bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6088: Charting new cancer dependencies with patient derived organoids
Authors: Neiswender James V. , Brenan Lisa , Bertea Tate , Guo Jimmy , Anderson Ashley , Wong Megan , Posner Zoe , Kapner Kevin , Hennessey Connor , Wie Sarah , Boyle Isabella , De Kegel Barbara , Dempster Joshua , Tseng Yuen-Yi (Moony) , Root David , Aguirre Andrew , Vazquez Francisca 
Published: April 2023

Abstract
The number of patients benefiting from precision cancer medicine (PCM) is very limited. The Cancer Dependency Map Initiative aims to dramatically accelerate PCM by systematically identifying the landscape of cancer vulnerabilities across all tumors. Genome-wide knockout screens have been performed in over 1000 cancer cell lines, but these have been sourced from historically derived models, leaving many cancers underrepresented. Advances have been made in model derivation by growing cells in 3D formats, such as organoids or spheroids. These models present an opportunity to screen new cancer types, but come with challenges that require a new pipeline. Here, we present a set of screens using a genome wide CAS12 library in organoid tumor models representing novel subtypes of pancreatic, esophageal, and gastric cancer, along with treatment-resistant breast, ovarian, and prostate cancer organoids. We show that genome-wide screening of these models is feasible and can be achieved with quality comparable to 2D cell lines. Our work uncovered a set of novel dependencies associated with cell-ECM interactions that have not previously been identified in 2D models. Our methods provide a framework for screening future patient derived 3D culture models and discovering vulnerabilities in new tumor types.
Citation Format: James V. Neiswender, Lisa Brenan, Tate Bertea, Jimmy Guo, Ashley Anderson, Megan Wong, Zoe Posner, Kevin Kapner, Connor Hennessey, Sarah Wie, Isabella Boyle, Barbara De Kegel, Joshua Dempster, Yuen-Yi (Moony) Tseng, David Root, Andrew Aguirre, Francisca Vazquez. Charting new cancer dependencies with 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 6088.
Abstract 6089: Identification of novel YAP/TAZ pathway regulators in the triple-negative breast cancer cell line MDA-MB231 using single-cell CRISPR screening
Authors: Berlak Mareike , Makowska Zuzanna , Klironomos Filippos , Kuehnlenz Julia , Kamburov Atanas , Steffen Andreas , Lange Martin , Nicke Barbara , Lesche Ralf , Staller Peter , Kopitz Charlotte , Naujoks Jan 
Published: April 2023

Abstract
The Hippo signaling cascade is a major pathway that integrates a broad spectrum of mechanosensory signals at the plasma membrane and regulates response via control of cell proliferation, self-renewal, differentiation, and apoptosis. Dysregulation of this pathway has been observed across a range of cancer types and results in an altered activity of its primary downstream effectors, the oncogenic transcription factors YAP/TAZ. For example, both germline and somatic loss-of-function mutations in the tumor suppressor gene NF2, a component of Hippo, induce hyperactivation of YAP/TAZ, transcriptional changes and ultimately result in tumor growth. The Hippo signaling pathway is an attractive target for drug discovery efforts, however, it is highly complex and still incompletely understood. Hence it is indispensable to get a deeper insight into the Hippo - YAP/TAZ signaling axis. To this end, we performed a genome-wide CRISPR knockout screen in the triple-negative breast cancer (TNBC) cell line MDA-MB231 (NF2LOF) expressing a YAP/TAZ reporter construct. We identified both negative and positive regulators of YAP/TAZ in breast cancer cells. In a second step, screening hits were further characterized in a focused single-cell CRISPR screen (Perturb-Seq), aiming at better understanding of the effects on YAP/TAZ activity regulation and downstream effects on gene expression. Here we present the technical details of our screening approaches and the results of perturbing known and novel regulators of YAP/TAZ on single cell level. We discuss the use of Perturb-Seq in the initial validation of hits from genome-wide screens and provide data that may serve as a basis for future drug discovery efforts, seeking for novel and effective treatments for triple-negative breast cancers and other malignancies with Hippo pathway alterations.
Citation Format: Mareike Berlak, Zuzanna Makowska, Filippos Klironomos, Julia Kuehnlenz, Atanas Kamburov, Andreas Steffen, Martin Lange, Barbara Nicke, Ralf Lesche, Peter Staller, Charlotte Kopitz, Jan Naujoks. Identification of novel YAP/TAZ pathway regulators in the triple-negative breast cancer cell line MDA-MB231 using single-cell CRISPR screening [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 6089.
Abstract 6233: Omacetaxine reduces c-MYC expression and demonstrates antitumor effects in osteosarcoma
Authors: Farrell Kristen B. , Thamm Douglas H. 
Published: April 2023

