bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2445: PPM1G enhances hepatocellular carcinoma stemness via interacting with YBX1
Authors: Liu Shan , Fang Xiaona , Luo Jie , Huang Jiao , Yang Yuma , Liu Beilei , Huang Jinlin , Wong Ching Ngar , Zhang Baifeng , Gong Lanqi , Ban Liuxian , Yan Qian , Guan Xinyuan 
Published: April 2023

Abstract
PPM1G is a member of protein phosphatase family, marked as Mg2+/Mn2+ dependent 1G. PPM1G protein mainly has three domains: phosphatase domains at both ends and acidic domain (AD) in the middle. It was highly expressed in both embryonic stem cells and hepatocellular carcinoma (HCC) by mRNA-seq data. From pan-cancer view, it was up-regulated in tumor tissue of 24 pan-cancer types and predicted worse overall survival (OS) for 9 cancers. In GSE40267 dataset, PPM1G overexpressed significantly in lung metastasis HCC patients than patients without metastasis. And both from TCGA and ICGC-JP database analysis showed PPM1G was an independent poor prognostic factor for both OS and disease-free survival (DFS) in HCC patients. In vitro, our functional experiments showed that the stemness features such as sphere formation, ALDH assay and atRA (Tretinoin) assay were undermined by knock down (KD) of PPMIG. In HepG2 and 8024 KD cell lines, the tumor capacity of proliferation, cell-cycle, foci-formation, migration invasion and cisplatin induced apoptosis were also impaired. In vivo, KD of PPM1G strongly suppressed the subcutaneous and liver orthotopic tumor formation and lung metastasis and cancer stemness by limited dilution experiment was also significantly weakened. For the mechanism exploration, firstly, GO analysis showed genes highly positive correlated with PPM1G (Spearman R &gt; 0.5) enriched in mRNA splicing. Secondly, YBX1 (role as RNA m5C and m6A reader protein and chemotherapy resistance gene) was screened out by three database (RBP2GO, HiPredict and GEPIA) followed with in vivo CO-IP experiment and immunofluorescence colocalization. The YBX1 expression level was not affected by PPM1G from Western Blot. Lastly, the AD of PPM1G but not the phosphatase domain was interacted with YBX1 by PPM1G cut-off and CO-IP experiments. So, the above evidence proved that PPM1G could interact with YBX1 to promote HCC stemness and tumor growth and metastasis.
Citation Format: Shan Liu, Xiaona Fang, Jie Luo, Jiao Huang, Yuma Yang, Beilei Liu, Jinlin Huang, Ching Ngar Wong, Baifeng Zhang, Lanqi Gong, Liuxian Ban, Qian Yan, Xinyuan Guan. PPM1G enhances hepatocellular carcinoma stemness via interacting with YBX1 [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 2445.
Abstract 2447: XPC suppresses cancer stem cells via inhibiting STAT1-mediated expression of SOX2 in NSCLC
Authors: Li Na , Bai Xuetao , Cai Shurui , Banerjee Ananya , Yang Yajing , Ge Qianyun , Wang Linzhou , Wang Qi-En 
Published: April 2023

