bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1064: PDX Like Me: A molecular profile-based search tool
Authors: Begley Dale A. , Krupke Debra M. , Neuhauser Steven B. , Richardson Joel E. , Sundberg John P. , Bult Carol J. 
Published: August 2019

Abstract
Patient Derived Xenografts (PDXs) are generated through the engraftment of human tumor tissue into a specialized (usually, immunodeficient) mouse host strain. PDXs are a useful pre-clinical platform for evaluating the efficacy of single agent and combination therapies that are targeted to specific genomic characteristics of a patient’s tumor. We have implemented the PDX Like Me search tool to assist researchers in identifying PDX models whose tumors match - or are similar to - molecular profiles comprised of one or more genes and one or more genomic characteristics (e.g., copy number status, mutation, and expression). The PDX Like Me interface uses a search syntax similar to the Onco Query Language used by the popular cBioPortal resource.
PDX Like Me is one of several search interfaces supported by the Mouse Models of Human Cancer database (formerly, the Mouse Tumor Biology database). MMHCdb (http://tumor.informatics.jax.org) is a comprehensive resource of information on both genetically engineered mouse models (GEMMs) and PDX models of human cancer that has been expertly curated from peer-reviewed scientific publications and direct data submissions from individual investigators and large-scale programs. MMHCdb provides an easy-to-use search interface as well as tools for visualizing associated data from these models. Information in the database is standardized using controlled vocabularies and official gene and mouse strain nomenclature. MMHCdb contains data from spontaneous or endogenously induced tumors from genetically defined mice. MMHCdb holds data on over 7,500 different strains including over 93,000 tumor frequencies and over 2,250 pathology reports with over 6,300 images from over 4,600 references. MMHCdb provides access to clinical, pathology, dosing study results, and genomics data from over 450 PDX models distributed by The Jackson Laboratory. MMHCdb in collaboration with EMBL-EBI has also co-developed the PDX Finder resource to provide a comprehensive global catalog of PDX models available for researchers.
MTB is supported by NCI grant CA089713.
Citation Format: Dale A. Begley, Debra M. Krupke, Steven B. Neuhauser, Joel E. Richardson, John P. Sundberg, Carol J. Bult. PDX Like Me: A molecular profile-based search tool [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 1064.
Abstract 1066: Drug resistant PDX models for testing targeted drug sensitivity
Authors: Cheng Jijun , Zhang Feifei , Zhou Zhen , Long Yuan , Xu Wenhua , Zhao Shizhu , Chen Hongkui , Lu Shun , Wen Danyi 
Published: August 2019

Abstract
Advanced lung cancer of late stage patients is selectively sensitive to available targeted therapeutics and often develops resistance to early sensitive drug treatment, thus, the patient-derived xenograft (PDX) models are critical to evaluate drug sensitivity and resistance. We established PDX models from routine surgery tissues, as well as from tumor cells in pleural effusion specimens and from biopsies of advanced cancer patients who are refractory to treatments. Genetic profiling of the PDX lung models revealed a group of them with TKI drug-associated EGFR mutations (L858R, T790M, Exon19del, C797S). Among them, are an AZD9291-resistant sub-group with EGFR double mutations (Exon19Δ, T790M) in the clinic before AZD9291 treatment, and yet, acquired resistance to AZD9291 either through emergence C797S mutation or T790M loss in EGFR or through mutations in other pathways, providing insights into potential combo therapies. Indeed, combinations of AZD9291 with Cetuximab as well as with inhibitors targeting other signaling pathways such as MEK, are efficacious against an AZD9291-resistant lung PDX model with EGFR triple mutations (Exon19Δ, T790M, C797S). We also establish valuable lung models resistant to ALK inhibitors, Avastin, PD-1 antibody drugs, and resistant hematopoietic models. In summary, functional drug sensitivity profiling and genetic profiling with drug resistant PDX models provide insights into resistance mechanisms as well as precise therapeutic options against resistance emergence.
Citation Format: Jijun Cheng, Feifei Zhang, Zhen Zhou, Yuan Long, Wenhua Xu, Shizhu Zhao, Hongkui Chen, Shun Lu, Danyi Wen. Drug resistant PDX models for testing targeted drug sensitivity [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 1066.
Abstract 107: Extracellular vesicles from cancer associated fibroblasts induce drug resistance via integrinβ1/FAK signaling in gastric cancer cells
Authors: Uchihara Tomoyuki , Yonemura Atsuko , Miyake Keisuke , Yasuda Tadahito , Itoyama Rumi , Iwatsuki Masaaki , Baba Yoshifumi , Yoshida Naoya , Baba Hideo , Ishimoto Takatsugu 
Published: August 2019

