bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1577: Gene expression studies using microgel embedded pancreatic cancer spheroids
Authors: Prasad Saumya , Chandra Anil , Lonardo Enza , Parasido Erika , Albanese Christopher , Mercato Loretta L. del 
Published: September 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is known to be one of the deadliest cancers due to its late diagnosis and faster metastasis rate1. Thus, the time required to test the patient-derived cancer cells against different therapeutics becomes extremely crucial. Gene expression analysis using real-time PCR is vital, typically when designing patient-specific therapeutics. 2D tumor models do not represent the true picture of the tumor in vivo. In order to perform these gene expression studies, robust 3D cancer models are required2. The traditional techniques of generating cancer spheroids using U-bottom wells and hanging drop methods are effective but are limited by scalability as well as the limitations associated with the traditional organoid architecture. Gene expression studies of spheroids under different combinations of drug treatment thus requires many well defined and easy to handle spheroids. Here, we are trying to perform real-time PCR studies to access the gene expression changes on MIA PaCa-2 microgel based spheroids generated using co-axial droplet microfluidics with or without stromal cells. This 3D platform will enable gene expression studies in miniature co-culture tumor models. In addition, PCR and single-cell sequencing analyses will define the gene expression changes in the recently described conditionally reprogramed, patient-derived, primary PDAC cultures3. The establishment and analysis of this 3D model is fast, reproducible and can be easily scaled to enable high-throughput screening, thereby providing an opportunity to design patient-specific precision medicine.
The research leading to these results received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 759959, ERC-StG “INTERCELLMED”).
References:
(1) Adamska, A.; Domenichini, A.; Falasca, M. Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. Int. J. Mol. Sci. 2017, 18 (7).
(2) Moreira, L.; Bakir, B.; Chatterji, P.; Dantes, Z.; Reichert, M.; Rustgi, A. K. Pancreas 3D Organoids: Current and Future Aspects as a Research Platform for Personalized Medicine in Pancreatic Cancer. Cell. Mol. Gastroenterol. Hepatol. 2018, 5 (3), 289-298.
(3) Parasido, E.; Avetian, G. S.; Naeem, A.; Graham, G.; Pishvaian, M.; Glasgow, E.; Mudambi, S.; Lee, Y.; Ihemelandu, C.; Choudhry, M.; et al. The Sustained Induction of C-MYC Drives Nab-Paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells. Mol. Cancer Res. 2019, 17 (9), 1815-1827.
Citation Format: Saumya Prasad, Anil Chandra, Enza Lonardo, Erika Parasido, Christopher Albanese, Loretta L. del Mercato. Gene expression studies using microgel embedded pancreatic cancer spheroids [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 1577.
Abstract 1580: Distinct pathways of lytic and blastic bone metastases in prostate cancer patients
Authors: Ihle Claire L. , Provera Meredith D. , Straign Desiree M. , Smith E. Erin , Edgerton Susan M. , Van Bokhoven Adrie , Lucia M. Scott , Owens Philip 
Published: September 2020

Abstract
The most common metastatic lesions of prostate cancer are in the bone and can be classified into three distinct pathologic subtypes: lytic, blastic, and an indeterminate mixture of both. There is no immunotherapy guidance for treating patients based on lytic or blastic tumor induced bone disease. To identify distinct tumor and stroma in lytic and blastic prostate cancer bone metastases, we investigated a cohort of decalcified formalin-fixed and paraffin-embedded (FFPE) patient bone biopsy specimens that contained metastatic prostate cancer with lytic or blastic features. Tissue sections were utilized for immunohistochemistry (IHC) staining, isolation of RNA for gene expression, and Digital Spatial Profiling (DSP) of changes in both the tumor and microenvironment. A diverse set of unique immune cell populations and signaling pathways to both lytic and blastic types of prostate cancer metastases were present. High proportions of macrophages were present in lytic tumor induced bone disease, and T cells were present in lytic and blastic samples. In blastic lesions, immune cells were enriched for pSTAT3 and components of the JAK-STAT pathway. In lytic lesions, immune cells exhibited enhanced pAKT activity and components of the PI3K-AKT pathway. Expression of key immune checkpoint targets were identified in blastic prostate cancer, providing new therapeutic targets for patients with bone metastases. To further investigate which individual cells comprising the stroma and tumor have active JAK-STAT signaling, we performed fluorescent multiplex-IHC (mIHC). A tumor and myeloid panel of antibodies was used to identify on a single cell resolution which specific cell types are enriched for pSTAT3 in the tumor microenvironment. The identification of pAKT or pSTAT3 as promising therapeutic targets could be rationally employed to individual patients. The presence of macrophages and T cells in samples suggest that conventionally “cold” prostate cancer bone metastases warrant reappraisal as capable immunotherapy responders. Biopsies could guide selection of patients into appropriate therapeutic interventions based on protein levels and RNA expression of desired targets in metastatic disease.
Citation Format: Claire L. Ihle, Meredith D. Provera, Desiree M. Straign, E. Erin Smith, Susan M. Edgerton, Adrie Van Bokhoven, M. Scott Lucia, Philip Owens. Distinct pathways of lytic and blastic bone metastases in prostate cancer patients [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 1580.
Abstract 1591: Single cell analysis of uveal melanoma reveals new evolutionary complexity
Authors: Durante Michael A. , Rodriguez Daniel A. , Kurtenbach Stefan , Kuznetsoff Jeffim N. , Sanchez Margaret I. , Decatur Christina L. , Snyder Helen , Feun Lynn G. , Livingstone Alan S. , Harbour J. William 
Published: September 2020