Abstract
Omacetaxine mepesuccinate (OMX), also known as homoharringtonine, is a protein translation inhibitor approved for use in chronic myeloid leukemia. Recent studies suggest OMX may be effective against other cancer types with high rates of protein translation, and may be successful against protein targets that are difficult to inhibit by reducing their translation rates. Using both canine and human osteosarcoma (OS) cell lines, we have investigated the efficacy of OMX against osteosarcoma and expression of c-MYC. OMX provides significant growth inhibition of OS cells with IC50 values in the low nanomolar range. OMX also reduces migration and invasion capabilities of OS cells. Strikingly, we observed reduction in levels of c-MYC protein in most canine and human OS cell lines after OMX exposure. This reduction was both dose and time dependent. We also investigated the efficacy of OMX against OS in an orthotopic mouse OS model. OMX is a promising candidate for treatment of OS in both dogs and humans, and potentially additional cancers dependent on c-MYC.
Citation Format: Kristen B. Farrell, Douglas H. Thamm. Omacetaxine reduces c-MYC expression and demonstrates antitumor effects in osteosarcoma [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 6233.
Abstract 6237: Small molecule screen identifies pyrimethamine as an inhibitor of NRF2-driven esophageal hyperplasia
Authors: Paiboonrungruang Chorlada , Xiong Zhaohui , Li Yahui , Bowman Brittany , Huang Zhi , Chen Vivian , Weissman Bernard , Williams Kevin P. , Major M Ben , Chen Xiaoxin 
Published: April 2023

Abstract
Objective: NRF2 is a master transcription factor that regulates the stress response. NRF2 is frequently mutated and activated in human esophageal squamous cell carcinoma (ESCC), which drives resistance to chemotherapy and radiation therapy. Therefore, a great need exists for NRF2 inhibitors for targeted therapy of NRF2high ESCC.
Design: We performed high-throughput screening of two compound libraries from which hit compounds were further validated in human ESCC cells and a genetically modified mouse model. Mechanism of action of one compound was explored by biochemical assays.
Results: Using high-throughput screening of two small molecule compound libraries, we identified 11 hit compounds as potential NRF2 inhibitors with minimal cytotoxicity at specified concentrations. We then validated two of these compounds, pyrimethamine and mitoxantrone, by demonstrating their dose- and time-dependent inhibitory effects on the expression of NRF2 and its target genes in two NRF2Mut human ESCC cells (KYSE70 and KYSE180). RNAseq and qPCR confirmed the suppression of global NRF2 signaling by these two compounds. Mechanistically, pyrimethamine reduced NRF2 half-life by promoting NRF2 ubiquitination and degradation in KYSE70 and KYSE180 cells. Expression of an Nrf2E79Q allele in mouse esophageal epithelium (Sox2CreER;LSL-Nrf2E79Q/+) resulted in an NRF2high phenotype, which included squamous hyperplasia, hyperkeratinization, and hyperactive glycolysis. Treatment with pyrimethamine (30mg/kg/day, p.o.) suppressed the NRF2high esophageal phenotype with no observed toxicity.
Conclusion: We have identified and validated pyrimethamine as an NRF2 inhibitor that may be rapidly tested in the clinic as a radiation and chemotherapy sensitizer for NRF2high ESCC.
Citation Format: Chorlada Paiboonrungruang, Zhaohui Xiong, Yahui Li, Brittany Bowman, Zhi Huang, Vivian Chen, Bernard Weissman, Kevin P. Williams, M Ben Major, Xiaoxin Chen. Small molecule screen identifies pyrimethamine as an inhibitor of NRF2-driven esophageal hyperplasia [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 6237.
Abstract 6705: Molecular detection of circulating cancer cells with cancer stem cell or mesenchymal characteristics in esophageal squamous cell carcinoma
Authors: Tan Zhen , Ko Josephine Mun-Yee , Yu Valen Zhuoyou , Ng Hoi Yan , Law Simon , Lung Maria Li 
Published: April 2023