Abstract
Background: Cancer-associated fibroblasts (CAFs) enhance tumor progression through secretion of soluble factors. Although we demonstrated that direct-interaction between CAFs and cancer cells confer on gastric cancer (GC) cells the ability to invade extracellular matrix (ECM), the molecular mechanism underlying the drug resistance by soluble factors from CAFs has not been determined.
Methods: We have established primary fibroblasts from more than 100 GC patients and collected conditioned medium (CM) of CAFs. Human GC cell lines cultured in normal medium or CAF-CM were examined the drug resistance with or without extracellular matrix (ECM). We isolated extracellular vesicles (EVs) from CAF-CM by ultracentrifugal separation. We performed RNA sequencing of GC cell lines and mass analysis of GC-EVs and CAF-EVs.
Results: GC cells treated with CAF-CM or CAF-EVs did not show morphological change on normal coated plates. Notably, we found that GC cells with CAF-CM or CAF-EVs on ECM-coated plates showed unique network formation and cisplatin resistance. Given that the morphological change appeared within 1-3 hours, we predicted that the stimulation by CAF-EV had an impact on the expression pattern of membrane proteins in GC cells. Mass analysis using isolated CAF-EVs was conducted and revealed that CAF-EVs contained high amount of annexin family protein members. Moreover, we showed that annexin in CAF-EVs is critical for network formation and drug resistance of GC cells. Finally, we identified integrinβ1/FAK signaling was activated in GC cells treated with CAF-EVs during network formation.
Conclusions: These findings highlight the underlying mechanism whereby CAF-EVs in tumor-microenvironment confer GC cells on drug resistance.
Citation Format: Tomoyuki Uchihara, Atsuko Yonemura, Keisuke Miyake, Tadahito Yasuda, Rumi Itoyama, Masaaki Iwatsuki, Yoshifumi Baba, Naoya Yoshida, Hideo Baba, Takatsugu Ishimoto. Extracellular vesicles from cancer associated fibroblasts induce drug resistance via integrinβ1/FAK signaling in gastric 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 107.
Abstract 1081: Smad3 silences neutrophil anticancer activity in the tumor microenvironment
Authors: Tang Patrick Ming-Kuen , Tang Philip Chiu-Tsun , Chung Jeff Yat-Fai , Huang Xiao-Ru , To Ka-Fai , Lan Hui-Yao 
Published: August 2019

