bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1519: ALDH1A1 enhances micro homology-mediated end joining by increasing POLQ expression
Authors: Lavudi Kousalya , Banerjee Ananya , Cai Shurui , Li Na , Bai Xuetao , Qi-En Wang 
Published: June 2022

Abstract
Aldehyde dehydrogenase (ALDH) is a superfamily of 19 known enzymes that participated in the metabolism of endogenous and exogenous aldehydes. ALDH1A1 is a major subtype contributing to high ALDH activity out of all ALDH isoforms and plays a critical role in the maintenance of cancer stem cells. Our previous studies have shown that ALDH1A1 is able to reduce the sensitivity of BRCA2-/- ovarian cancer cells to PARP inhibitors by enhancing microhomology-mediated end joining (MMEJ). MMEJ uses 5-25 base pair micro homologous sequences to align the broken strands before joining, and this repair pathway requires DNA polymerase θ (Pol θ, encoded by POLQ). Here we show that ALDH1A1 can increase the expression of Pol θ, at both mRNA and protein levels, in ovarian cancer cell lines. ALDH1A1 is reported to catalyze the production of all-trans retinoic acid (ATRA), which can bind to the retinoic acid receptor (RAR), and promote transcription of the downstream target genes that possess retinoic acid response element (RARE) in their promoter regions. Interestingly we identified several RAREs in the promoter region of the POLQ gene. Thus, we hypothesized that ALDH1A1 promotes Pol θ expression via activation of the RAR signaling pathway. We found that ATRA and RAR agonist (CH55) increased but pan RAR antagonist (AGN193109) treatment decreased the expression of POLQ, indicating that the RAR pathway is involved in the transcription of POLQ. We also demonstrated that RARα can bind to the promoter region of Pol Q, activation of RAR signaling by treatment with ATRA or CH55 increased the enrichment of K27 acetylated histone H3 in this promoter region. Moreover, we showed that mutated ALDH1A1 lacking the enzyme activity was unable to enhance POLQ transcription. These data suggest that ALDH1A1 enhances the Pol Q expression by increasing the production of ATRA which further activates the RAR signaling pathway.
Citation Format: Kousalya Lavudi, Ananya Banerjee, Shurui Cai, Na Li, Xuetao Bai, Wang Qi-En. ALDH1A1 enhances micro homology-mediated end joining by increasing POLQ expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1519.
Abstract 1543: Regulatory role of miR-410 in prostate cancer
Authors: Sreekumar Amritha , Patel Nikhil , Saini Sharanjot 
Published: June 2022

Abstract
Prostate cancer (PCa), a leading cause of male cancer related mortality, is dependent upon androgens acting via androgen receptor (AR) signaling. Androgen targeted therapies are often used as the first line of treatment for prostate cancer that are effective initially. However, PCa eventually progresses to castration-resistant stage that has limited treatment options. Castration-resistant prostate cancer (CRPC) is treated by second generation of AR pathway inhibitors such as Enzalutamide and Abiraterone. Resistance to these agents develop owing to various mechanisms such as evolution to androgen-independent neuroendocrine prostate cancer (NEPC). In this study, we examined the potential role of miR-410 in different stages of prostate cancer. Analyses of miR-410 in PCa clinical samples and patient-derived xenograft (PDX) models showed that miR-410 is frequently upregulated in PCa. Its expression was further increased in CRPC cases with neuroendocrine differentiation (NED). We examined the functional role of miR-410 by stably expressing miR-410 in androgen dependent and androgen independent cell lines. Our data suggests a context dependent role of miR-410 in prostate cancer cell lines. In androgen independent cell line, miR-410 plays an oncogenic role by impacting epithelial to mesenchymal transition (EMT) via directly targeting SNAIL. Also, it was found to increase the expression of neuronal genes such as Synaptophysin and neural transcription factor BRN2. However, in androgen dependent cell line, miR-410 was found to target PTEN. In conclusion, our data suggests that miR-410 play an important regulatory role in prostate cancer with effects on EMT and neuronal differentiation programs.
Citation Format: Amritha Sreekumar, Nikhil Patel, Sharanjot Saini. Regulatory role of miR-410 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1543.
Abstract 1557: Defining the regulatory effects of candidate oncogenic non-coding RNA LINC00473 in fibrolamellar carcinoma
Authors: Ma Rosanna K. , Kanke Matt , Vakili Khashayar , Sethupathy Praveen 
Published: June 2022