Abstract
Esophageal squamous cell carcinoma (ESCC) is a clinically challenging disease that requires a multidisciplinary approach. Unfortunately, the scarcity of ESCC genomic data hinders the understanding of ESCC biology, disease progression and rational therapy design. Circulating tumor cells (CTCs), which are shed from the primary and metastatic tumors and then circulate within the peripheral vasculature, reflect the existing tumor heterogeneity. Here, we utilized the non-biased size-based CTC enrichment strategy in combination with the real-time RT-PCR to molecularly characterize the CTCs with cancer stem cell (CSC) or mesenchymal properties in ESCC. Comprehensive data from ESCC cell lines, mouse ESCC xenograft models and clinical ESCC peripheral blood samples emphasize the importance of TWIST1 (Twist Family BHLH Transcription Factor 1) in ESCC progression. Gain-of-function and loss-of-function analyses demonstrate that TWIST1 promotes cell migration, invasion and colony formation in ESCC cells. Moreover, positive TWIST1 expression is responsible for the chemoresistance of ESCC cells to Cisplatin and is correlated with poor overall survival in ESCC patients. In addition, we show that TWIST1 promotes malignant potential, including tumor growth, invasion and chemoresistance via the TWIST1-TGFBI-ZEB1 signaling pathway in ESCC. Meanwhile, the TWIST1-TGFBI-ZEB1 signaling pathway confers immunosuppressive conditions to the tumor microenvironment, which in turn contributes to EMT to promote tumor progression. Collectively, these findings indicate that TWIST1 has a novel role in ESCC carcinogenesis by regulating tumorigenicity and cancer stem cell properties that may be useful as a prognostic monitoring biomarker and a promising therapeutic target in clinical ESCC treatment.
Citation Format: Zhen Tan, Josephine Mun-Yee Ko, Valen Zhuoyou Yu, Hoi Yan Ng, Simon Law, Maria Li Lung. Molecular detection of circulating cancer cells with cancer stem cell or mesenchymal characteristics in esophageal squamous cell carcinoma [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 6705.
Abstract 6722: RNAScope in situ hybridization as a novel approach for the spatiotemporal assessment of RD3 mRNA expression in neuroblastoma
Authors: Somasundaram Dinesh Babu , Aravindan Sheeja , Yu Zhongxin , Baker Ashley , Aravindan Natarajan 
Published: April 2023

Abstract
Our recent investigations unveiled the transcriptional and translational loss of Retinal degeneration Protein 3 in neuroblastomas (NB) when compared to the healthy adult and fetal tissues. Further, our preclinical studies with patient derived cellular systems and mouse model of high-risk NB (HR-NB) demonstrated that RD3 loss orchestrates disease progression. More importantly, we defined the therapy pressure driven acquired loss of RD3 in neuroblastomas, its crucial function in the evolution of progressive disease (PD), and further defined the prognostic and predictive significance of RD3 loss in NB. In this study, we investigated the use of RNAScope as a sensitive and specific method for the evaluation of spatiotemporal RD3 transcriptional loss in NB. We investigated the expression of RD3 mRNA in FFPE NB (n = 100) tissues utilizing RNAScope with custom archived RD3 specific probes comparing it with the matched RD3 protein (IHC) expression patterns. With positive (PPIB) and negative (DapB) controls in place, our results displayed definite and specific RD3 mRNA expression in NB. We observed a statistically significant association of RD3 mRNA loss to the disease progression and poor clinical outcomes. Further, we observed significant correlation to the loss of RD3 transcription to the evolution of progressive disease. More importantly, the expression gradients of RD3 mRNA observed with RNAScope assay (compared in terms of no treatment vs progressive disease, primary vs metastatic disease, relapsed vs no relapse, favorable to unfavorable disease) illustrate the concordance with the RD3 IHC outcomes. Our results provide a reference basis for better RD3 mRNA readouts in NB, and more importantly identify the technically sound, adaptable (high throughput/single event, manual/automatic) RNAScope in situ hybridization assay as an alternate approach to detect spatiotemporal expression of RD3 mRNA. Together, the results provide a new, descriptive, and efficient platform, RNAScope for assessing spatiotemporal RD3 mRNA expression that could better inform disease prognosis and therapy response in children with NB.
Funding: This work was partially or in full, funded by Department of Defense DoD-CA210339 and Oklahoma Center for the Advancement of Science and Technology, OCAST-HR19-045.
Citation Format: Dinesh Babu Somasundaram, Sheeja Aravindan, Zhongxin Yu, Ashley Baker, Natarajan Aravindan. RNAScope in situ hybridization as a novel approach for the spatiotemporal assessment of RD3 mRNA expression in neuroblastoma. [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 6722.
Abstract 6729: Urea cycle metabolism is disturbed in Fibrolamellar carcinoma
Authors: Shirani Mahsa , Levin Solomon , Tomasini Michael D. , Knox James , Shebl Bassem , Requena David , Clark Jackson , Heissel Søren , Alwaseem Hanan , Surjan Rodrigo , Lahasky Ron , Molina Henrik , Lyons Barbara , Migler Rachael D. , Coffino Philip , Simon Sanford M. 
Published: April 2023

