bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2468: Phosphorylation of Thr55 mediates the tumor suppression activities of p53
Authors: He Fan , Chen Lihong , Chen Jiandong 
Published: September 2020

Abstract
P53 is a transcription factor that plays a central role in the regulation of cell cycle, apoptosis and senescence. In unstressed cells, p53 is kept at low level under the strict control of its negative regulators. Upon DNA damage or oncogenic stress, p53 is activated via post-translational modifications. The phosphorylation of serine and threonine, such as Ser15 and Ser46, play important roles in p53 regulation. However, data for Thr55 (T55) phosphorylation is limited and functions of T55 phosphorylation remain elusive. We have previously defined an intramolecular interaction in p53 which modulates DNA binding. The observation of altered intramolecular interactions in T55A and T55D mutants leads to the hypothesis that T55 phosphorylation might affect p53 functions. We generate a T55 phospho-specific antibody to investigate the regulation through this site. The results show T55 phosphorylation is induced by DNA damage compounds. We induce the expression of wild type and T55A mutant p53 in p53 null H1299 cells via the transduction of doxycycline-inducible lentiviral gene expression plasmids. T55A mutant p53 exhibits significantly weaker inhibition of cell viability compared with wild type p53 containing cell in the existence of DNA damaging compounds. Consistently, T55A mutant p53 induces lower mRNA expression level of several important apoptosis related genes and higher MDM2 level in comparison with wild type p53. Overall, our results reveal that phosphorylation of Thr55 is induced by several DNA damaging compounds and alters the expression of p53 target genes, leading to an enhanced tumor suppression.
Citation Format: Fan He, Lihong Chen, Jiandong Chen. Phosphorylation of Thr55 mediates the tumor suppression activities of p53 [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 2468.
Abstract 2469: RCC2 promotes esophageal cancer growth by regulating activity and expression of the Sox2 transcription factor
Authors: Calderon-Aparicio Ali J. , Yamamoto Hiroyuki , de vitto Humberto , Zhang Tianshun , Wang Qiushi , Bode Ann M. , Dong Zigang 
Published: September 2020

Abstract
RCC2 is a protein located in the centrosome, which ensures that cell division proceeds properly. Previous reports show that RCC2 is overexpressed in some cancers and could play a key role in tumor development, but the mechanisms concerning how this occurs are not understood. Further, no evidence exists regarding its role in esophageal cancer. We studied the relevance of RCC2 in esophageal cancer growth and the mechanisms explaining how this process occurs. RCC2 was highly expressed in mouse and human tissues as well as esophageal cancer cell lines, and this overexpression was associated with tumorigenicity. RCC2 promoted cell proliferation, anchorage-independent growth, and migration. These oncogenic effects were accompanied by overexpression of Sox2, an important transcription factor promoting esophageal cancer. RCC2 upregulated and stabilized Sox2 expression by inhibiting proteasome degradation. Likewise, RCC2 increased the transcriptional activity and promoter binding of Sox2. In vivo studies indicated that RCC2 and Sox2 were overexpressed in esophageal tumors compared to normal controls, and this upregulation occurs in the basal cell layer for both proteins. In conditional knockout mice, RCC2 deletion decreased the tumor nodule formation and progression in the esophagus compared with “wild type” mice. PCNA expression, a cell proliferation marker, was also downregulated in RCC2 knockout mice. Overall, our data show for the first time that RCC2 is an important protein for the stabilization and transcriptional activation of Sox2 and further promotion of malignancy in cancer.
Citation Format: Ali J. Calderon-Aparicio, Hiroyuki Yamamoto, Humberto de vitto, Tianshun Zhang, Qiushi Wang, Ann M. Bode, Zigang Dong. RCC2 promotes esophageal cancer growth by regulating activity and expression of the Sox2 transcription factor [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 2469.
Abstract 2504: Modeling molecular development of breast cancer in canine mammary tumors
Authors: Graim Kiley , Gorenshteyn Dmitriy , Robinson David G. , Carriero Nicholas J. , Cahill James , Chakrabarti Rumela , Goldschmidt Michael H. , Durham Amy C. , Funk Julien , Storey John D. , Kristensen Vessela N. , Theesfeld Chandra L. , Sorenmo Karin U. , Troyanskaya Olga G. 
Published: September 2020

