bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4634: Identifying and analyzing tumor subtypes using custom morphology markers for NanoString® GeoMx® Digital Spatial Profiler
Authors: Runyon Jessica , Baichwal Vijay , Stauffer Weston , Nievera Christian 
Published: April 2023

Abstract
Molecular subtyping studies have allowed the allocation of cancer into groups based on similar molecular, morphological, and clinical characteristics. Such studies are critical to help researchers identify actionable targets for drug design and biomarkers to predict therapeutic response. Based on multi-omics data, various approaches have been used to identify and analyze tumor subtypes and their correlation with tumor immunity and immunotherapy success. The NanoString GeoMx Digital Spatial Profiler is one approach that combines morphological context with spatial transcriptomics on a single tissue specimen. A critical step in this approach involves staining with morphology markers to identify relevant regions of interest (ROIs) for analysis. Yet, widespread adoption of GeoMx DSP has revealed a significant limitation, namely that researchers base transcriptional analysis of thousands of RNA targets on the spatial information provided by only a few morphology markers. Recent efforts have greatly expanded the availability of morphology markers to facilitate cell type-specific analyses. To evaluate the ability of this technology to selectively enrich specific cell types, we developed custom morphology markers to stain non-small-cell lung cancer (NSCLC) tissue specimens of various subtypes. Focusing on squamous cell carcinoma and adenocarcinoma, we stained with P40 and TTF-1 and transcriptionally profiled cell type-specific ROIs with the Cancer Transcriptome Atlas panel. Differential gene expression analysis of the whole transcriptome was performed using GeoMx DSP Analysis Suite software. The data reveal differences in gene expression in several key cancer pathways between tumor subtypes are correlated with the presence or absence of specific cell types. The data support the use of custom morphology markers for cell type stratification in tumor subtypes, providing more meaningful gene expression analysis. Ongoing work continues to explore the utility of this technology for cell type-specific gene expression analysis within different tumor subtypes.
Citation Format: Jessica Runyon, Vijay Baichwal, Weston Stauffer, Christian Nievera. Identifying and analyzing tumor subtypes using custom morphology markers for NanoString® GeoMx® Digital Spatial Profiler. [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 4634.
Abstract 4679: Molecular pathology and BTKi pharmacology of DLBCL-PDXs
Authors: Wang Jingjing , Wang Yueying , Qian Wubin , Xue Jia , Guo Sheng , Zhang Likun , Li Henry Qixiang 
Published: April 2023

Abstract
Diffuse large B-cell lymphoma (DLBCL), the largest subtype of non-Hodgkin’s lymphoma (NHL, ~40%), is a heterogeneous disease with diverse pathogenesis, represented by different subtypes/genotypes based on lymphoma related specific gene expression profiling according to cell-of-origin (COO) and/or mutation profiles, likely influencing their responses to drug treatment. Patient derived xenografts (PDXs) represent powerful experimental system to investigate heterogeneous molecular pathology, and their corresponding pharmacology of DLBCLs. We created a unique cohort of 19 PDXs representative of diverse subtypes of de novo DLBCL patients, along with 15 EBV transformed DLBCLs during xenografting, followed by comprehensive molecular pathological analysis, using “EBV scan”, COO and LymphGen algorithm. The 19 de novo DLBCL-PDXs were classified into activated B cell-like (7/19 ABC, including 2 EBV+), germinal center B-cell-like (4/19 GCB) and unclassified (8/19 including 4 EBV+); the 15 EBV transformed DLBCL include two ABC, one GCB and 12 unclassified. The de novo DLBCL-PDXs were also annotated as MCD, BN2, N1, A53, ST2, and unknown genotypes. Clustering and principal component analysis (PCA) clearly separated EBV+ DLBCL-PDXs (regardless of de novo DLBCL, EBV-associated, or EBV transformed DLBCLs) from the EBV− de novo DLBCL-PDXs, suggesting distinct molecular pathogenesis, while no apparent difference between the two EBV+ DLBCLs suggested the similar pathogenesis. The expanded mouse clinical trial of BTKi using drinking water administration of ibrutinib (0.16mg/ml) showed: 1) EBV− MCD and BN2 genotype are largely sensitive, suggesting these models’ dependency of chronic BCR signaling; 2) all EBV+ DLBCLs, regardless of the origin or genotypes, are all insensitive; 3) there are some cases of EBV− non-MCD/BN2 models being sensitive, likely due to the presence of certain related activating mutations. Molecular pathology analysis also demonstrated EBV+ PDXs, including significantly elevated BCL2 and down-regulated BCL6, in contrast to EBV− DLBCL-PDXs, implicating possible sensitivity to respective treatments. In summary, these observations in PDXs, some of which are consistent with the retrospective analysis of clinical trials, can be used to help develop BTKi and other treatment for DLBCLs.
