bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4593: Glioblastoma tumors that respond poorly to bevacizumab therapy show upregulation of an angiogenesis gene set
Authors: Lodha Roshan , Muller-Greven Gaelle , Guo Lydia , Gladson Candece 
Published: April 2023

Abstract
Glioblastoma (GBM) is the most common primary brain tumor in adults with a 15-month median survival, despite surgical-resection and radio-chemotherapy, and a recurrence rate of 90%. Despite improving survival in only a small percentage of patients, bevacizumab, a monoclonal antibody toward vascular endothelial growth factor-A, is frequently used to treat recurrent-GBM. To find predictors of poor-response to bevacizumab, we performed RNA-sequencing on multiple GBM patient-derived xenograft (PDX) tumors after orthotopic propagation in athymic nude mice. The study was repeated, and once PDX-tumors were established, mice were treated with bevacizumab and grouped based on survival. Bioinformatic-analysis of RNA-sequencing data demonstrated differential gene expression in tumors that were poor-responders to bevacizumab (no survival change) as compared to tumors that were good-responders (longer survival), along with upregulation of an angiogenesis gene set in poor-responders. Within this gene set, multiple genes known to be regulated by the early growth response 1 (EGR1) transcription factor were identified; CHRNA7 (cholinergic-receptor-nicotinic-α7-subunit) was selected for further study based on the reported role in promoting cancer cell migration and proliferation. Results were validated at the protein level using immunohistochemical staining. Additionally, Sry-box transcription factor-10 (SOX10) showed upregulation in poor-responders, potentially driven by impaired proteosome degradation. SOX10 is known to promote mural-cell coverage of neovasculature, cancer cell migration, and glioma development when cooperating with platelet-derived growth factor-B (PDGFB). In summary, GBM PDX-tumors with upregulated expression of an angiogenesis gene set and of two transcriptional regulators (EGR1 and SOX10) demonstrated a poor response to bevacizumab; upregulation of these genes could be used to predict bevacizumab response.
Citation Format: Roshan Lodha, Gaelle Muller-Greven, Lydia Guo, Candece Gladson. Glioblastoma tumors that respond poorly to bevacizumab therapy show upregulation of an angiogenesis gene set. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4593.
Abstract 46: High-plex spatial transcriptomic characterization of canine tumor tissue
Authors: Church Sarah E. , London Cheryl , Toedebusch Christine M. , Sutton Ben , Weigel Sarah , Piazza Erin 
Published: April 2023

Abstract
Background: Combination therapy to treat hematological and solid malignancies including chemotherapy, radiation, targeted and immunotherapy all hold huge potential for eliciting clinical responses. Informative pre-clinical testing of these approaches can be greatly facilitated using immune competent animals with spontaneous tumors. Pet dogs are immunologically outbred, immune competent and develop spontaneous tumors such as non Hodgkin’s lymphoma, glioblastoma, osteosarcoma, urothelial carcinoma and melanoma that share remarkable clinical, biological and genetic features with their human counterparts. As such, pre clinical testing of therapeutic approaches in dogs with cancer promises to accurately inform human clinical trial design. For this comparative approach to provide maximum information to accelerate human clinical translation of novel combination therapies and identify correlative biomarkers of therapeutic response, it is necessary to develop research tools for deep interrogation of the canine tumor microenvironment (TME). Here we present spatial transcriptomic analysis of multiple canine tumor and tissue types using GeoMx® digital spatial profiler (DSP) Canine Cancer Atlas (CCA) panel.
Methods: FFPE slides or tissue microarrays were used to profile tumor and normal tissue from canines. Each slide was stained with tissue specific immunofluorescent antibodies, including Pan-cytokeratin, CD45, Vimentin, IBA1, CD3, and/or CD68. Regions of interest were selected to assess the TME and normal tissue as possible. Slides were then run on the DSP using the CCA panel that contains 1900-canine specific genes using standard DSP methods.
Results: We were able to spatially detect over 1700 genes across multiple tissue types from canines, including osteosarcoma, glioblastoma, melanoma and normal tissues. Genes were detected in spatial compartments including malignant tumor, tumor stroma and normal tissue.
Conclusions: Together the GeoMx CCA allow for interrogation of the TME of multiple tumor types and has the potential to inform spatial biomarkers for response to therapy, as well as translate the effectiveness of these therapies to humans.
Citation Format: Sarah E. Church, Cheryl London, Christine M. Toedebusch, Ben Sutton, Sarah Weigel, Erin Piazza. High-plex spatial transcriptomic characterization of canine tumor tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 46.
Abstract 4644: Modeling the effects of niche specific microenvironmental changes on patient-derived organoids
Authors: von Schlichting Jennifer , Peidli Stefan , Morkel Markus , Blüthgen Nils , Simon Leona 
Published: April 2023