Abstract
Malignancy in cancer is a consequence of the progressive accumulation of mutations in a tumor, with profound implications for drug selection and treatment. However, in human studies, inter-patient variability obscures molecular signatures of tumor progression because patients usually present with a single mammary tumor. In contrast, dogs frequently exhibit multiple naturally occurring mammary tumors in the same individual. Moreover, canine mammary tumors (CMTs) and human breast cancer have similar histopathological profiles and clinical presentation. We leverage the CMT model to elucidate genome-wide molecular changes clinically relevant in human breast cancer, focusing on signals underlying tumor development. We develop a robust, generally applicable, computational analysis framework (FREYA) for analysis of CMTs for comparative oncology. Using FREYA, we RNA profile 89 samples from 16 dogs, and demonstrate that CMTs recapitulate human breast cancer subtypes. We then extract molecular profiles of breast cancer progression at three distinct stages (normal, pre-malignant and malignant) and identify signatures of gene expression reflective of tumor progression. Focusing on the transitions to malignancy, we identify transcriptional patterns and biological pathways specific to malignant tumors and distinct from those characterizing pre-malignant tumors or normal tissue. We find that human breast cancer patients whose tumors exhibit strong CMT malignancy signatures have significantly decreased survival, indicative of the importance of the tumor progression processes identified in CMTs to human breast cancer prognosis. Altogether, our comprehensive genomic characterization demonstrates that CMTs are a powerful translational model of breast cancer, providing insights that inform our understanding of tumor development in humans. To catalyze and support similar analyses and use of the CMT model by other biomedical researchers, we publicly share all of our data and provide FREYA, a robust data processing pipeline and statistical analyses framework, at freya.flatironinstitute.org.
Citation Format: Kiley Graim, Dmitriy Gorenshteyn, David G. Robinson, Nicholas J. Carriero, James Cahill, Rumela Chakrabarti, Michael H. Goldschmidt, Amy C. Durham, Julien Funk, John D. Storey, Vessela N. Kristensen, Chandra L. Theesfeld, Karin U. Sorenmo, Olga G. Troyanskaya. Modeling molecular development of breast cancer in canine mammary tumors [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 2504.
Abstract 2509: Genetic heterogeneity and evolutionary history of high grade ovarian carcinoma and matched distant metastases
Authors: Masoodi Tariq , Siraj Sarah , Siraj Abdul K. , Azam Saud , Qadri Zeeshan , Parvathareddy Sandeep K. , Alkuraya Fowzan S. , Al-Kuraya Khawla S. 
Published: September 2020

Abstract
BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian carcinoma, associated with poor clinical outcome and metastatic disease. Although, metastatic processes are becoming more understandable, the genomic landscape and metastatic progression in HGSOC has not been elucidated.
METHODS: Multi-region whole-exome sequencing was performed on HGSOC primary tumors and their metastases (n=33 tumor regions) from 6 patients. The resulting somatic variants were analyzed to delineate tumor evolution and metastatic dissemination, and to compare the repertoire of events between primary HGSOC and metastasis.
RESULTS: All cases presented branching evolution patterns in primary HGSOC, with three cases further showing parallel evolution in which different mutations on separate branches of a phylogenetic tree converge on the same gene. Furthermore, linear metastatic progression was observed in 67% of cases with late dissemination in which the metastatic tumor mostly acquires the same mutational process active in primary tumor, and parallel metastatic progression, with early dissemination in the remaining 33.3% of cases. Metastatic specific SNVs were further confirmed as late dissemination events. We also found the involvement of metastatic-specific driver events in the Wnt/β-catenin pathway.
CONCLUSIONS: This study provides deeper insights into clonal evolution and mutational processes that can pave the way to new therapeutic targets.
Citation Format: Tariq Masoodi, Sarah Siraj, Abdul K. Siraj, Saud Azam, Zeeshan Qadri, Sandeep K. Parvathareddy, Fowzan S. Alkuraya, Khawla S. Al-Kuraya. Genetic heterogeneity and evolutionary history of high grade ovarian carcinoma and matched distant 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 2509.
Abstract 2528: Tumor-derived exosomal miR-619-5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4
Authors: Jung Sang Yong , Kim Dong Ha , Cho Yong-Hee , Choi Yun Jung , Kim Seon Ye , Sung Ki Jung , Lee Chae Won , Lee Hyeon Jeong , Choi Chang-Min , Lee Jae Cheol , Rho Jin Kyung 
Published: September 2020