Abstract
Fibrolamellar carcinoma (FLC) is a rare form of liver cancer that disproportionately affects adolescents, usually presents at advanced stages with no known risk factors or serum biomarkers, and exhibits high intrinsic drug resistance. The signature genetic event of FLC was identified in 2014 as a ~400kb heterozygous deletion resulting in the DNAJB1-PRKACA (or DP) fusion oncogene. The DP fusion occurs in over 80% of FLC patients and is sufficient for tumorigenesis in mice. Targeting DP pharmacologically has proved challenging; therefore, we performed multiple genome-scale studies to identify and target candidate downstream effectors that drive FLC development and progression. LINC00473, a primate-specific long non-coding RNA (lncRNA), emerged as a top candidate oncogene. Multiple models reveal strong induction of LINC00473 in FLC, including: (1) primary tumor relative to normal liver; (2) FLC patient-derived xenograft tumors (PDX); and (3) a newly developed FLC cell line derived from the PDX. Importantly, LINC00473 is upregulated in response to the fusion oncogene in HEK293 cells that express DP via CRISPR/Cas9-mediated deletion, and is dramatically downregulated in FLC cells upon DP knockdown by three independent siRNAs (collaboration with Alnylam Pharmaceuticals, Inc). Stable in vitro suppression of LINC00473 using two distinct short hairpin RNAs results in RNA depletion and significant reduction of cell proliferation. Concordantly, the stable overexpression of LINC00473 in FLC cells leads to a robust increase in gene expression and elevated cell proliferation. These data suggest that LINC00473 is a key regulator of FLC cell growth and survival. Next, to investigate the regulatory effects of LINC00473, we first determined that the lncRNA is enriched in the nucleus of FLC cells using subcellular fractionation followed by qRT-PCR, suggesting a role in transcriptional regulation. To investigate if LINC00473 acts downstream of the DP fusion to regulate gene expression programs mediating FLC phenotypes, we performed RNA-seq on FLC cells that harbor stable LINC00473 knockdown or overexpression. These data enabled us to define the altered gene expression profiles that result from LINC00473 dysregulation. Overall, this study elucidates the functional role of LINC00473 in the progression of FLC and helps advance the field by providing important biological insights into this disease.
Citation Format: Rosanna K. Ma, Matt Kanke, Khashayar Vakili, Praveen Sethupathy. Defining the regulatory effects of candidate oncogenic non-coding RNA LINC00473 in fibrolamellar carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1557.
Abstract 1573: Paradoxical roles of peritumoral myofibroblasts in intrahepatic cholangiocarcinoma growth and metastasis
Authors: Tian Cheng , Li Liyuan , Li Yizhen , Yang Wentao , Fan Li , Brown Anthony , Morrison Michelle , Yang Jun J. , Glazer Evan S. , Zhu Liqin 
Published: June 2022

Abstract
Background and Rationale: Intrahepatic cholangiocarcinoma (iCCA) is an aggressive type of primary liver cancer characterized by its highly desmoplastic stroma. Compared to the ample knowledge on the protumorigenic functions of iCCA intratumoral myofibroblasts (iMFs), little is known about the activation status of MFs in the tumor-surrounding liver (peritumoral myofibroblasts, pMFs) and their potential role in iCCA development.
Results: We examined MF activation in both patient iCCA tumors and an iCCA orthotopic allograft mouse model. We found there was a significant, tumor-induced activation and accumulation of pMFs at the tumor border. Using an in vitro spheroid coculture system, we confirmed that iCCA-liver interaction induced rapid pMF activation at their interface. We found that MFs mixed within tumor spheroids as iMFs had a pro-proliferative effect on iCCA tumor cells similar to the previous reports. However, when the same MFs were seeded around iCCA spheroids as pMFs, they exerted a strong suppressive effect on tumor cells growth. Interestingly, prolonged iCCA-pMF coculture elicited marked tumor cell invasion and dissemination which did not occur in iCCA-iMF coculture. We found vascular cell adhesion protein 1 (Vcam1), a glycoprotein that has been implicated in solid tumor metastasis, was part of the dynamic regulation of tumor cell behaviors by iCCA-pMF interaction. Vcam1 was upregulated in the tumor cells at the early, growth-suppressing phase of iCCA-pMF interaction both in vitro and in vivo, and was then downregulated in tumor cells when they started to disseminate. Systemic blocking of Vcam1 activity in iCCA allograft mouse models using a Vcam1 neutralizing antibody slowed the primary tumor growth but promoted tumor cell dissemination.
Conclusion: Our data suggest that pMFs are beyond simple pro- or anti-tumorigenic in iCCA development. iCCA development induces rapid activation and accumulation of pMFs at the tumor border which suppress tumor growth at early stage but eventually elicit tumor cell dissemination at late stage.
Citation Format: Cheng Tian, Liyuan Li, Yizhen Li, Wentao Yang, Li Fan, Anthony Brown, Michelle Morrison, Jun J. Yang, Evan S. Glazer, Liqin Zhu. Paradoxical roles of peritumoral myofibroblasts in intrahepatic cholangiocarcinoma growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1573.
Abstract 1611: Temporal recapitulation of genome instability in an iPSC model of osteosarcoma
Authors: Becklin Kelsie Lynn , Madden Rebecca , Mills Lauren , Thue Nicole , Carroll Nathan , DeFeo Anthony , Moriarity Branden , Webber Beau 
Published: June 2022

