bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1510: Exposure to butyrate metabolite mediates genomic instability in oropharyngeal keratinocytes
Authors: McGhee Eva , Li Mengtao , Lin Yi-Ling , Su-Velez Brooke , Carr Nefertari , Njubigbo Chinelo , Sadeghi Rohun , Sadegh Matin , Handler Julian , Handler Adin , Long Naomi , Vadgama Jay 
Published: June 2022

Abstract
Human Papillomavirus (HPV), a non-enveloped epitheliotropic double stranded DNA virus, is an etiological agent of oral cancer, and can be cleared by host immunity. A small percentage of patients that develop persistent infection with oncogenic HPV show an increased risk of developing an HPV-associated malignancy. Head and neck, oropharyngeal cancer is related to the persistent infection by high-risk HPV type 16, E6/E7 oncoproteins. The E6/E7 oncoproteins significantly contribute to the carcinogenic genomic instability effect of high-risk HPV through the degradation of two proteins, p53 and pRB, respectively. The human oropharynx often harbors anaerobic bacteria that produce a variety of byproducts, including butyrate. Butyrate is a modulator of induced genomic instability, influencing the development of HPV oral cancer when implanted in a syngeneic mouse model. In this study, we investigate butyrate co-treatment with HPV E6/E7 in vitro. This treatment increased cellular proliferation, DNA double strand breaks, and genetic instability processes associated with apoptosis regulation. These data indicate that in connection with butyrate, HPV E6/E7 oncoproteins can promote increased upregulation of apoptosis, disrupt cell cycle regulation, and decrease DNA double strand break repair. Epigenetics and chromosomal instability events have been noted, specifically, the deletion of the distal region of chromosome 11q22-23 in E6/E7 transfected keratinocytes. These results indicate that HPV-16, E6/E7 oncoproteins plus butyrate treatment can influence genomic changes in mouse keratinocytes, which may further promote oral carcinogenesis.
Citation Format: Eva McGhee, Mengtao Li, Yi-Ling Lin, Brooke Su-Velez, Nefertari Carr, Chinelo Njubigbo, Rohun Sadeghi, Matin Sadegh, Julian Handler, Adin Handler, Naomi Long, Jay Vadgama. Exposure to butyrate metabolite mediates genomic instability in oropharyngeal keratinocytes [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 1510.
Abstract 1528: Molecular mechanisms of TSLP as a therapy for CRLF2 B-Cell acute lymphoblastic leukemia
Authors: Alkashgari Hossam , Stoian Cornelia , Ruiz-Jimenez Caleb , Coats Jacqueline , Casiano Carlos A. , Dovat Sinisa , Payne Kimberly J. 
Published: June 2022

Abstract
B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of leukemia in children. B-ALL characterized by cytokine receptor-like factor 2 (CRLF2) overexpression (CRLF2 B-ALL) has a survival rate of &lt;30% and is the highest risk sub-group of B-ALL in both adults and children. CRLF2 is a receptor component for the cytokine thymic stromal lymphopoietin (TSLP). TSLP plays a role in the survival and proliferation of B-cell precursors, thus explaining the oncogenic role of increased CRLF2 signaling in CRLF2 B-ALL. To our surprise, we found that high-levels of TSLP eliminated leukemia cells in patient-derived xenograft (PDX) models of CRLF2 B-ALL. CRLF2 and IL-7 receptor-alpha (IL-7Ra) form the heterodimer type-I cytokine receptor for TSLP cytokine. Binding of TSLP to its CRLF2 receptor complex induces JAK-STAT5 and PI3K-AKT pathway signals. TSLP shares the IL-7Ra with Interleukin 7 (IL-7) which has a heterodimer receptor consisting of IL-7Ra and the common gamma chain. High-levels of IL-7 (50 ng/ml) have been shown to induce IL-7Ra internalization and degradation in T-cells. We hypothesize that high-level TSLP induces internalization and degradation of IL-7Ra leading to CRLF2 signal inhibition, death of CRLF2 B-ALL cells and the anti-leukemia effects that we have observed in PDX mice. To test this hypothesis, we treated CRLF2 B-ALL cell lines with different TSLP concentrations to observe the effect of TSLP on its receptor and CRLF2 signaling. Flow cytometry data showed that continuous or a pulse of high-dose TSLP induced a loss of surface IL-7Ra expression for up to 24 hours. Phosphorylation assays showed that cells cultured with high-dose TSLP were unresponsive to subsequent TSLP-induced phosphorylation events (pSTAT5 and pRPS6), indicating CRLF2 signal inhibition. In conclusion, high-dose TSLP induces loss of (IL-7Ra) and inhibition of CRLF2 signaling. These results suggest that TSLP exerts its anti-leukemia effects by shutting down CRLF2-mediated signals possibly via the loss of the IL-7Ra receptor component.