Abstract
Tumor microenvironment (TME) is a new therapeutic target for cancer, however it is highly heterogeneous and still largely unknown. Recently, we revealed that Smad3 is essential for TME-driven cancer progression, better understanding of the underlying mechanism may uncover novel therapeutic targets for cancer. Indeed, Smad3-dependent TME (Smad3-TME) is originated from bone marrow, where neutrophils are the most abundant leukocytes but their role in cancer is still controversial. Here, we are the first study to reveal the regulatory role of Smad3 in tumor-associated neutrophils (TAN). Interestingly, we observed that knockout of Smad3 (Smad3-KO) dramatically increased TAN population in mice bearing syngeneic melanoma B16F10 and lung carcinoma LLC, where the anticancer N1 phenotypes were significantly induced in the SMad3-KO TME-isolated TAN. Unexpectedly, adoptive transfer of Smad3-KO bone marrow-derived neutrophils markedly suppressed the progression of LLC-tumor on Smad3-WT mice in vivo, and their enhanced cancer-killing activity was confirmed by co-culture assay in vitro. Furthermore, microarray analysis identified a total of 4416 differentially expressed genes associated with Smad3-KO neutrophils under cancer condition in vitro, but the presence of Smad3 largely decreased the transcriptome diversity; especially on genes associated with virus defense response including an anticancer cytokine IL-28. Silencing of IL-28 significantly reduced the anticancer efficiency of Smad3-KO TAN on LLC-bearing mice in vivo. Mechanistically, we uncovered that IL-28A serves as a direct Smad3 target gene and specifically down-regulated in neutrophils under TGF-β1 or LLC-secretome stimulations; showing by ChIP and dual-luciferase reporter assays in vitro. Thus, targeting Smad3 precisely on TAN may represent as a novel and effective immunotherapy for cancer. Acknowledgments: This study was supported by Lui Che Woo Institute of Innovative Medicine (CARE program), Research Grants Council of Hong Kong (GRF 14117815, 14121816, 14163317, C7018-16G, TRS T12-402/13N), Health and Medical Research Fund (03140486, 14152321), Innovation and Technology Fund of Hong Kong (ITS/068/18), Direct Grant for Research CUHK (2017.002).
Note: This abstract was not presented at the meeting.
Citation Format: Patrick Ming-Kuen Tang, Philip Chiu-Tsun Tang, Jeff Yat-Fai Chung, Xiao-Ru Huang, Ka-Fai To, Hui-Yao Lan. Smad3 silences neutrophil anticancer activity in the tumor microenvironment [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 1081.
Abstract 1085: Neuropilin-1 deficient macrophages as a treatment strategy for glioblastoma
Authors: Caponegro Michael D. , Tsirka Stella E. 
Published: August 2019

Abstract
Post-diagnosis survival of grade IV glioblastoma (GB) is a dismal 14 months in patients receiving standard of care therapy. With the development of immunotherapeutic strategies targeting non-cancerous, stromal cells of the tumor microenvironment (TME), new avenues are being pursued in clinical trials and pre-clinical animal models of advanced GB. Glioma-associated microglia/macrophages (GAMs) of the TME promote chemoattraction, immune suppression, neoangiogenesis, and tumor cell survival, which parallels tumor-infiltrating macrophage behavior of other solid malignancies. GAMs are now recognized as a potentially practical immunotherapeutic target in GB. Previously in our lab, we have shown that GAM-specific deletion of the cell surface co-receptor Neuropilin-1 (NRP1) drastically reduces pro-tumorigenic behavior of infiltrating microglia and/or macrophages in murine glioma by reducing immunosuppressive tendencies and neoangiogenesis. As an extension to our genetically-ablated mouse model, we present here a platform by which these NRP1-deficient monocytic cells can be harvested ex vivo and locally delivered into the TME of the bulk glioma lesion, to exert anti-tumorigenic effects. To our knowledge, this is the first attempt to deliver cells of monocytic origin intratumorally as a therapeutic option.
Citation Format: Michael D. Caponegro, Stella E. Tsirka. Neuropilin-1 deficient macrophages as a treatment strategy for glioblastoma [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 1085.
Abstract 1086: Immune checkpoint inhibitors CD300A and LAIR1 are associated with poor prognosis in clear cell renal cell carcinoma
Authors: Sjolund Jonas , Lindgren David , Nilsson Helén , Johansson Martin E. , Axelson Hakan , Pietras Kristian 
Published: August 2019