Abstract
Tumor-derived exsosomes (TEXs) contain enriched miRNAs act as novel non-invasive biomarkers for cancer diagnosis, and they are involved in cancer progression. In this study, we aimed to investigate which and how exosomal miRNA affect cancer progression in non-small cell lung cancer (NSCLC). We found that the only of A549 cell-released exosomes promote an angiogenic phenotype in HUVEC cells compared to other lung cancer cell-released exosomes. Using a miRNA array and RNA sequencing approach, we identified that specific miRNAs can modulate angiogenesis in A549 cell-released exosomes. Among these miRNAs, miR-619-5p significantly induced angiogenesis in HUVEC cells. Subsequently, RCAN1.4 was identified as a target of miR-619-5p and the suppression of RCAN1.4 inhibited the angiogenesis of HUVEC cells. Furthermore, the suppression of RCAN1.4 by miR-619-5p promoted the cellular mobility and proliferation in in vitro, as well as in vivo, tumor growth and metastasis in non-small cell lung cancer (NSCLC) cells. In patients with non-small cell lung cancer (NSCLC), the level of RCAN1.4 expression was significantly lower in tumor tissues than normal lung tissues, whereas the level of miR-619-5p was a significant higher in tumor tissue than normal lung tissues. We also found that there was a significant inverse correlation between the expression of miR-619-5p and that of RCAN1.4. In addition, miR-619-5p expression was higher in exosomes isolated from plasma of patients with NSCLC than normal. Finally, hypoxia condition led to enhance the amount of miR-619-5p within NSCLC cells-derived exosomes. In conclusion, exosomal miR-619-5p promotes tumor growth and metastasis of NSCLC by regulating RCAN1.4 in endothelial and tumor cells, and it can serve as a diagnosis and prognostic indicator for NSCLC patients.
Citation Format: Sang Yong Jung, Dong Ha Kim, Yong-Hee Cho, Yun Jung Choi, Seon Ye Kim, Ki Jung Sung, Chae Won Lee, Hyeon Jeong Lee, Chang-Min Choi, Jae Cheol Lee, Jin Kyung Rho. Tumor-derived exosomal miR-619-5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4 [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 2528.
Abstract 2654: B cells produce IL-27 in breast cancer to upregulate PD-L1 expression and promote tumor progression
Authors: Yan Hui , Viswanadhapalli Suryavathi , Perez Dariela , Chupp Daniel , Fernandez Maria , Wang Jingwei , Wu Shuai , Rivera Carlos E. , Moroney Justin B. , Taylor Julia , Im John , Luo Yiliao , Liu Junhao , Gangadhara Sareddy , Curiel Tyler , Casali Paolo , Vadlamudi Ratna , Xu Zhenming 
Published: September 2020