Citation Format: Hossam Alkashgari, Cornelia Stoian, Caleb Ruiz-Jimenez, Jacqueline Coats, Carlos A. Casiano, Sinisa Dovat, Kimberly J. Payne. Molecular mechanisms of TSLP as a therapy for CRLF2 B-Cell acute lymphoblastic leukemia [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 1528.
Abstract 1556: Long non-coding RNA WNT5A-AS1 shows sex-dimorphic differences in survival for males with glioblastoma
Authors: Miller Aunay , Wang Junwen , Loftus Joseph , Tran Nhan L. 
Published: June 2022

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival time of 12-15 months and 5-year survival rate of 5%. Despite the application of advanced genetics and biological breakthroughs in GBM, the outcome for GBM remains dismal. Previous genome-wide association studies (GWAS) for GBM shows that the incidence rate for GBM in males is 1.6 times higher in men than women, with men displaying overall worse outcomes. In-vivo studies in gender-matched isogenic murine astrocytic cell lines show that the rate of astrocytic transformation is higher in males than in females, corroborating the GWAS findings in human GBM. Thus, understanding how sex effects GBM biology may provide insight into the mechanism of gliomagenesis and response to therapy. To explore the molecular mechanisms by which transformation of GBM increases in males, we used DESeq2 to assess differentially expressed genes between male and female patients. We found that a long non-coding RNA WNT5A-AS1 is overexpressed in males [log2(fold change) of 1.40; FDR = 0.036], regardless of cofounding factors such as IDH1 status, age, and race. Next, we examined if expression of WNT5A-AS1 is correlated with survival within male patients versus female patients in the TCGA-GBM dataset. In males, WNT5A-AS1’s expression is significantly correlated with patient overall survival (P = 0.042, N=109), but not in female (P = 0.585, N=60). Male patients with high expression of WNT5A-AS1 display poor survival outcomes compared to males with low expression. WNT5A-AS1 is located in the upstream, promoter region of WNT5A. Q-PCR quantification of WNT5A expression increases in male GBM specimens as compared to GBM specimens from females. The role that WNT5A-AS1 plays in regulating WNT5A expression is unclear to date. Interestingly, WNT5A expression shows a positive correlation with patient survival in males, with high expression displaying better survival outcomes (p=0.0272). We have data obtained from a subset of patient samples showing an inverse relationship between WNT5A and WNT5A-AS1 expression. This suggests that there may be an inverse correlation between WNT5A-AS1 and WNT5A expression, which elucidates that WNT5A-AS1 may be regulating WNT5A expression. Current ongoing studies will evaluate the role of WNT5A-AS1/WNT5A in sex-differences of GBM progression.
Citation Format: Aunay Miller, Junwen Wang, Joseph Loftus, Nhan L. Tran. Long non-coding RNA WNT5A-AS1 shows sex-dimorphic differences in survival for males with glioblastoma [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 1556.