Abstract
Here, we present an approach to study the effects of microenvironmental changes on inter- and intratumoral heterogeneity using colorectal cancer (CRC) patient-derived organoids. We identified relevant paracrine interactions between stromal and tumor cells based on the expression of ligand-receptor pairs in single cell-RNAseq data of 12 colorectal cancer patients. Physiological relevance was tested by adding CRC stroma-derived ligands to patient-derived organoids. A systematic screening of different conditions was enabled by multiplexed mass cytometry and scRNAseq analysis. We also aimed to model the effects of a changing extracellular matrix composition, by supplementing the laminin/collagen IV rich environment with other known ECM proteins such as collagen I to identify the impact of a changing substrate on cell plasticity. We found that ECM parameters as well as niche specific paracrine factors affect proliferation, differentiation, and developmental trajectories of colorectal cancer patient-derived organoids. We hypothesize that supplementing patient-derived organoids in vitro with physiologically relevant factors and substrates may expand the phenotypic space in which organoid cells differentiate, resulting in a more versatile preclinical model system.Our data provide insights into non-genetic sources of inter- and intratumoral heterogeneity resulting in differential drug responses. Additionally, they can serve as guidelines to improve existing patient-derived colorectal cancer models and provide a feasible approach to address common limitations in organoid culture.
Citation Format: Jennifer von Schlichting, Stefan Peidli, Markus Morkel, Nils Blüthgen, Leona Simon. Modeling the effects of niche specific microenvironmental changes on patient-derived organoids. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4644.
Abstract 4647: Potential of TIMP3 regulating the versican status in the colorectal cancer tumor microenvironment
Authors: Field Anna , Kraus Sean , Matkowskyj Kristina , Deming Dustin , Pasch Cheri A. , Zhang Wei 
Published: April 2023

Abstract
Background: In colorectal cancer (CRC), versican (VCAN) accumulation has been found to negatively correlate with CD8+ tumor infiltrating lymphocyte (TIL) abundance and its proteolysis into versikine (Vkine) positively correlates with TIL abundance. TIMP3 has demonstrated the ability to inhibit several ADAMTS proteases able to cleave VCAN to Vkine. Here we investigate the correlation of TIMP3 accumulation in CRCs with the VCAN status and CD8+ T cell infiltration.
Methods: Matched primary and metastatic CRC samples from 156 patients who had resected oligometastatic CRC were stained for VCAN, Vkine, TIMP3, and CD8+ TILs. VCAN, Vkine, and TIMP3 were scored using an intensity binning system ranging from 0-3+ and T cells in the epithelium were reported per high power field (HPF). Tumors were designated as high (2 or 3+) or low (0 or 1) for both VCAN and Vkine and positive (+; 1-3) or negative (0) for TIMP3. Tumors designated VCAN low and Vkine high are considered VCAN proteolytic predominant (VPP) and all other combinations are considered VCAN proteolytic weak (VPW).
Results: Across the whole dataset, 52% of cancers were VCAN high and 24% were VPP. TIMP3 was detected in 33% of cancers. The frequency of TIMP3 was similar between primary and metastatic tumors (39% and 29%, respectively). Of the VCAN high cancers, 42% were TIMP3+ whereas 61% of the TIMP3+ samples are VCAN high. Of the Vkine high cancers, 44% were TIMP3+ and 36% of VPP cancers were TIMP3+. The prevalence of the VPP phenotype was similar between the TIMP3+ and negative cancers. Additionally, among the TIMP3+ samples 68% were Vkine high versus 46% in TIMP3 negative cancers (p=0.001). VCAN proteolysis correlates with higher CD8+ TIL abundance, thus we assessed the number of CD8+ TILs in TIMP3+ and negative tumors. The TIMP3+ cancers had a median of 2 CD8+ TILs/HPF and the TIMP3 negative cancers has a median of 3 CD8+ TILs/HPF. For VPP cancers, those that were also TIMP3+ had a median of 3 CD8+ TILs/HPF compared to TIMP3 negative cancers which had a median of 6 CD8+ TILs/HPF (p=0.2).
Conclusions: TIMP3 correlates with higher levels of VCAN accumulation but does not correlate with lower levels of proteolysis. Future studies are needed to better clarify the impact of TIMP3 and other mediators in regulating VCAN accumulation and proteolysis in the tumor microenvironment.
Citation Format: Anna Field, Sean Kraus, Kristina Matkowskyj, Dustin Deming, Cheri A. Pasch, Wei Zhang. Potential of TIMP3 regulating the versican status in the colorectal cancer tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4647.
Abstract 466: A potential pro-oncogenic role of SERPINB4 in melanoma
Authors: Chhabra Gagan , Shirley Carl A. , Robarge Rachel K. , Rizvi Hassan A. , Ndiaye Mary A. , Ahmad Nihal 
Published: April 2023