Abstract
Osteosarcoma (OS) is characterized by widespread genomic instability, with cellular transformation associated with extensive structural (SV) and copy number variation (CNV). TP53 and RB1 mutations contribute to the initiation and maintenance of genome instability, which serves as a key driver of relapse. Significant effort has been made to model OS genome instability; however, current models have limited capacity to recapitulate genomic instability in real time. To model OS initiation and development, TP53 and RB1 mutations were installed in human iPSC using CRISPR/Cas9, followed by differentiation to mesenchymal (iMSC) and osteoblast (iOB) lineages in vitro. Functional assays of transformation were then conducted at intermediate stages of development for each genotype. Compared to isogenic WT controls, TP53-/- and TP53-/-/RB1-/- iOB exhibited increased proliferation, whereas anchorage independent growth was only observed in TP53-/-/RB1-/- iOB. Overexpression of cMYC and hRAS significantly increased the magnitude of these results in iOB. In contrast to iOB, TP53-/-/RB1-/- iMSC did not form colonies without cMYC and hRAS overexpression. To evaluate this phenomenon in vivo, iMSC and iOB were injected into the calcaneal bone of immunodeficient mice. Consistent with our in vitro observations, TP53-/-/RB1-/- and TP53-/-/RB1-/-+cMYC/hRAS iOB, and TP53-/-/RB1-/-+cMYC/hRAS iMSC gave rise to tumors. Histological evaluation of MSC-derived tumors revealed a largely undifferentiated pleomorphic phenotype, with a progressive increase in complexity in tumors derived from later stage iOB. Global gene expression signatures of xenografted tumors bore a striking similarity to OS patient samples compared to other pediatric tumors. In follow-on experiments, a progressive increase in cytogenetic abnormalities were observed in mutant but not WT iMSC, which became more pronounced in mutant iOB and correlated with a transformed phenotype. We are currently evaluating the temporal kinetics of this process, including through the use of low-coverage whole genome sequencing to elucidate the existence of recurrent patterns. These data highlight the utility of our iPSC approach as a novel model of OS, allowing for the first time the ability to study the evolution of genome instability in real time. We envision that this approach may uncover heretofore undiscovered common patterns underlying the seemingly chaotic nature of OS genomes, providing new opportunities for therapeutic intervention.
Citation Format: Kelsie Lynn Becklin, Rebecca Madden, Lauren Mills, Nicole Thue, Nathan Carroll, Anthony DeFeo, Branden Moriarity, Beau Webber. Temporal recapitulation of genome instability in an iPSC model of osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1611.
Abstract 1623: AXL-STAT3 targeting of lung tumor microenvironments
Authors: Taverna Josephine Amalia , Hung Chia-Nung , Chen Meizhen , Michalek Joel , Chen Chun-Liang , Kirma Nameer , Chou Chih-Wei , Tan Xi , Wang Chiou-Miin , Zhao Zhang , Nguyen Duy , DeArmond Daniel , Huang Tim 
Published: June 2022