Abstract 1567: Increased extracellular matrix stiffness induces hypersecretion of chemoresistance-promoting cancer associated fibroblast-derived exosomes in pancreatic cancer
Authors: Xiao Weikun , Eun Chae-Young , Zhang Xinyu , DeKalb Charlene , Pahlavan Mahsa , Mahgoub Bayan , Knaneh Hanaa , Sohrabi Alireza , Seidlits Stephanie K. , Hill Reginald 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with few effective treatments. Despite recent advances in in other cancers, the five-year survival rate of PDAC is still only 10%, with most patients succumbing to their disease within the first year. One of the main factors responsible for this poor outcome is the development of chemoresistance in nearly all clinical cases. While the intrinsic factors that facilitate chemoresistance in the tumor cells have been studied extensively, fewer studies have elucidated how the complex and unique microenvironment surrounding the tumor affects therapeutic responses. The abundant stromal cells and the stiff desmoplastic microenvironment constitute more than 90% of the primary tumor bulk. However, there is a lack of high-throughput, easily tunable models to recapitulate this complex microenvironment, in order to identify a critical cell-extrinsic factors that could drive acquired chemoresistance in PDAC cells. To address this issue, we have developed a Matrigel-based, orthogonally tunable 3-dimensional (3D) culture system to co-culture mouse derived PDAC organoids and host-matching cancer-associated fibroblasts (CAFs). Using this system, we found that matrix-activated CAFs readily remodel the desmoplastic matrix through lysol-oxidase dependent crosslinking. Moreover, our novel system demonstrates how collagen-I and matrix stiffness affect chemoresistance via the hypersecretion CAF-derived exosomes. Interestingly, our data show that it is CAF-derived exosomes, not the organoid-derived exosomes, that are most important in regulation of proliferation and chemoresistance. Lastly, we identified key cell surface integrins for collagen-I as therapeutic targets to prevent desmoplastic matrix-mediated chemo-resistance in PDAC. Our study provides insights into how matrix composition and stiffness affect therapeutic outcome in PDAC. Moving forward, therapies aimed at interrupting how PDAC cells and stomal cells sense the matrix microenvironment could be utilized to eventually overcome matrix-mediated chemoresistance in PDAC.
Citation Format: Weikun Xiao, Chae-Young Eun, Xinyu Zhang, Charlene DeKalb, Mahsa Pahlavan, Bayan Mahgoub, Hanaa Knaneh, Alireza Sohrabi, Stephanie K. Seidlits, Reginald Hill. Increased extracellular matrix stiffness induces hypersecretion of chemoresistance-promoting cancer associated fibroblast-derived exosomes in pancreatic 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 1567.
Abstract 1574: LSD-germline variant drive oncogenicity
Authors: Yoon Hyundong , Song Seulki , Ha Yeeun , Koh Youngil , Yoon SungSoo 
Published: June 2022

Abstract
Lysosome storage disease (LSD) is a congenital metabolic disorder caused by mutations in genes involved in the function of lysosomes. Defects in the genes encoding hydrolases and transporters and enzyme activators are found in LSD’s, leading to the accumulation of macromolecules in the late endocytic system. And this disruption of lysosomal homeostasis increases the induction of endoplasmic reticulum and oxidative stress, proliferative signal transduction, extracellular matrix degradation, Integrin-β4-mediated cell migration and invasion, and consequently can promote the development of oncogenic cells and malignant tumors. It is known that the function of lysosomes is very important in cancer diseases. Recently, through a preliminary study, we found that the incidence of myeloproliferative neoplasm (MPN) increases statistically significantly when the LSD putative pathogenic germline variant (PPGV) is present. Based on this, we performed single-cell RNA (scRNA) sequencing using MPN patient samples of both LSD PPGV carrier and non-carrier. We tried to determine how the LSD PPGV affects MPN cancer progression at the single-cell level. To confirm functional differences between the two groups, DEG, pathway enrichment, LR-pair interaction, and transcription enrichment analyses were performed. In the analysis, immune cells were composed of T-cell, NK-cell, and Monocyte (in the order of frequency). It was confirmed that Lysosome-related (ER, Golgi, etc.) functions were upregulated in the carrier group compared to the non-carrier group across cell types. In addition, in the ligand-receptor (LR)-pair interaction analysis targeting Immune cells, it was possible to find a statistically significant difference (average log2 fold change&gt;0.7 and p-value&lt;0.05) candidate LR-pair (IL6-IL6R*IL6ST) that upregulates in the carrier group compared to the non-carrier group. The candidate LR-pair found by our team has been previously known as a cytokine-related gene that plays an inflammatory or fibrosis-related role in MPN and affects cancer progression. Also, in the Transcription Factor Enrichment analysis conducted together, it was confirmed that the statistically significant (NES&gt;2 and FDR&lt;0.01) candidate Transcription Factor (STAT1), which operates dependent on the candidate LR-pair, is upregulated. In conclusion, we found the possibility that genes and functions related to cancer progression can be up-regulated by LSD germline variants. In addition, we plan to conduct additional studies to determine the exact mechanism of contribution to cancer development by the LSD germline variant.
Citation Format: Hyundong Yoon, Seulki Song, Yeeun Ha, Youngil Koh, SungSoo Yoon. LSD-germline variant drive oncogenicity [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 1574.