Abstract
Despite recent therapeutic advancements, melanoma remains one of the deadliest forms of skin cancer. Melanoma metastasis and recurrence is associated with the existence of heterogeneous cell populations within tumors that have the ability to both initiate metastatic programs and bypass immune recognition. Tumor cells achieve immune evasion by interfering with immune signaling to limit immune cell infiltration, allowing tumor cell proliferation and growth. SERPINB4 (Squamous Cell Carcinoma Antigen 2 or SCCA2), a serine protease inhibitor, has been shown to regulate the host immune response against tumor cells by inhibiting immune cell activity. Interestingly, certain cancer cell types have been reported to overexpress SERPINB4. However, the expression profile and the functional significance of SERPINB4 in melanoma is not known. In this study, employing ‘The Cancer Genome Atlas’ (TCGA), we found that SERPINB4 is overexpressed and significantly associated with lower overall survival in patients with melanoma. Next, employing a panel of human melanoma cell lines, we demonstrated that SERPINB4 is overexpressed in melanoma cells when compared to normal human melanocytes. In addition, CRISPR knockout of SERPINB4 in high-SERPINB4-expressing A375 melanoma cells resulted in a significant decrease in proliferation of melanoma cells in comparison to control cells. Conversely, forced overexpression of SERPINB4 in low-SERPINB4-expressing SK-MEL-2 and SK-MEL-28 melanoma cells significantly increased melanoma cell proliferation. Moreover, RT-qPCR analyses suggested that SERPINB4 overexpression significantly increased, while its knockout significantly decreased epithelial-mesenchymal transition (EMT) markers (N-cadherin, β-catenin, Snail and Zeb1) in melanoma cells. Additionally, SERPINB4 manipulation significantly modulated the expression of genes involved in antigen-presentation (MHC Class I molecules, HLA-A, -B, and -C) in melanoma cells. Taken together, our data suggested a potential oncogenic role of SERPINB4 in melanoma. Our study also suggested that SERPINB4 might be a promising therapeutic target for melanoma. Indeed, additional in vitro mechanistic and in vivo studies are needed to firmly establish the mechanism and therapeutic potential of SERPINB4 for melanoma management.
Citation Format: Gagan Chhabra, Carl A. Shirley, Rachel K. Robarge, Hassan A. Rizvi, Mary A. Ndiaye, Nihal Ahmad. A potential pro-oncogenic role of SERPINB4 in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 466.
Abstract 4684: Genomic and transcriptomic analysis of a diffuse pleural mesothelioma patient-derived xenograft library
Authors: Sen Triparna 
Published: April 2023

Abstract
Background: Despite recent treatment advances, malignant pleural mesothelioma (MPM) is an aggressive, recalcitrant malignancy. Currently, the histologic subtype (epithelioid/non-epithelioid/biphasic) is the primary prognostic factor; other potential biomarkers to guide therapeutic strategies remain elusive. Even with multimodality therapies, recurrence is high in early-stage disease. In the unresectable/metastatic setting, there are only two FDA-approved regimens, both in the first-line setting: cisplatin/pemetrexed and ipilimumab/nivolumab. Unfortunately, most who respond to first-line treatment experience disease progression within a year. Therapeutic and diagnostic advances in DPM are hindered by a paucity of well-annotated preclinical models which can faithfully recapitulate the complex genomic interplay of the disease.
Methods: We established a library of patient-derived xenografts (PDX) from patients with DPM. We performed multi-omic analyses on available PDX and patient samples to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes. Targeted next-generation sequencing (NGS; MSK-IMPACT), immunohistochemistry, and histologic subtyping were performed on all available samples. RNA-sequencing was performed on all available PDX samples. Clinical outcomes and treatment history were annotated for all patients. Platinum-doublet progression free survival (PFS) was determined from the start of chemotherapy until radiographic/clinical progression and grouped into &lt; or ≥ 6 months.
Results: The mutational landscapes of PDX models strongly correlated with paired tumor samples. There were some differences in CDKN2A/B mutations and relative enrichment of NF2 with fewer BAP1 alterations, the significance of which is being investigated. When compared by histological subtype, we observed an upregulation of genes involved in NOTCH and EMT signaling in the epithelioid models. Models derived from patients with shorter overall survival or poor response to platinum doublet had higher expression of WNT/β-catenin signaling, hedgehog pathway, and epithelial-mesenchymal transition signaling as well as downregulation of immune-activation pathways, including type I and II interferon signaling and inflammatory response pathways.
Conclusions: This library of MPM PDXs, the largest to date, effectively mimics human disease and provides unprecedented insight into the genomic, transcriptomic, and protein landscape of MPM. These PDX models will inform future clinical investigations and provide an important new preclinical resource.
Citation Format: Triparna Sen. Genomic and transcriptomic analysis of a diffuse pleural mesothelioma patient-derived xenograft library. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4684.
Abstract 4696: Characterizing CD39 and CD73 cell subtypes in the tumor microenvironment using MultiOmyx
Authors: Todorov Courtney , Gallagher Kevin , Wortman Juliana , Nunns Harry , Parnell Erinn , Leones Eric , Yeung Elaine , Russell Blair , Sahafi Flora , Au Qingyan 
Published: April 2023