Abstract
Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) have been shown to improve the survival of patients with clear cell renal cell carcinoma (CCRCC). However, a benefit for CCCRC patients was observed with the FDA-approved PD-1 inhibitor Nivolumab irrespective of PD-1 ligand (PD-L1) expression status indicating there are potentially additional CCRCC checkpoint molecules worth exploring for targeted therapy. We therefore analyzed RNAseq data (n=534, CCRCCs; n=72, normal kidney specimens) from the TCGA project, and found that PD-L1 was not upregulated in CCRCC when compared to normal tissue whereas other checkpoint members i.e. CD300A and LAIR1 were among the most significantly upregulated genes in CCRCCs. In terms of overall survival, high expression of PD-L1 was associated with better outcome in CCRCCs while high expression of CD300A and LAIR1 were significantly associated with worse outcomes. We confirmed these findings in two independent cohorts of CCRCC patients. Furthermore, we performed cell type enrichment analysis, which showed that CD300A and LAIR1 are most likely expressed by tumor-associated macrophages in the CCRCC tumor microenvironment. Our results suggest that PD1/PDL1 might be suboptimal targets in CCRCC and that there are additional unexplored immune checkpoint molecules that warrant our attention.
Note: This abstract was not presented at the meeting.
Citation Format: Jonas Sjolund, David Lindgren, Helén Nilsson, Martin E. Johansson, Hakan Axelson, Kristian Pietras. Immune checkpoint inhibitors CD300A and LAIR1 are associated with poor prognosis in clear cell renal 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 1086.
Abstract 1097: Establishment of murine immune and stroma reference bench for TME study on in vivo models
Authors: Xue Jia , An Xiaoyu , Chen Xiaobo , Qian Wubin , Li Henry Q. , Guo Sheng 
Published: August 2019

Abstract
Cancer is a heterogeneous disease and highly related to immunological system. Experimental animal models such as patient derived xenograft (PDX) are excellent system to understand tumor microenvironment (TME), especially for immunotherapy. Deconvolution analysis on bulk tissue genomics of these in vivo tumor models is one of cost-effective ways to investigate TME. Several groups have released robust deconvolution algorithms with human immune cell signature. Our previous research on ~1600 transcriptomes of PDX collection identified various human immune and stromal contents in 24 different cancer types. However, no appropriate mouse immune signature generated from single standard platform could be used so far to study murine immune and stromal contents. To this end, we established a reference dataset by performing transcriptome sequencing of over 10 types of mouse immune and stromal cells, including different subtypes of B cells, T cells, monocytes, macrophages, dendritic cells, neutrophils, natural killer cells, cancer associated fibroblasts, glial cell and epithelial cell, etc. These cells were isolated from 3 different tissues (bone marrow, lymph node and spleen) on tumor-bearing and non-tumor-bearing mice covering a variety of mouse strains. We identified the transcriptomic landscape of murine immune system as well as difference across source tissues/organs and mouse strains. Based on this reference set, which is generated from single standard protocol, we defined precision gene signatures for studied cells and refined deconvolution algorithms for mouse TME studies. We further evaluated multiple algorithms by flow cytometry. In conclusion, our murine immune and stroma reference dataset will be essential basis for model selection in immunotherapy study in future.
Note: This abstract was not presented at the meeting.
Citation Format: Jia Xue, Xiaoyu An, Xiaobo Chen, Wubin Qian, Henry Q. Li, Sheng Guo. Establishment of murine immune and stroma reference bench for TME study on in vivo models [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 1097.
Abstract 1099: Organotypic tumor tissue slices provide versatile platform for immuno-oncology
Authors: Sivakumar Ramya , Chan Marina , Yeung Raymond , Gujral Taranjit S. 
Published: August 2019