Abstract
Dynamic tumor microenvironments contain a myriad of cell subtypes, each providing a unique functionality in support of malignant growth. To prepare a metastatic niche, a tight network must be present to coordinate the delivery and sharing of co-stimulatory signals among malignant tumor epithelial cells and supportive host cells. AXL and STAT3 cascades are critical components of intracellular signaling networks, as they translate multiple external stimuli into specific cellular responses. Single cell profiling of lung tumors reveals that AXL collaborates with STAT3 to create a unified tumor ecosystem favoring hybrid epithelial-to-mesenchymal transition states of lung epithelial cells, pro-tumorigenic remodeling of fibroblasts and M2 polarization of macrophages. Disruption of AXL-STAT3 circuit with AXL inhibitor and JAK inhibitor not only compromises this co-dependency in A549 lung cancer cells implanted in xenograft mice, but also limits their ability to conscript murine fibroblasts, macrophages and other immune cells that form a symbiotic community for tumor growth. Our preclinical work suggests that combined targeting of AXL-STAT3 circuit could disturb the communication among diverse cell subtypes in the lung tumor microenvironment, thus limiting the metastatic progression. Our co-culture studies reveal that AXL signaling in lung cancer cells and fibroblasts exerts an IL-11 mediated paracrine effect on macrophages to sustain STAT3 signaling for M2 polarization and cancer stemness mimicry. In vivo drug testing in A549 mouse xenograft model demonstrate that AXL-STAT3 inhibition leads to reduction in host cell recruitment and attenuates M2 polarization of macrophages and pro-tumorigenic remodeling of stromal fibroblasts. AXL-STAT3 targeting to dismantle lung tumor microenvironments is a promising therapeutic strategy and may establish new treatment paradigms for patients with lung adenocarcinoma.
Citation Format: Josephine Amalia Taverna, Chia-Nung Hung, Meizhen Chen, Joel Michalek, Chun-Liang Chen, Nameer Kirma, Chih-Wei Chou, Xi Tan, Chiou-Miin Wang, Zhang Zhao, Duy Nguyen, Daniel DeArmond, Tim Huang. AXL-STAT3 targeting of lung tumor microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1623.
Abstract 1636: A new invasive zebrafish model of Ewing sarcoma reveals EWSR1-FLI1-driven dysregulation of heparan sulfate proteoglycan metabolism in developing tumors
Authors: Vasileva Elena , Warren Mikako , Triche Timothy , Amatruda James 
Published: June 2022

Abstract
Ewing sarcoma (ES) is a malignant bone and soft-tissue tumor with an extremely poor prognosis for patients with metastatic or relapsed disease. ES is characterized by the appearance of a chimeric fusion oncogene, most frequently EWSR1-FLI1 (EF1). In the absence of a representative in vivo model the role of tumor cell/microenvironmental interactions in tumor initiation and progression remains a subject of constant debate. To address these concerns, we developed an innovative Cre-inducible model of ES in zebrafish which allows broad mosaic expression of human EF1 in zebrafish, which causes rapid onset of ES at high penetrance. This invasive model allows study of the behavior of GFP-labeled cancer cells during tumor initiation and progression, in a complex developmental context which is not currently possible in mammals. We found that observed tumors express canonical EF1 target genes and stain for known ES markers including CD99. Proteomic analysis revealed that EF1 expression affects heparan sulfate proteoglycan (HSPG) metabolism and activates HSPG-mediated ERK signaling in EF1 expressing cells, promoting cancer cell survival and proliferation. Proteoglycans are key regulators of signaling of cell surface receptors, playing an essential role in cell-to-cell communication. Targeting heparan sulfate proteoglycans with the specific heparan sulfate antagonist Surfen reduces ERK1/2 signaling and decreases tumorigenicity of ES cells in vitro and in vivo. These results highlight the important role of the extracellular matrix in ES tumor growth and the potential of agents targeting proteoglycan metabolism as novel therapies for this disease.
Citation Format: Elena Vasileva, Mikako Warren, Timothy Triche, James Amatruda. A new invasive zebrafish model of Ewing sarcoma reveals EWSR1-FLI1-driven dysregulation of heparan sulfate proteoglycan metabolism in developing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1636.
Abstract 170: Development of diacylglycerol kinase assays to facilitate isoform specific inhibitor discovery
Authors: AbdulSalam Safnas F. , Eason Mia M. , Fowle Holly A. , Stuart Anna L. , Horiuchi Kurumi Y. 
Published: June 2022