Citation Format: Jingjing Wang, Yueying Wang, Wubin Qian, Jia Xue, Sheng Guo, Likun Zhang, Henry Qixiang Li. Molecular pathology and BTKi pharmacology of DLBCL-PDXs. [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 4679.
Abstract 4723: DNA G-quadruplex facilitates MYC enhancer-promotor interaction
Authors: De Lima Dieila Giomo , Guimarães Gustavo Narvaes , Bianco Bianca Caroline , De Souza Ana Paula , Planello Aline Cristiane 
Published: April 2023

Abstract
Background: G-quadruplexes (G4) are nucleic acid secondary structures formed in guanine-rich regions of DNA or RNA. The biological significance of G4 has been attributed to the regulation of gene expression, and more recently, to the stabilization and generation of enhancer-promotor interaction. Since G4 are enriched in the promoter region of the proto-oncogene MYC, we sought to investigate the role of G4 in stabilizing the enhancer-promoter loop using the locus 8q24 (hg38) 127,700,000-128,500,000 that contains the MYC gene as a model.
Methods: Two different cell lines were used, the spontaneously immortalized, non-oncogenic human epidermal keratinocyte (HaCaT), in which the enrichment of G4 in the MYC promoter was demonstrated, and the primary normal human epidermal keratinocyte (nHEK) that is depleted of G4 in MYC promoter. Both cell lines were exposed to the G4 selective stabilizer 360-A drug and the half-maximal inhibitory concentration (IC50) could be calculated. Gene expression was accessed by RT-qPCR and DNA methylation by Methylation-Sensitive High Resolution Melting (MS-HRM). Chromatin Conformation Capture (3C-qPCR) technique was performed interrogating the MYC gene (chr8:127,733,798-127,744,729) and the putative enhancer in the lncRNA PVT1 gene (chr8:127,914,509-127,922,393) to compare the frequency of promoter-enhancer interaction between the two cell lines.
Results: The HaCaT cells showed interaction between the MYC promoter and the distal region. The nHEK cells that are not enriched for G4 showed no promoter interaction with the distal region. The use of 360-A in IC50 did not change the results. The gene expression analysis of the MYC showed higher expression in HaCaT cells compared to nHEK. There was no difference in DNA methylation in the MYC promoter between the two cell lines.
Conclusions: The data suggest an important role of G4 for the interaction of the MYC promoter and downstream enhancer. Additional analyzes of other genomic regions enriched for G4 should be performed to confirm the mechanism.
Citation Format: Dieila Giomo De Lima, Gustavo Narvaes Guimarães, Bianca Caroline Bianco, Ana Paula De Souza, Aline Cristiane Planello. DNA G-quadruplex facilitates MYC enhancer-promotor interaction. [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 4723.
Abstract 4822: Signaling pathways associated with stress factors in gastrointestinal cancers
Authors: Sanchez Amayrani , Doxtater Kyle D. , Lopez Samantha , Leslie Sophia , George Elias , Dhevan Vijian , Jaggi Meena , Chauhan Subhash , Tripathi Manish K. 