Abstract
Organotypic tissue slices represent one of the most physiologically-relevant culture systems for studying the tumor microenvironment. The thin slices of tumor cut out using automated vibratome retain the original architecture and cellular composition of the tumor from several days up to weeks depending on the investigated tumor model. The slice culture has been emerging as a versatile platform for studying cancer cell-host cell interactions. However, a thorough characterization of the multicellular organotypic culture system, particularly its immune component, is still unresolved to allow a better understanding of its potential applications. Here, we carried out a comprehensive characterization of immune cell composition in organotypic tumor slices prepared from several different syngeneic mouse tumor models. We generated several syngeneic mouse tumor models and harvested the primary tumors to make tumor slices. We then immunophenotyped the major tumor infiltrating leukocytes (TILs) by flow cytometry to understand the immune makeup of these slices immediately after the harvest, over a period of 7 days and upon treatment of various immuno-modulators. We found that the immune compositions of tumor slices do not deviate from that of the tumor cores, immediately after harvest, across all the syngeneic tumor models. During the 7-day follow-up, despite an initial decline in the overall cell viability which stabilized on day 3, we observed a consistent percentage of TILs out of total viable cells, suggesting that the relative composition of tumor and immune populations can be maintained in the tumor slice over time. Among the TILs, macrophages were the predominant immune cell type detected, similar to that observed in many human solid tumors. Macrophages remained viable till day 7 while other cell types were mostly viable till day 5, providing a window of time sufficient to support many short-term perturbation studies. Further, we found that these immune cell populations were responsive to the treatment with immunomodulators. For example, we observed an upregulation of co-stimulatory markers, CD86 and MHC-II, on macrophages and DCs upon stimulation with the pro-inflammatory cytokine IFN γ, further supporting the application of tumor slice in the study of immuno-oncology. Overall, these data support the approach of utilizing tumor slice culture as a platform for studying tumor microenvironment and evaluating efficacy of immune modulatory drugs.
Citation Format: Ramya Sivakumar, Marina Chan, Raymond Yeung, Taranjit S. Gujral. Organotypic tumor tissue slices provide versatile platform for immuno-oncology [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 1099.
Abstract 1101: Characterization of spatial distribution of tumor-infiltrating CD8+ T cells refines their prognostic impact in pancreatic cancer
Authors: Masugi Yohei , Abe Tokiya , Kitago Minoru , Shinoda Masahiro , Sakamoto Michiie 
Published: August 2019

Abstract
Background: The abundance of cytotoxic T cell infiltrates has important implications for patient outcome and therapeutic design in pancreatic ductal adenocarcinoma (PDAC), although intratumoral heterogeneity remains a major challenge for the better understanding of complicated immune microenvironment of PDAC. We aimed to characterize spatial CD8+ cell distribution within PDAC tissues, which might refine the prognostic role of tumor-infiltrating CD8+ lymphocytes.
Methods: We measured CD8+ cell density in tumor center, tumor margin, or whole tumor area, as well as CD8+ cell proximity to carcinoma cells, using fluorescent multiplex immunohistochemistry-based tissue computation on whole tissue sections of 214 surgically resected PDACs. Multivariable Cox proportional hazards regression analysis was performed to assess the association of CD8+ cell density with pancreatic cancer-specific survival, adjusting for major clinicopathologic and immune-related features, including the programmed cell death 1 ligand 1 (CD274, PD-L1) expression and the extent of tertiary lymphoid structures.
Results: We found a substantial heterogeneity in CD8+ cell density with, on average, a 2-fold-lower density in tumor center than in tumor margin. In multivariable model, the trend of prolonged survival with higher CD8+ cell density was stronger for tumor center, compared to tumor margin or whole tumor area (P for trend = 0.002, 0.07, or 0.009, respectively). Tumor CD274 expression and extensive tertiary lymphoid structures were appeared to be associated with higher CD8+ cell density in tumor margin, but not with CD8+ cell density in tumor center. The mean distance from tumor cells to the adjacent CD8+ cells correlated inversely with CD8+ cell density in tumor center (Spearman correlation efficient, -0.89), although the density of CD8+ cells proximate to cancer cells did not show any prognostic correlation.
Conclusion: Our data have shown a prognostic significance of CD8+ cell density in tumor center of PDAC, where CD8+ cell infiltration has been severely limited, suggesting a major role of pro-tumorigenic effect of immunosuppressive microenvironment in pancreatic cancer.
Citation Format: Yohei Masugi, Tokiya Abe, Minoru Kitago, Masahiro Shinoda, Michiie Sakamoto. Characterization of spatial distribution of tumor-infiltrating CD8+ T cells refines their prognostic impact in pancreatic 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 1101.