Abstract
CD39 and CD73 are membrane bound enzymes that function together to convert extracellular adenosine 5’-triphospate (ATP)/adenosine diphosphate (ADP) into adenosine. CD39 first catalyzes ATP/ADP into adenosine monophosphate (AMP), which is then converted by CD73 into adenosine. Accumulation of extracellular adenosine creates an immunosuppressive tumor environment and facilitates tumor growth and metastasis. Conversely, the presence of ATP promotes a pro-inflammatory, tumor-suppressive environment. Suppression of CD73/CD39 activity and reduction of extracellular adenosine has been shown to support an antitumor immune response. Therefore, the targeting of CD73 and CD39, both individually as well as in combination with immune checkpoint inhibitors for biomarkers such as PD-1 and CTLA-4, is an emerging strategy for cancer therapeutics. CD73/CD39 have been described in multiple cell types, including tumor cells, fibroblasts, endothelial cells, tumor infiltrating lymphocytes (TILs), myeloid cells, and natural killer (NK) cells. While known to be expressed on multiple cell types, the spatial characterization of CD39 and CD73 in the tumor microenvironment (TME) is still poorly understood. Characterizing the diversity of active CD73 and CD39 populations in the tumor environment will help improve development of targeted therapies for cancer treatment. The multiplex immunofluorescence (mIF) platform MultiOmyx will be used to define the distinct populations of cells expressing CD73 and/or CD39 in the TME. MuliOmyx is a proprietary mIF platform for the visualization and characterization of up to 60 protein biomarkers in a single FFPE section. Herein we report the design and use of a novel panel of commercially-available antibodies broad enough to characterize CD39 and CD73 subpopulations in the TME of a variety of tumor indications including lung, prostate, and colon cancer. Using this panel in combination with proprietary deep-learning based image analysis, CD39 and CD73 positive cells can be characterized into different immune and TME subtypes. Understanding of the variety and phenotype of CD39 and CD73 expressing cells in the TME is crucial to define the populations being targeted by therapies for cancer treatment.
Citation Format: Courtney Todorov, Kevin Gallagher, Juliana Wortman, Harry Nunns, Erinn Parnell, Eric Leones, Elaine Yeung, Blair Russell, Flora Sahafi, Qingyan Au. Characterizing CD39 and CD73 cell subtypes in the tumor microenvironment using MultiOmyx. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4696.
Abstract 4733: Effect of KDM6A mutation in bladder cancer
Authors: Le Ninh B. , Qiu Hong , Fink Emily E. , Sona Surbhi , Ting Angela H. , Lee Byron H. 
Published: April 2023

Abstract
As of 2020, bladder cancer is the tenth most common cancer in the world, with a heavier toll exerted on males. Its higher tumor recurrence and progression rates cause major treatment challenges. One of the most frequent mutations in bladder cancer is in lysine-specific demethylase 6A (KDM6A). This gene encodes for ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX), which catalyzes the demethylation of di- and tri- methylated histones H3 lysine 27 and works as part of “COMPASS-LIKE” protein complexes to coordinate many transcriptional processes. The molecular basis for how KDM6A mutations promote carcinogenesis is still under investigation. In this study, we use single-cell RNA sequencing data from bladder cancers with and without KDM6A mutations in both human and mice to examine the effects of KDM6A mutations on the cellular composition and gene expression of tumor and normal bladders. In mice without tumors, KDM6A mutations seem to correlate with enrichment of macrophages in the bladder tissue microenvironment. The opposite is true, however, in the presence of tumors, as there were not only more macrophages but also more dendritic cells in wildtype mice. This pattern was also observed in human, suggesting differences in immune infiltrates in the tumor microenvironment are part of the phenotype of KDM6A mutation. Lastly, KDM6A mutations may also impact urothelial cell states at baseline, as KDM6A KO mouse bladders contain higher proportions of intermediate cell populations compared with their wildtype counterparts. Together, these observations contribute to a better understanding of the role KDM6A plays in bladder cancer.
Citation Format: Ninh B. Le, Hong Qiu, Emily E. Fink, Surbhi Sona, Angela H. Ting, Byron H. Lee. Effect of KDM6A mutation in bladder cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4733.