Abstract
Uveal melanoma (UM) is a highly metastatic cancer that is largely unresponsive to molecular and immune therapy. We used scRNA-seq and other methods to analyze 59,915 tumor and non-neoplastic cells from 8 primary and 3 metastatic UMs. This analysis confirmed the class 1/class 2 transcriptomic landscape established from bulk analysis and revealed newly identified subclonal genomic complexity and transcriptional states consistent with phenotype plasticity. The immune compartment comprised a previously unappreciated diversity of cell types. There was low expression of CTLA4 and PD1, but strong expression of a different checkpoint molecule. These findings revealed a dynamic ecosystem in which UM and immune cells co-evolve along trajectories associated with specific genomic aberrations, and they may explain the poor response of UM to current immunotherapy regimens. We identified a new promising candidate for immune checkpoint blockade in metastatic UM.
Citation Format: Michael A. Durante, Daniel A. Rodriguez, Stefan Kurtenbach, Jeffim N. Kuznetsoff, Margaret I. Sanchez, Christina L. Decatur, Helen Snyder, Lynn G. Feun, Alan S. Livingstone, J. William Harbour. Single cell analysis of uveal melanoma reveals new evolutionary complexity [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 1591.
Abstract 1617: Developing new mouse models of metastatic lung cancer
Authors: Wells Julie , Maser Richard S. , McGee Teresa , Memishian Wendy , Doty Rosalinda , Bult Carol J. 
Published: September 2020

Abstract
INTRODUCTION: The focus of this work is to develop new mouse models for metastatic lung cancer. Lung cancer is the leading cause of cancer deaths worldwide and greater than 90% of human cancer deaths are due to metastasis. Metastatic disease in most existing mouse models of lung cancer is typically sporadic and often requires aging mice for several months. These factors limit the usefulness of mouse models for basic and pre-clinical research aimed at effective treatment of metastatic disease.
METHODS AND RESULTS: We have developed a new mouse model of lung cancer and are in the process of developing two additional models. In the first model, we added mutations in Dicer1, an RNAse III enzyme within the microRNA (miRNA) biosynthesis pathway to a mouse model of Kras-driven pulmonary adenocarcinoma. When we combined conditional expression of an oncogenic allele of Kras (KrasG12D), deletion of both alleles of Trp53 and one allele of Dicer1 in Club cells with expression of truncated Dicer1 in alveolar type II cells, we generated mice with metastatic pulmonary adenocarcinoma. In 30% of these mice, metastatic tumors were observed in the lymph nodes within 11 weeks of tumor induction. In a second mouse model, we switched the cell types expressing the various mutations to determine the effects of cell of origin on tumor progression and metastasis. Our preliminary results suggest that adenocarcinoma develops even faster when KrasG12D is expressed and Trp53 and one allele of Dicer1 are deleted in alveolar type II cells. Finally, based on an analysis of human lung cancer genomics data from TCGA, we generated a mouse model with mutations in Zfhx4 and are crossing these mice with our models that express oncogenic KrasG12D, delete expression of Trp53 and one allele of Dicer1 and truncate the second allele of Dicer1 to determine the effects of adding Zfhx4 mutations on progression and metastasis of pulmonary adenocarcinoma.
CONCLUSIONS: Through cell type specific truncation/deletion of Dicer1 we have generated new mouse models that rapidly develop pulmonary adenocarcinomas and metastatic disease. These models have potential for both understanding the basic processes of metastasis and for pre-clinical studies aimed at preventing and/or treating metastatic lung cancer.
Citation Format: Julie Wells, Richard S. Maser, Teresa McGee, Wendy Memishian, Rosalinda Doty, Carol J. Bult. Developing new mouse models of metastatic lung cancer [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 1617.
Abstract 1644: Detection and quantification of lymphedema using optical coherence tomography lymphangiography
Authors: Kwan Jennifer Y. , Demidov Valentin , Jones Blake , Shi Wei , Williams Justin , Flueraru Costel , Yip Kenneth W. , Liu Fei-Fei , Vitkin Alex 
Published: September 2020