Abstract
B cells frequently infiltrate breast cancer (BCa) tumors, but their roles are inadequately understood. As shown by our analyses of the TCGA datasets and human BCa arrays, tumoral expression of B cell hallmark factors (e.g., CD20 and PAX5) coincides with those of the two subunits of pleiotropic cytokine IL-27, EBI3 and IL-27p28, whose expression is associated with poor prognosis in patients. In syngeneic mouse models, B cells promote BCa progression and do so by producing IL-27, but not IL-35 (IL-12/EBI3 heterodimer). Upon treatment by recombinant IL-27 or co-culturing with IL-27-producing B cells, BCa cells as well as targeted B lymphocytesactivate STAT1/STAT3 and upregulate immune checkpoint PD-L1 and chemokine receptor CXCR3, blocking of which synergistically arrest BCa cell proliferation in vitro and tumor growth in vivo, concomitant with reduction in PD-L1+B cells. Finally, B cell-specific deficiency in IL-27 receptor or PD-L1 inhibits BCa tumorigenesis, showing the dual functions of tumor-infiltrating B cells, i.e., IL-27 production for paracrinic PD-L1 upregulation.
Citation Format: Hui Yan, Suryavathi Viswanadhapalli, Dariela Perez, Daniel Chupp, Maria Fernandez, Jingwei Wang, Shuai Wu, Carlos E. Rivera, Justin B. Moroney, Julia Taylor, John Im, Yiliao Luo, Junhao Liu, Sareddy Gangadhara, Tyler Curiel, Paolo Casali, Ratna Vadlamudi, Zhenming Xu. B cells produce IL-27 in breast cancer to upregulate PD-L1 expression and promote tumor 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 2654.
Abstract 2667: CaMKK2 knockout in mice challenged by orthotopic GBM leads to upregulation of MHC II on TAMs and an increase in accumulation of CD4+ TILs
Authors: Chakraborty Molly A. , Tomaszewski William H. , Polania Jessica Waibl , Riley Lauren S. , Racioppi Luigi , Sanchez-Perez Luis A. , Sampson John H. 
Published: September 2020

Abstract
Glioblastoma (GBM) is the most lethal primary brain tumor in adults, with the median survival time for GBM patients being only about 15 months. Although immunotherapy treatments have been successful in more immunogenic tumors, it has shown very limited success in GBM. This could be because it is difficult for T cells to infiltrate the tumor, and the tumors have a very immunosuppressive tumor microenvironment (TME) that can often consist of up to about 30 percent tumor associated macrophages (TAMs) by mass. Thus, two ways of possibly improving immunotherapy treatments on GBMs would be to increase the number of tumor infiltrating lymphocytes (TILs) present, and to target tumor-supportive cells such as TAMs. Calmodulin Dependent Protein Kinase Kinase 2 (CaMKK2) is a gene that has been shown to be highly expressed in myeloid cells and is known to alter their phenotype. Recent studies in breast cancer have shown that myeloid cells adopt a more immunostimulatory phenotype in murine knockout CaMKK2 models. However, it is not well understood how CaMKK2 causes this immunosuppressive effect and warrants further exploration. The data from our experiments help to answer this question. High-dimensional flow cytometry with 15 parameters was used in order to determine the identities of immune cells found in the tumor of wildtype and CaMKK2-/- mice. The results of our experiments show that there appear to be more CD4+ TILs present in the TME of knockout mice and that there is an increase in MHC II expression on TAMs found in knockout mice. Since CD4+ TILs recognize peptides presented on MHC II molecules, and there is an increase in the number of CD4+ TILs and expression of MHC II on TAMs in knockout mice, we hypothesize that a stronger immune response could be instigated against the tumor. Therefore, it can be concluded that a possible reason that knocking out CaMKK2 leads to a less immunosupressive TME is because MHC II expression on TAMs is upregulated, and the number of CD4+ TILs in the TME is increased. Whether or not the increase in MHC II expression causes the increase in the number CD4+ TILs requires further exploration. This makes CaMKK2 a promising therapeutic target to treat tumors with immunosuppressive TMEs such as GBM.
Citation Format: Molly A. Chakraborty, William H. Tomaszewski, Jessica Waibl Polania, Lauren S. Riley, Luigi Racioppi, Luis A. Sanchez-Perez, John H. Sampson. CaMKK2 knockout in mice challenged by orthotopic GBM leads to upregulation of MHC II on TAMs and an increase in accumulation of CD4+ TILs [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 2667.
Abstract 2774: Longitudinal characterization of patient-derived orthotopic xenograft brain tumor models
Authors: Schueler Julia , Heins Mariette , Shatillo Artem , Lehtimäki Kimmo , Peille Anne-Lise , Stenius Taina-Kaisa , Bragge Timo , Rytkönen Jussi , Miszczuk Diana , Huhtala Tuulia 
Published: September 2020