Abstract 1599: Genes subject to changes in heterogeneity can function as regulators of metastasis
Authors: Yang Dongbo , Dann Christopher , Valdespino Andrea , Robinson-Mailman Lydia , Chen Mengjie , Pott Sebastian , Rosner Marsha 
Published: June 2022

Abstract
Tumor cell heterogeneity has been strongly implicated in metastatic progression of solid tumors such as triple-negative breast cancer (TNBC), leading to resistance and recurrence. Raf Kinase Inhibitory Protein (RKIP or PEBP1) effectively suppresses metastasis in TNBC but is lost in many patients. We hypothesize that RKIP works in part by reducing the variability of gene expression in TNBC cells. To test whether RKIP reduces overall transcriptional heterogeneity, we compared the variation in gene expression between individual cells in metastatic (low RKIP) versus non-metastatic (high RKIP) TNBC tumors. Single-cell RNA-sequencing revealed transcriptional heterogeneity was decreased with RKIP overexpression. Many cancer regulatory genes were more homogeneous and up-regulated in the RKIP-expressing cells. Among these enriched and homogenously expressed genes is KMT5C, a histone methyltransferase that facilitates epigenetic transcriptional repression. Cell, mouse, and clinical studies suggest KMT5C expression blocks invasion, extravasation, and colonization of tumor cells, consistent with a role as a novel suppressor of metastasis. These studies reveal the importance of genes involved in heterogeneity as potential regulators of metastatic progression in cancer.
Citation Format: Dongbo Yang, Christopher Dann, Andrea Valdespino, Lydia Robinson-Mailman, Mengjie Chen, Sebastian Pott, Marsha Rosner. Genes subject to changes in heterogeneity can function as regulators of 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 1599.
Abstract 171: ERK dynamics are essential for colon tissue patterning
Authors: Pond Kelvin W. , Chakrabarti Jayati , Thorne Curtis A. , Paek Andrew L. 
Published: June 2022

Abstract
Maintaining the correct ratio of cellular niches in space and time allows tissues to perform their complex functions and create patterns. This maintenance of tissue patterning is often dysregulated during cancer development. In order to study tissue patterning, temporal and spatial resolution of communication between single cells is required. To explore how this complex process is controlled, we developed a patient-derived organoid screening platform to study both tissue patterning and kinase pathway dynamics in single cells across hundreds of conditions. Unlike normal and polyp-derived organoids, tumor organoids displayed a lack of patterning reminiscent of in vivo dysplasia. Using this system, we discovered that waves of Erk signaling induced by apoptotic cells are critical for maintaining tissue patterning in human colonic organoids. Using a small molecule-based screen, we discovered novel kinases which limit Erk activation across tissues and help maintain patterning. Perturbation of Erk restricting kinases results in dysfunctional colonic wound repair and re-establishment of tissue patterns in vivo.
Citation Format: Kelvin W. Pond, Jayati Chakrabarti, Curtis A. Thorne, Andrew L. Paek. ERK dynamics are essential for colon tissue patterning [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 171.
Abstract 1742: Molecular characterization of CRPC pathogenesis and development of a novel anti-PSMA-drug conjugated hybrid nanoparticle therapy with reduced cellular toxicity
Authors: Chellappagounder Thangavel 
Published: June 2022

Abstract
Background: Metastatic castration-resistant prostate cancer (mCRPC) is responsible for most of PCa deaths. Androgen deprivation therapy (ADT), taxanes and enzalutamide are the standard care for CRPC and mCRPC. Unfortunately, these approaches often fail to prevent tumor relapse due to at least in part, the inherently low oxygen levels within the prostate tumor environment. In addition to this, lower drug stability and fast drug clearance among ADT patients are the major therapeutic limitations in drug delivery and drug efficacy. Therefore, it is clinically warranted to develop an increased drug stability system to enhance the drug efficacy. Recent developments in drug delivery system including our earlier report, nanoparticle loaded drugs shows greater stability and better drug efficacy with sub-optimal drug concentrations in vitro. It is an essential to develop an ideal CRPC preclinical model system to test the anti-PSMA-drug conjugated hybrid nanoparticle efficacy with high drug stability with limited cellular toxicity.
Materials and Methods: CRPC lines were developed from PSMA proficient LNCaP, LAPC4, C4-2, 22Rv1, and PSMA deficient PC3-ML cells with intermittent hypoxia. CRPC cells were analyzed for proliferation, RB status, AR signaling, migration invasion and drug resistance in both in vitro and in vivo. Further, CRPC bone metastases clinical samples from Thomas Jefferson University Hospital were compared with preclinical CRPC model. Efficient anti-PSMA-drug conjugated hybrid nanoparticle therapy was established.