Abstract
Diacylglycerol (DAG) and phosphatidic acid (PA) are two key second messengers in signaling and metabolic pathways. Diacylglycerol kinase (DGK) phosphorylate DAG to produce PA, acting as a central switch between the various signal transduction pathways activated by these second messengers. Ten DGK isoforms (α, β, γ, δ, ε, ζ, η, θ, ι, and κ) have been identified and categorized into five classes based on their structural features. DGKα is highly expressed in several cancers including hepatoma, lymphoma and melanoma, and has been shown to promote cancer survival by positively regulating proliferative activity through several signaling pathways, attracting interest to DGKα as a potential therapeutic target. DGKα and ζ are expressed at high levels in T cells, and shown to promote T cell anergy, pointing to inhibition of these DGK isoforms as a means of enhancing T cell anti-tumor activity and restoring T cells function. Several DGK isoforms have also been implicated in disease contexts such as hypertension, autoimmunity, type II diabetes, epilepsy, and bipolar disorder. Current DGK inhibitor discovery efforts are focused on DGKα and ζ, but to our knowledge no compounds have proceeded to clinical trial-to date. To facilitate these efforts, we have developed a DGK screening panel including compound profiling assays for all DGK isoforms. This is an essential tool for identification of potent and isoform selective inhibitors towards therapeutically relevant DGK isoforms. Further, we present kinetic characterization of all isoforms and lipid substrate specificity studies of DGKs.
Citation Format: Safnas F. AbdulSalam, Mia M. Eason, Holly A. Fowle, Anna L. Stuart, Kurumi Y. Horiuchi. Development of diacylglycerol kinase assays to facilitate isoform specific inhibitor discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 170.
Abstract 1726: Novel, high-throughput multiplexed immunofluorescence staining method for assessing spatial relationships of immuno-oncology biomarkers in whole slide FFPE tissue
Authors: Schaefer Rachel , Liu Linying , McLane Michael , Perez Oscar , Circelli Jacob , Coltharp Carla , Zheng Yi 
Published: June 2022

Abstract
As cancer research has progressed, the role of the immune system in tumor development has been discovered to be increasingly more important. There is a need to explore the spatial relationships between tumor and immune cells in tissue to help better predict therapeutic treatment outcomes in patients in the growing field of immuno-oncology. We have developed a new single cell multiplexed immunofluorescence staining method along with our patented multi-spectral imaging (MSI) technology to allow scientists to detect up to six biomarkers simultaneously on one tissue section, which provides an end-to-end, fully automated workflow from staining to image analysis. In this study, we show a methodology that allows primary antibodies to be applied as a single cocktail in one incubation step followed by amplified detections using Opal fluorescent dye technology. Formalin-fixed paraffin-embedded (FFPE) samples were stained on the Leica BOND RX࣪ automated staining system using our new multiplex procedure and compared to 3,3′-Diaminobenzidine (DAB) chromogenic immunohistochemistry assay. Multispectral scans were acquired on the Akoya Vectra Polaris® imaging system with optimized acquisition parameters. Image analysis was performed with a phenotyping algorithm in inForm® analysis software and intensity analysis was performed in R using phenoptr and phenoptrReports. The six multiplexed biomarkers are shown to be comparable in staining patterns to their DAB counterparts. Whole slide image scans were successfully unmixed and treated as individual monoplexes, but combined at will to observe the spatial relationships. This easy-to-use staining method simplifies tissue-based multiplex immunofluorescence by providing primary antibody cocktailing and cyclic deposition of fluorescent Opal dyes while maintaining strong staining intensity and the ability to spectrally unmix different wavelengths from the image for visualization and spatial analysis. This novel method will provide researchers with a flexible and readily available solution for staining patient samples to investigate spatial phenotypic signatures, aiding in the development of targeted immune therapies.
Citation Format: Rachel Schaefer, Linying Liu, Michael McLane, Oscar Perez, Jacob Circelli, Carla Coltharp, Yi Zheng. Novel, high-throughput multiplexed immunofluorescence staining method for assessing spatial relationships of immuno-oncology biomarkers in whole slide FFPE tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1726.