, Helen M. Moore. The NCI Best Practices for Biospecimen Resources: 2016 revised recommendations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5947. doi:10.1158/1538-7445.AM2017-5947
Abstract 936: Single cell analysis reveals cancer stem cell heterogeneities in hepatocellular carcinoma
Authors: Zheng Hongping , Pomyen Yotsawat , Hernandez Maria , Li Caiyi , Livak Ferenc , Greten Tim , Budhu Anuradha , Wang Xin 
Published: July 2017

Abstract
Tumor heterogeneity represents a major obstacle to effective cancer treatment and personalized medicine. Hepatocellular carcinoma (HCC) is clinically and biologically heterogeneous, which is partly attributed to the presence of hepatic cancer stem cells (CSCs). CSC surface makers can have overlapping expression or exclusive expression of different subpopulations of hepatic CSCs, and these cells may contain different oncogenic changes. The existence of various CSC surface-marked subpopulations might pose a problem for CSC targeted therapeutics. Little is known about whether there are shared or distinct pathways in different subpopulations. Moreover, it remains unknown whether heterogeneity exists within certain subpopulations. Thus, we propose to profile the global transcriptome of surface-marked CSCs (EpCAM+, CD133+ and CD24+) at the single-cell level using index flow cytometric sorting and single-cell RNA sequencing technology.
We statistically compared mRNA transcriptomes of individual single cells of triple positive (EpCAM+/ CD133+ /CD24+) CSCs and triple negative (EpCAM-/ CD133- /CD24-) cells. Further, we compared the triple positive and the triple negative cells at the single cell level in terms of their self-renew capability in both normoxic and hypoxic conditions. Our results show that at the single cell level, the transcriptomic profiles show a high-degree of heterogeneity in HCC cell lines, meanwhile, there is a dramatic difference between triple positive and triple negative cells in their transcriptomic profiles. There is a high-degree of intra-tumor and inter-tumor heterogeneity observed in single cell transcriptomes of HCC patients’ samples. Triple positive CSC single cells show continuous rather than discrete stemness-related gene expression patterns. In parallel, the self-renewal capability of triple positive cells also exhibits heterogeneity, while triple negative cells show little self-renewal capability. Thus, our single cell analysis study reveals molecular and biological heterogeneity of cancer stem cells in HCC, which may provide insight into the underlying mechanisms of how CSCs contribute to tumor heterogeneity and underscore key pathways and novel targets for hepatic CSC therapy.
Citation Format: Hongping Zheng, Yotsawat Pomyen, Maria Hernandez, Caiyi Li, Ferenc Livak, Tim Greten, Anuradha Budhu, Xin Wang. Single cell analysis reveals cancer stem cell heterogeneities in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 936. doi:10.1158/1538-7445.AM2017-936
Abstract LB-125: Snail determines the efficacy of mTOR-targeted therapies by transcriptional repression of 4E-BP1
Authors: Wang Jun , Ye Qing , Guo Yubin , Cao Yanan , Huang Xiuping , Mi Wenting , Liu Side , Wang Chi , Evers B. Mark , She Qing-Bai 
Published: July 2017

Abstract
The mTOR inhibitors, including the second generation of mTOR kinase inhibitors, for cancer treatment have been evaluated in clinical trials, but their overall activity as monotherapy is limited. The cap-dependent translation repressor, 4E-BP1, is an important effector of the mTOR kinase in controlling cell proliferation and tumor growth. Loss of 4E-BP1 expression in cancer has been linked to malignant progression and poor prognosis. However, the molecular mechanism(s) by which 4E-BP1 is downregulated in cancer remain largely unknown. Here, we identify Snail as a novel repressor of 4E-BP1 expression that can be exploited to alter mTOR-targeted therapies. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Mechanistically, we show that Snail binds to three E-boxes present in the human 4E-BP1 promoter to repress transcription of 4E-BP1. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly inhibits 4E-BP1 expression, and promotes cap-dependent translation and resistance to the anti-proliferative effect of mTOR kinase inhibitors. Conversely, genetic depletion of Snail restores 4E-BP1 expression and sensitizes cancer cells to mTOR inhibition by enhancing the translation-repressive function of 4E-BP1 on cell proliferation and tumor growth. Thus, our findings reveal a critical role for Snail in determining the therapeutic response to mTOR kinase inhibitors, and suggest that Snail may be a potential marker for predicting the efficacy of mTOR-target therapies in the clinic. Moreover, our work highlights the importance of combining Snail inhibition with mTOR kinase inhibitors for the treatment of tumors in which Snail overexpression occurs with reduced 4E-BP1 expression.
Citation Format: Jun Wang, Qing Ye, Yubin Guo, Yanan Cao, Xiuping Huang, Wenting Mi, Side Liu, Chi Wang, B. Mark Evers, Qing-Bai She. Snail determines the efficacy of mTOR-targeted therapies by transcriptional repression of 4E-BP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-125. doi:10.1158/1538-7445.AM2017-LB-125
Abstract LB-310: PYK2 as a therapeutic target for pancreatic cancer
Authors: Hu Jing , Gao Chenxi , Chen Guangming , Gao Xuan , Zhang Dennis H. , Kuan Shih-Fan 
Published: July 2017

Abstract
Since nearly 100% of pancreatic ductal adenocarcinoma (PDAC) carried mutational activation of KRAS, KRAS and its effectors are theoretically ideal candidates for PDAC therapeutic intervention. Unfortunately, attempts to directly inhibit oncogenic KRAS or known RAS effector pathways have been either unsuccessful or proven ineffective. As a result, there is significant interest in identifying novel downstream effectors of oncogenic KRAS signaling that could be amenable to pharmacologic intervention. Our results suggest that PYK2 (proline-rich tyrosine kinase 2, a non-receptor cytoplasmic tyrosine kinase) is a novel downstream mediator of mutant KRAS signaling and a new actionable therapeutic target for PDAC. Specifically, our studies revealed: (1) mutant KRAS activated PYK2 gene transcription in a YAP1 (Yes-associated protein 1)-dependent manner. Hippo pathway effector YAP1 is a transcription cofactor and a powerful downstream effector of mutant KRAS in PDAC. (2) PYK2 levels were drastically elevated in mouse PanINs (pancreatic intraepithelial neoplasia) and human PDAC tissues. (3) Functionally, Whole-body deletion of PYK2, even heterozygous deletion, remarkably suppressed PanIN formation and progression to PDAC in the Pdx1-Cre KRASG12D mice model. Further, knockdown of PYK2 abrogated tumor growth in a PDAC cell line xenograft model, indicating that PYK2 is required for PDAC maintenance. (4) Mechanistically, PYK2 directly phosphorylated β-catenin at tyrosine (Y) 654 to promote the Wnt/β-catenin pathway and increased RelA/p65 phosphorylation at serine (S) 536 to promote the NF-κB pathway in PDAC cells. Because both pathways are essential for PDAC development in mice, we propose that PYK2 contributes to PDAC through upregulating Wnt/β-catenin and NF-κB pathways. Overall, our study has revealed that PYK2 is a new actionable target for treating PDAC.
Citation Format: Jing Hu, Chenxi Gao, Guangming Chen, Xuan Gao, Dennis H. Zhang, Shih-Fan Kuan. PYK2 as a therapeutic target for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-310. doi:10.1158/1538-7445.AM2017-LB-310