Results: Hypoxia resistance models show CRPC, RB loss, hormone therapy resistance in vitro and in vivo. Anti-PSMA-drug conjugated hybrid nanoparticle shows enhanced drug stability and drug efficacy in vitro and in vivo. Interestingly we observed fibrosis, immune impairment and inactive RB in bone metastatic CRPC samples correlated with our preclinical studies. Further, our clinical bone metastases samples present osteoblastic, osteolytic and osteoblastic & osteolytic nature. Anti-PSMA conjugated-drug loaded hybrid nanoparticles localized to PSMA specific cells in vitro & in vivo, causing cell cycle arrest. Drug loaded anti-PSMA conjugated hybrid nanoparticles did not cause major toxicities in mice.
Conclusion: Hypoxia resistant mCRPC models are ideal and are comparable with CRPC induced bone metastases in patient’s samples. Drug-loaded anti-PSMA conjugated hybrid nanoparticles targets PSMA specific prostate cancer cells and show enhanced drug stability and drug efficacy in CRPC preclinical model.
Citation Format: Thangavel Chellappagounder. Molecular characterization of CRPC pathogenesis and development of a novel anti-PSMA-drug conjugated hybrid nanoparticle therapy with reduced cellular toxicity [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 1742.
Abstract 177: Ex vivo 3D culture of adenoid cystic carcinoma PDX models recapitulate disease biomarkers and predict drug response
Authors: Millard Melissa , DesRochers Teresa M. , Wick Michael J. , Kaufman Jeffrey , Burr Nicole Spardy 
Published: June 2022

Abstract
Adenoid cystic carcinoma (ACC) is a rare, glandular cancer whose incidence rate and limited 2D cell culture capability make it difficult to study primary patient samples. Although well characterized ACC patient-derived xenografts (PDX) have proven to be a useful model to study disease mechanisms and therapeutic sensitives, animal drug studies are relatively low throughput, costly, and take months to accomplish. Ex vivo 3D cell culture can provide a high-throughput, less costly, and significantly faster platform for these drug studies but are hampered by the rarity of tissue. To address this unmet need for models of rare tumor types we developed 3D spheroid (3D-XPDXs™) and microtumor (3D-XPDXmt™) models of ACC using PDX as the primary tissue source. ACC PDX cells readily formed spheroids in our 3D-XPDXs™ platform, remained viable for up to 14 days, and maintained disease-relevant biomarkers such as MYB and c-kit. 3D-XPDXmt™ represent a more complex model of ACC by incorporating extracellular matrix. ACC 3D-XPDXmt™ displayed tumor-like morphologies concordant with the parental tumors and exhibited MYB and c-kit biomarker expression for up to 56 days in culture. Drug response profiling (DRP) was performed using the 3D-XPDXs™ ACC model with KIYATEC’s validated KIYA-PREDICT™ DRP platform. The screening panel consisted of drugs and drug-like compounds currently in use or under investigation for use in ACC, including broad-spectrum chemotherapies and targeted agents. Individualized drug responses were noted for each model as they exhibited differential sensitivities to DNA-damaging agents, microtubule stabilizers, and c-kit targeting kinase inhibitors mirroring the diversity of clinical outcomes. KIYA-PREDICT™ also identified drugs and drug-like compounds that uniformly inhibited viability. This is significant because there is currently no standard of care drugs for ACC, as few, if any have demonstrated homogenous responses in test populations. Monensin has been shown to inhibit activity of the MYB transcription factor, making it an attractive candidate drug for the treatment of ACCs which have a high prevalence of MYB activating alterations. In our study, monensin was effective in all three models with IC50 concentrations in the low micromolar range. These results correlate well with immunohistochemical staining of MYB in ACC 3D-XPDXs™ and 3D-XPDXmt™. Taken together, this data represents a new ex vivo 3D cell culture platform for the study of ACC biology and potential therapies.
Citation Format: Melissa Millard, Teresa M. DesRochers, Michael J. Wick, Jeffrey Kaufman, Nicole Spardy Burr. Ex vivo 3D culture of adenoid cystic carcinoma PDX models recapitulate disease biomarkers and predict drug response [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 177.