Published: April 2023

Abstract
Gastrointestinal (GI) cancer affects various significant organs along the gastrointestinal tract, which contains several of the leading cancer-related deaths in the United States. According to the American Cancer Society, colorectal and liver cancers are among the top ten leading deaths due to cancer, ranking third and sixth, respectively. In the Rio Grande Valley region with a majority Hispanic population, colorectal cancer and liver have a higher occurrence than in the entire state of Texas. However, for many, a cancer diagnosis can worsen with stress, which is also a common occurrence within the Rio Grande Valley region due to 30% of its population living in poverty. Stress can cause changes to the immune system's functionality and the inflammatory response that could lead to insufficient surveillance for any potential oncogenicity. When the Hypothalamic-Pituitary-Adrenal (HPA) axis becomes activated by stress, it will release several stress hormones, such as leptin and cortisol, in response that can play a role in the progression and growth of cancer tumors. To further explore this relationship, hepatocellular carcinoma (HCC) cells and colorectal cancer (CRC) cells were treated with cortisol and leptin at various time points to create models mimicking acute and chronic stress exposure. Afterward, the mRNA mean fold change levels were obtained utilizing the RT-PCR method to determine the levels of each gene in various liver and colorectal cancer cell lines.Additionally, a kinase assay will provide further insight and evidence into the signaling pathway based on the results of the RT-PCR. The current results have shown an upregulation of lncRNA MALAT1, ZNF384, and YB-1 genes at varying degrees depending on the cell line, stress hormone, and duration of treatment. Consequently, these findings have shown an upregulation of oncogenic long non-coding RNA and transcription factors, presenting a signaling oncogenic pathway model by stress factors in HCC and CRC cell lines. Therefore, understanding the role of stress-factors in the oncogenicity and progression of cancer can aid in creating therapeutics for a population where stress can play a role in cancer disparity.
Citation Format: Amayrani Sanchez, Kyle D. Doxtater, Samantha Lopez, Sophia Leslie, Elias George, Vijian Dhevan, Meena Jaggi, Subhash Chauhan, Manish K. Tripathi. Signaling pathways associated with stress factors in gastrointestinal cancers. [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 4822.
Abstract 4842: Stress-induced mitochondrial adaptations in the polyaneuploid cancer cell state
Authors: Li Melvin , Kostecka Laurie G. , Amend Sarah R. , Pienta Kenneth J. 
Published: April 2023

Abstract
Metastatic cancer is responsible for 90% of cancer deaths and is incurable due to resistance to all systemic anticancer therapies. While the classic model of therapy resistance is described by the presence of pre-existing resistant clones from tumor cell heterogeneity, our lab proposes the polyaneuploid cancer cell (PACC) state as a survival mechanism that cancer cells access when exposed to environmental stress such as hypoxia and chemotherapy. Our preliminary data has shown that cells that enter the PACC state exhibit repeated whole genome doubling, an increase in cell size, and proliferative arrest. In addition, we observed that a subpopulation of PACCs can give rise to non-polyploid, proliferative progeny after release from chemotherapy, modeling cancer recurrence. We hypothesize that the PACC state drives therapeutic resistance and elimination of this adaptive state is key in tackling the incurability of cancer. Mitochondria are essential organelles that have multifaceted roles in the cellular stress response and drug resistance. They integrate metabolic pathways for ATP generation and macromolecule biosynthesis, regulate apoptotic cell death, and activate stress response mechanisms in presence of drug treatment. We found that cells in the PACC state increase mitochondrial biogenesis and live cell imaging with MitoTraker dyes indicate that they also have higher activity per mitochondria when compared to parental cells. Cells that accessed the PACC state also had higher levels of TCA cycle metabolites including citrate, isocitrate, alpha-ketoglutarate, succinate, fumarate, and malate, suggesting increased mitochondrial function. Future work includes analysis of mitochondrial morphology via live cell confocal microscopy and of mitochondrial function via metabolic flux analysis on glucose and glutamine metabolism of cells in the PACC state. Our eventual goal is to characterize how cells in the PACC state alter their mitochondrial structure and function to survive therapy. Identifying vulnerabilities of the PACC phenotype will enable new therapeutic approaches to overcome therapy resistance in cancer.