Abstract
In fibrolamellar hepatocellular carcinoma (FLC), hyperammonemic encephalopathy is a common occurrence and occasionally causes death. Using mass spectrometry, we quantitatively analyzed the proteomes of FLC patient’s tumor and adjacent normal, to find pathways that are changed in FLC. These data identified multiple proteins that were altered in the proteome, among these, enzymes involved in metabolism of ammonia. These results were confirmed with immunofluorescence demonstrating that these alterations occur in all tumor cells. These results suggest that FLC cells have defects in the two primary ammonia detoxification pathways in the liver, which are responsible for detoxification of 70% of the ammonia in the body: 1) consumption of ammonia by glutamine synthetase (GLUL), and 2) addition of ammonia by ornithine carbamoyltransferase (OTC) to the urea cycle. Additionally, they also generate extra ammonia because of upregulation of glutaminase (GLS). This was tested with a targeted metabolomics of the reactants and products of these enzymes. The results were consistent with both a loss of the two pathways for consumption of ammonia activation of a pathway for generating ammonia. This production of ammonia is consistent with the observation that surgical resection of fibrolamellar reduces the ammonia in patients. All FLC patients with hyperammonemic encephalopathy and documented urine test results showed increased urinary orotic acid, evidence of blockage of the OTC pathway. This study implies that hyperammonemic encephalopathy in FLC may require alternatives to commonly used therapies.
Citation Format: Mahsa Shirani, Solomon Levin, Michael D. Tomasini, James Knox, Bassem Shebl, David Requena, Jackson Clark, Søren Heissel, Hanan Alwaseem, Rodrigo Surjan, Ron Lahasky, Henrik Molina, Barbara Lyons, Rachael D. Migler, Philip Coffino, Sanford M. Simon. Urea cycle metabolism is disturbed in Fibrolamellar carcinoma. [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 6729.
Abstract 673: p38γ MAPK remodels tumor microenvironment facilitating breast cancer progression and brain metastasis
Authors: Yuan Xiangliang , Chen Hao-Nien , Badu-Nkansah Akosua , Duan Yimin , Yu Dihua 
Published: April 2023