Abstract
Purpose: Imaging of the lymphatic system is important for monitoring and quantification of the vasculature of tumours and in lymphatic disorders (e.g. lymphedema, an obstruction of the lymphatic system that occurs as a side-effect of cancer treatments such as radiation and/or surgery). Traditional methods of lymphangiography require injection of a contrast agent to visualize the lymphatic system, which may be suboptimal when there is lymphatic obstruction. Thus, there is a need to develop intrinsic-contrast, high-resolution volumetric (3D) non-invasive quantitative in vivo imaging systems for both pre-clinical and potentially clinical use.
Methods: An emerging non-invasive 3D imaging technology called optical coherence tomography (OCT) lymphangiography was optimized to visualize lymphatic vasculature and edema within tissues of C57BL/6 mice under normal and surgically-induced lymphedematous conditions. A murine tail lymphedema model was created by micro-surgical obstruction of the superficial and deep lymphatic networks under a dissecting microscope. OCT imaging was validated against fluorescent microscopy, an established but contrast-agent-dependent lymphangiography technique, as well as histology. Fluorescent microscopy was performed with intradermal injection of FITC-dextran followed by imaging with the AxioZoom.V16 Stereo Zoom Microscope. Immunofluorescence staining was performed with an anti-LYVE1 (Lymphatic Vessel Endothelial Receptor 1) antibody.
Results: Comparing 3D OCT images and their 2D projections under normal and lymphedematous conditions showed significantly different networks. Quantification analysis revealed increased lymphatic vasculature dilation (~4X in vessel diameters, p&lt;0.01) and increased fluid accumulation (~3X in edematous regions, p&lt;0.05) under lymphedema conditions. Lymphatic vascular dilation and edema were confirmed by fluorescent microscopy and histology.
Conclusions: OCT is an emerging non-invasive volumetric imaging modality that can be adapted to visualize lymphatic vasculature within normal and lymphedematous tissues without the use of vascular contrast agents. Furthermore, OCT has the ability to quantify the degree of vessel dilation and edema accumulation.
Citation Format: Jennifer Y. Kwan, Valentin Demidov, Blake Jones, Wei Shi, Justin Williams, Costel Flueraru, Kenneth W. Yip, Fei-Fei Liu, Alex Vitkin. Detection and quantification of lymphedema using optical coherence tomography lymphangiography [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 1644.
Abstract 1700: Excessive ROS in ovarian cancer cells impairs anti-tumor capacities of immune cells through exosomal miR-155/PD-L1 pathway
Authors: Li Xiang , Wang Gao-chan , He Jun 
Published: September 2020

Abstract
Background and Objective: Genetic and metabolic alterations in cancer cells promote the sustained oxidative stress as reflected by excessive production of reactive oxygen species (ROS). We and other groups have identified that the ROS-sensitive microRNAs regulate the cancer cell response to ROS. However, it has yet to be determined how these miRNAs convey the ROS signal to downstream effectors and thus produce biological consequences. Accumulative evidence indicates that tumor-derived exosomes are emerging mediators of tumorigenesis. In this study, we aimed to investigate how ROS convey the oncogenic signals through cellular interactions via exosomes within the tumor microenvironment.
Methods and Results: Through NanoString nCounter miRNA analysis, we identified miR-155-5p as the most abundant miRNAs enriched in the exosomes derived from epithelial ovarian cancer (EOC) cells treated with a ROS scavenger N-acetylcysteine (NAC). Mechanistically, tumor exosomal miR-155-5p was transferred to tumor-associated macrophages (TAM), directly targeting PD-L1 to inhibit the infiltration of TAM into tumor microenvironment. The role of tumor-derived exosomal miR-155-5p was determined by co-culture experiments and gain or loss of function studies in vitro, and confirmed in xenograft mouse models in nude mice and immunocompetent mice. In addition, we established a 3D-3-culture system to entail the co-culture of NAC-treated EOC cell spheroids, TAM and T cells. We found that CD8+ T-cell ratio was increased and production of IFN-γ, IL-2, and TNF-α was promoted. What's more, the immunocompetent EOC mouse model was established and treated with NAC-modified mouse ovarian cancer cell-released exosomes. The results showed that NAC-modified tumor growth was significantly reduced compared to control group. Further analysis showed that miR-155-5p increased in TAM, while PD-L1 expression levels decreased in macrophages from tumors and spleens. Moreover, the T cell function was also augmented as evaluated by the expression of Ki-67 and Granzyme B on CD8+ T cells.
Conclusion: In conclusion, our study reveals a novel mechanism underlying PD-L1 expression in EOC. Ovarian cancer cells with excessive ROS levels release exosomes that mediate the interaction between cancer cells and immune cells; it is this interplay that produces an immunosuppressive tumor microenvironment by upregulation of PD-L1 in macrophages, and eventually contributes to the progress of EOC through the ROS/miR-155-5p/PD-L1 pathway.
Citation Format: Xiang Li, Gao-chan Wang, Jun He. Excessive ROS in ovarian cancer cells impairs anti-tumor capacities of immune cells through exosomal miR-155/PD-L1 pathway [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 1700.
Abstract 1717: Targeted NanoSpheres (TNS): An effective, non-toxic nano-formulated therapeutic platform for broad use in cancer treatment
Authors: Kang Hyunggyoo , Nagy Jon , Triche Timothy 
Published: September 2020