Citation Format: Melvin Li, Laurie G. Kostecka, Sarah R. Amend, Kenneth J. Pienta. Stress-induced mitochondrial adaptations in the polyaneuploid cancer cell state. [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 4842.
Abstract 4965: Targeting the mitotic kinesin, KIF18A, in chromosomally unstable cancers
Authors: Joseph James D. , Schutt Katherine , Fisher Kira , Queen Katelyn , Budington Olivia , Mao Weifeng , Liu Wei , Zhu Zhengqing , Zhang Xiangping , Xiao Yisong , Lai Kunmin , Gu Xiaohui , Stumpff Jason , Aswad Fred 
Published: April 2023

Abstract
Background: Chromosome instability (CIN), characterized by frequent and ongoing loss or gain of chromosome number, is commonly observed in tumor cells. Although long recognized as a vulnerability of cancer cells, potential CIN-selective therapeutic targets have only recently been discovered. Genetic studies from multiple groups have identified the mitotic kinesin, KIF18A, as selectively essential for the proliferation of CIN and aneuploid cells. By targeting KIF18A genetically and with novel small molecule inhibitors here we present data supporting KIF18A as therapeutic target in CIN tumors.
Methods and Materials: To explore the therapeutic potential of KIF18A, we evaluated the effects of KIF18A genetic depletion and small molecule inhibition in both CIN-positive and CIN-negative cell lines. Biochemical, cell proliferation and phenotypic assays were used to characterize the potency and cellular activity of reference and novel KIF18A small molecule inhibitors. Anti-tumor activity of KIF18A inhibitors was assessed in CIN-positive cell line xenograft models.
Results: In triple negative breast and colorectal CIN positive cancer cell lines siRNA mediated KIF18A knockdown and small molecule inhibition of the KIF18A ATPase activity both lead to a reduction in proliferation associated with an increase in mitotic index and multi-polar spindles. Consistent with KIF18A knockdown, KIF18A inhibition results in increased spindle length and chromosome alignment defects. Importantly, these effects are not observed with KIF18A knockdown or KIF18A inhibition in non-transformed, near diploid cells. In vivo, treatment of CIN-positive xenograft tumors with potent, novel KIF18A inhibitors results in robust anti-tumor activity with minimal impact on body weight.
Conclusions: Collectively our data support KIF18A as a therapeutic target and provide rationale for the continued development of potent selective small molecule KIF18A inhibitors for the treatment of CIN positive cancers.
Citation Format: James D. Joseph, Katherine Schutt, Kira Fisher, Katelyn Queen, Olivia Budington, Weifeng Mao, Wei Liu, Zhengqing Zhu, Xiangping Zhang, Yisong Xiao, Kunmin Lai, Xiaohui Gu, Jason Stumpff, Fred Aswad. Targeting the mitotic kinesin, KIF18A, in chromosomally unstable cancers. [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 4965.