Abstract
Major neoplastic diseases have high incidences of brain metastasis (BrM) which is a clinically dreadful consequence of advanced cancers with an abysmal prognosis. Unfortunately, our understanding of the biology and molecular mechanisms underlying BrM remains rudimentary. Improving our understanding of the pathogenesis of BrM will facilitate the rational development and prioritization of new therapeutic strategies. Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine protein kinases that are key players in various intracellular signaling pathways controlling many cellular processes, e.g., growth, differentiation, stress responses, and immune defense which have a key role in cancer progression. However, little is known regarding the role of MAPKs in the pathogenesis of BrM. Here, we report that p38γ mitogen-activated protein kinase (MAPK12) is overexpressed in multiple tumor types and associated with aggressive breast cancer progression and a poor outcome in BrM patients. Interestingly, we found that the lack of p38γ did not impact the proliferation of tumor cells ex vivo, but significantly reduced both the primary tumor growth and BrM in EO771 and other mammary tumor-bearing immunocompetent mouse models. Our preclinical data indicated that p38γ promoted tumor progression and BrM through remodeling tumor microenvironments in vivo. We have mapped the immune landscape of BrM lesions of EO771-bearing mice using high-dimensional single-cell profiling. Clearly, cytometry by time-of-flight (CyTOF) analysis of the BrM immune infiltrates revealed reprogramming of the immunosuppressive brain microenvironment toward a proinflammatory and antitumoral state with tumor-intrinsic p38γ depletion, as indicated by highly enriched dendritic cell (DC) and cytolytic T cell (CTL) populations in BrM. To explore the impact of p38γ depletion in breast cancer cells, we performed RNA sequencing on EO771 cells having p38γ knocked down versus the control cells. We found that p38γ knocked down led to the upregulation of pathways related to immune cell movement, thereby leading to an increased accumulation of antitumor immune cells in BrM. Together, our findings uncover an important role for tumor-intrinsic p38γ in shaping the brain immune microenvironment and underscore the potential of specific p38γ blockade in enhancing antitumor immunity for the treatment of breast cancer BrM.
Citation Format: Xiangliang Yuan, Hao-Nien Chen, Akosua Badu-Nkansah, Yimin Duan, Dihua Yu. p38γ MAPK remodels tumor microenvironment facilitating breast cancer progression and brain metastasis [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 673.
Abstract 6748: Tumor regression grade combined with post-therapy lymph node status: A novel independent prognostic factor for patients treated with neoadjuvant therapy followed by surgery in resectable, locally advanced gastroesophageal junction and gastric carcinoma
Authors: Yin Hongyan , Yao Qian , Jia Keren , Niu Dongfeng , Chong Xiaoyi , Li Yanyan , Feng Xujiao , Li Yilin , Shen Lin , Chen Yang 
Published: April 2023

Abstract
Background: Tumor regression grade (TRG) is a measure of histopathological response to neoadjuvant therapy (NAT). Post-therapy lymph node (ypN) metastasis was reported as a prognostic factor. However, the evaluation of the treatment effectiveness of NAT has not been well studied. Here, we explored whether TRG combined with ypN status could be a prognostic factor for gastroesophageal junction (GEJ) and gastric cancer (GC).
Methods: 376 patients with GEJ or GC receiving NAT in Peking University Cancer Hospital were retrospectively collected from January 1, 2003 to June 30, 2021. According to TRG and ypN status, patients were innovatively categorized into four groups: TRG0N0, TRG1-3N0, TRG0-1N+, and TRG2-3N+. We applied Kaplan-Meier method and log-rank test to examine the differences in disease free survival (DFS) and overall survival (OS) among four groups. Univariate and multivariate analyses were performed to elucidate the relationships between TRG combined with ypN status and prognosis.
Results: We observed significant survival differences among the four groups (P &lt; 0.001, respectively). Median DFS and OS of patients with TRG0N0, TRG1-3N0 and TRG0-1N+ were not reached, whereas median DFS and OS of patients with TRG2-3N+ were 17.37 months (95%CI, 14.14 to 20.60 months) and 39.97 months (95%CI, 27.05 to 52.89 months). TRG combined with ypN status was an independent predictor for both DFS (P &lt; 0.001) and OS (P &lt; 0.001) in multivariate analysis. Additionally, TRG combined with ypN status was significantly associated with different NAT (P &lt; 0.001). The TRG0N0 rate in patients accepting immunotherapy was 31.9%, which was the highest in all regimens.
Conclusion: Our results demonstrate that TRG combined with ypN status is a novel independent predictor of both DFS and OS in resectable, locally advanced GEJ and GC. Neoadjuvant immunotherapy achieved the highest TRG0N0 rate.
Citation Format: Hongyan Yin, Qian Yao, Keren Jia, Dongfeng Niu, Xiaoyi Chong, Yanyan Li, Xujiao Feng, Yilin Li, Lin Shen, Yang Chen. Tumor regression grade combined with post-therapy lymph node status: A novel independent prognostic factor for patients treated with neoadjuvant therapy followed by surgery in resectable, locally advanced gastroesophageal junction and gastric carcinoma [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 6748.