Abstract
Current cancer therapy relies on the use of cytotoxic agents (‘chemotherapy') that was developed over 50 years ago. These agents are very effective, but efficacy is limited by off-target toxicity to normal tissues. It is widely recognized that chemotherapy could be far more effective if higher doses could be delivered to the tumor and not to normal tissues. By refining the early formulations and after extensive testing, we developed a novel targeted nanoparticle called Targeted NanoSpheres or TNS. We showed this novel nano-formulated platform can overcome many deficiencies of conventional nanoparticles and therefore has enhanced potential as an effective delivery vehicle for virtually any type of cancer for which a suitable tumor cell surface antigen is present. We are exploring the development of NV103, a first-in-class anti-CD99 TNS (CD99-TNS/Ir), for the treatment of Ewing Sarcoma (EWS), a highly lethal pediatric and young adult bone and soft tissue tumor driven by a fusion protein, typically EWS/FLI1 in over 85% of cases. This platform is also being investigated for other types of cancer that either express CD99, or other tumor antigens like GD2 and B7-H3. In addition, a variety of payloads, including small molecules chemotherapeutics like irinotecan and doxorubicin, as well as plasmids, siRNA, ASOs, and mRNA, have been successfully incorporated and effectively delivered with documented superior anti-tumor effect. NV103 itself showed significant anti-tumor effect in hepatocellular carcinoma and prostate tumor cell lines and xenografts. In all cases, systemic toxicity is minimized by use of targeting antibodies that enhance tumor delivery while minimizing systemic exposure of normal tissues.
Citation Format: Hyunggyoo Kang, Jon Nagy, Timothy Triche. Targeted NanoSpheres (TNS): An effective, non-toxic nano-formulated therapeutic platform for broad use in cancer treatment [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 1717.
Abstract 1720: Preclinical treatment of pancreatic ductal adenocarcinoma using targetable self-assembled gemcitabine nanoparticles
Authors: Fu Zhang 
Published: September 2020

Abstract
The prognosis of pancreatic ductal adenocarcinoma (PDAC) patients remains poor, and new effective therapies are urgently needed. Cytotoxic gemcitabine (GEM) is currently used as a standard-of-care drug for PDAC treatment but its efficacy is greatly compromised mainly due to quick metabolism in the body and drug resistance. Here we introduce a new simple approach to effectively deliver GEM to PDAC-derived tumors through the combination of a prodrug strategy, nanoparticle formulation, and PDAC-specific targeting strategy. By covalently conjugating GEM with a hydrophobic moiety (i.e. linoleic acid) via amide linkage, the resulting GEM prodrug was conferred with an amphiphilic feature and showed spontaneously self-assembling behavior in aqueous solution. The self-assembled nanoparticles were spherical and monodispersed in water with a diameter less than 100 nm. To optimize the nanoparticles for the in vivo use, DSPE-PEG2k was used to co-assemble with the prodrug. A PDAC-specific peptide was further decorated on the particle surface to endow the nanoparticles with PDAC targeting effect. In vitro assays on PDAC cell lines showed that the modified GEM nanoparticles exhibited superior efficacy than free GEM, and the conjugation of the targeting peptide significantly facilitated the internalization of the nanoparticles into the targeted cancer cells. Furthermore, in vivo evaluation in xenograft-bearing animal models derived from either established cancer cells or patient tumor tissues showed that these GEM nanoparticles were remarkably effective to inhibit tumor growth with alleviated side effects. These data confirmed the effectiveness of our self-assembling GEM prodrug strategy. Moreover, this cost-effective strategy can potentially be applied broadly to many other chemotherapeutic drugs that are insufficiently effective because of pharmacologic obstacles.
Citation Format: Zhang Fu. Preclinical treatment of pancreatic ductal adenocarcinoma using targetable self-assembled gemcitabine nanoparticles [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 1720.