Abstract
Gliomas are the most common primary brain tumors and currently the prognosis is still poor. Due to this, it is one of the main areas in oncological research and drug development programs. Innovative therapies are vital to improve treatment outcomes but must be developed to enable trafficking across the blood brain barrier (BBB). For this advent, animal models provide important information prior to clinical studies. Among the different in vivo models, orthotopic PDX models represent best the tumor microenvironment and natural variability of tumors, hence providing the most reliable results over species.
In the brain tumor field, imaging has a central role in clinical diagnosis and as a prognostic factor to monitor therapy response in patients. Magnetic resonance imaging (MRI) is widely used for clinical diagnosis and disease follow up as it offers unprecedented soft tissue contrast and high spatial resolution non-invasive way. In addition to imaging, molecular profiling, e.g. circulating immune biomarkers and local oncometabolites in the tumor environment may facilitate as important translational biomarkers in development of immunotherapy for gliomas in addition to traditional histopathological readouts.
The purpose of this work was to analyze possible heterogeneity of tumors in vivo, growth rate and volume in stereotactically implanted orthotopic PDX brain tumor models using MRI/MRS imaging. In addition to imaging, neurological scoring was performed to monitor general animal welfare, cytokine profiles from plasma to observe immunological responses over time and determination of oncometabolites in plasma and brain tissues combined with traditional histopathological changes were performed. The data from orthotopic models was also compared to readouts in subcutaneous models.
As a conclusion, translational in vivo imaging techniques were applied to study orthotopic tumor progression combined with circulating immune biomarkers, and general welfare scoring. These readouts provide a powerful and translational research tool together with oncological disease animal models allowing comprehensive evaluation of disease progression and treatment interventions for in vivo studies.
Citation Format: Julia Schueler, Mariette Heins, Artem Shatillo, Kimmo Lehtimäki, Anne-Lise Peille, Taina-Kaisa Stenius, Timo Bragge, Jussi Rytkönen, Diana Miszczuk, Tuulia Huhtala. Longitudinal characterization of patient-derived orthotopic xenograft brain tumor models [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 2774.
Abstract 2793: Application of conditionally reprogrammed cell in in vitro drug sensitivity test and PDX modeling
Authors: Long Yuan , Xi Song , Wen Danyi 
Published: September 2020

Abstract
Tumor cell immortalization through conditional reprogramming, particularly from limited biopsy specimen, is an invaluable tool to generate propagating tumor cells for cell-based drug sensitivity assay and bio-banking in vitro. We have successfully reprogrammed primary tumor cells from a number of tumor types, including lung carcinoma, breast cancer and glioma .etc. The conditionally reprogrammed cells exhibited typical colonized growth, which is well maintained upon cryopreservation. In some cases, the cells can be passaged for multiple times and likely become sable cell lines. Like primary tumor cells, conditional reprogrammed tumor cells are reliable to test drug sensitivity in vitro. We attempt to extend conditional reprogrammed tumor cells to reconstitute and grow PDX models in vivo for testing drug efficacy. The conditional reprogrammed tumor cells could also be used in PDX establishment and the tumor formation rate is much higher than the primary tissue's. In summary, this study explores and expands application of conditional reprogrammed tumor cells in in vitro drug efficacy test and in vivo PDX Modeling.
Citation Format: Yuan Long, Song Xi, Danyi Wen. Application of conditionally reprogrammed cell in in vitro drug sensitivity test and PDX modeling [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 2793.