Abstract 4981: The potent quadruplex-binding compound QN-302 down-regulates the S100P gene in in vitro and in vivo models of pancreatic cancer: a potential therapeutic target and biomarker for PDAC
Authors: Williams Nicole , Worthington Jenny , Ahmed Ahmed , Arshad Tariq , Neidle Stephen 
Published: April 2023

Abstract
The compound QN-302, a tetra-substituted naphthalene diimide (ND) derivative has been designed to have high affinity for G-quadruplex (G4) nucleic acids. It has single-digit nM anti-proliferative activity in a panel of human pancreatic cancer cell lines (Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644) and anti-tumor activity in xenograft, orthotopic and genetic (KPC) models for pancreatic cancer (PDAC). Its mode of action involves the targeting of G4-forming sites in promoter regions of cancer-associated genes, where their prevalence is over-represented compared to other genes. Transcriptome analyses of QN-302 in MIA-PACA2 cells have confirmed genes involved in cancer-associated pathways and carry G4 motifs in their promoters as targets. We have found that expression of the S100P gene, a well-authenticated indicator of PDAC disease and progression, is highly down-regulated in QN-302 treated cells. The S100P gene contains at least five putative G4 motifs, including a classic G4 promoter site just upstream of the transcription start site. We have observed that transcriptome analyses on tumor material from human PDAC patients, and those from poorly differentiated as well as more highly differentiated tumors, have shown that the S100P gene is highly over-expressed (especially in poorly differentiated tumors). We now report on gene expression analysis of S100P using control and treated tumor tissues from a therapeutic study in PDAC MIA-PACA2 xenografts in mice, by means of RT-qPCR and Western blot analyses. The data shows statistically significant dose-dependent decreases in expression of S100P at both the mRNA (to ca 25% of control values) and protein levels (to ca 22% of control values), giving added confidence to the concept that the S100P gene is a therapeutic target in PDAC and may also be useful as a marker of QN-302 response in future clinical use. QN-302 is bio-available at therapeutic doses and is well tolerated at these levels in the animal models. It is being developed for clinical evaluation by Qualigen Therapeutics Inc and is currently at the pre-IND stage.
Citation Format: Nicole Williams, Jenny Worthington, Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The potent quadruplex-binding compound QN-302 down-regulates the S100P gene in in vitro and in vivo models of pancreatic cancer: a potential therapeutic target and biomarker for PDAC. [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 4981.
Abstract 5131: Pulmonary influenza infection promotes the awakening of dormant metastatic breast cancer cells
Authors: Chia Shi Biao , Johnson Bryan , Aguirre-Ghiso Julio A. , Rincon Mercedes , DeGregori James 
Published: April 2023

Abstract
Breast cancer is the most common form of cancer and the second cancer-causing death in females. Although remission rates are high if detected early, survival rates drop substantially when breast cancer becomes metastatic. The most common sites of metastatic breast cancer are bone, liver and lung. Respiratory viral infections inflict illnesses on countless people. The latest pandemic caused by the respiratory virus, SARS-CoV-2, has infected more than 600 million worldwide, with documented COVID-related death upward of 1 million in the United States alone. Respiratory viral infections result in increased inflammation with immune cell influx and expansion to facilitate viral clearance. Prior studies have shown that inflammation, including through neutrophils, can contribute to dormant cancer cells reawakening and outgrowth. Moreover, inhibition of IL6 has been shown to decrease breast cancer lung metastasis in mouse models. However, how respiratory viral infections contribute to breast cancer lung metastasis remains to be unraveled. Using MMTV/PyMT and MMTV/NEU mouse models of breast cancer lung metastasis and influenza A virus as a model respiratory virus, we demonstrated that acute influenza infection and the accompanying inflammation and immune cell influx awakens and dramatically increased proliferation and expansion of dormant disseminated cancer cells (DCC) in the lungs. Acute influenza infection leads to immune influx and expansion, including neutrophils and macrophages, with increased proportion of MHCII+ macrophages in early time points, and a sustained decrease in CD206+ macrophages starting 6 days post-infection until 28 days after the initial infection. Additionally, we observed a sustained accumulation of CD4+ T cells around expanding tumor cells for as long as 28 days after the infection. Notably, neutrophil depletion or IL6 knockout reversed the flu-induced dormant cell expansion in the lung. Finally, awakened DCC exhibited downregulation of vimentin immunoreactivity, suggesting a role for phenotypic plasticity in DCC outgrowth following viral infection. In conclusion, we show that respiratory viral infections awaken and increase proliferation of dormant breast cancer cells in the lung, and that depletion of neutrophils or blocking IL6 reverses influenza-induced dormant cell awakening and proliferation.
Citation Format: Shi Biao Chia, Bryan Johnson, Julio A. Aguirre-Ghiso, Mercedes Rincon, James DeGregori. Pulmonary influenza infection promotes the awakening of dormant metastatic breast cancer cells. [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 5131.