Abstract
Xeroderma pigmentosum group C (XPC) is a DNA repair factor mainly involved in nucleotide excision repair but also has functions beyond its role in DNA repair. More than 60% lung adenocarcinoma patients exhibit XPC copy number deletions, and among these patients, low XPC expression is correlated with a poor outcome, indicating that XPC may play a critical role in preventing lung cancer progression. Here, we revealed an inverse relationship between XPC expression and the abundance of cancer stem cell (CSC) subpopulation in non-small cell lung cancer (NSCLC). We demonstrated that knockdown of XPC leads to larger CSC subpopulations in lung cancer cells, while overexpression of XPC can inhibit the stemness properties of these cells. The RNA-seq analysis suggested that XPC can suppress the expression of SOX2, a critical stem cell-specific transcription factor. This finding was further validated in multiple NSCLC cell lines at both mRNA and protein levels. To further investigate the mechanism underlying XPC-mediated suppression of SOX2 expression, we performed quantitative proteomics combined with immuno-affinity purification and found that XPC can interact with STAT1, which is a transcription factor of SOX2. Moreover, XPC can inversely regulate the activation of STAT1 (pSTAT1-Y701), indicating that XPC may suppress SOX2 expression via inhibiting the STAT1 signaling. Taken together, we identified a novel mechanism behind poor outcomes of NSCLC patients with haploinsufficiency XPC. Low level of XPC in lung cancer cells de-represses the activity of STAT1, which further promotes the expression of stem cell-specific gene SOX2 and facilitates the maintenance of CSC subpopulations. Given that CSCs are believed to contribute to tumor progression and chemoresistance, enhanced stemness and expanded CSC populations in XPC haploinsufficiency NSCLC could be responsible for the poor outcome of these patients.
Citation Format: Na Li, Xuetao Bai, Shurui Cai, Ananya Banerjee, Yajing Yang, Qianyun Ge, Linzhou Wang, Qi-En Wang. XPC suppresses cancer stem cells via inhibiting STAT1-mediated expression of SOX2 in NSCLC [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 2447.
Abstract 2451: KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis
Authors: Yoon Changhwan , Lu Jun , Jun Yukyung , Kim Bang- Jin , Till Jacob , Kim Jong Hyun , Keshavjee Sara , Ryeom Sandra , Yoon Sam 
Published: April 2023

Abstract
Our previous work showed that KRAS activation in gastric cancer cells leads to activation of an epithelial-to-mesenchymal transition (EMT) program and generation of cancer stem-like cells (CSCs). Here we analyze how this KRAS activation in gastric CSCs promotes tumor angiogenesis and metastasis. Gastric cancer CSCs were found to secrete pro-angiogenic factors such as vascular endothelial growth factor A (VEGF-A), and inhibition of KRAS markedly reduced secretion of these factors. In a genetically engineered mouse model, gastric tumorigenesis was markedly attenuated when both KRAS and VEGF-A signaling were blocked. In orthotropic implant and experimental metastasis models, silencing of KRAS and VEGF-A using shRNA in gastric CSCs abrogated primary tumor formation, lymph node metastasis, and lung metastasis far greater than individual silencing of KRAS or VEGF-A. Analysis of gastric cancer patient samples using RNA sequencing revealed a clear association between high expression of the gastric CSC marker CD44 and expression of both KRAS and VEGF-A, and high CD44 and VEGF-A expression predicted worse overall survival. In conclusion, KRAS activation in gastric CSCs enhances secretion of pro-angiogenic factors and promotes tumor progression and metastasis.
Citation Format: Changhwan Yoon, Jun Lu, Yukyung Jun, Bang- Jin Kim, Jacob Till, Jong Hyun Kim, Sara Keshavjee, Sandra Ryeom, Sam Yoon. KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and 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 2451.
Abstract 2457: Restoring the balance between WNT and retinoic acid signaling to promote differentiation of cancer stem cells in treatment of colorectal cancer
Authors: Facey Caroline O. B. , Hunsu Victoria O. , Osmond Brian T. , Zhang Chi , Opdenaker Lynn M. , Boman Bruce M. 
Published: April 2023

Abstract
Dysregulated WNT signaling caused by mutation in the APC gene occurs in 80-90% of all colorectal cancer (CRC) cases. Progressive overpopulation of ALDH+ stem cells occurs during development of CRC in familial adenomatous polyposis (FAP) patients. Given that ALDH is a key member of the retinoic acid signaling (RA) pathway, we hypothesize that human CRC is caused by an imbalance between dysregulated WNT and RA signaling. Herein, we aim to restore proper WNT and RA signaling and identify a common link or target to induce differentiation of CSCs along the neuroendocrine cell (NEC) lineage. Accordingly, to determine the effects of restoring wt-APC in APC-mutant HT29 CRC cells, we conducted in vitro experiments to examine Wnt/β-catenin signaling, sensitivity to retinoids, cell proliferation, expression of stem cell markers, quantification of ALDH+ stem cells, and NEC maturation. We utilized Nanostring profiling, TCF reporter assay, western blot, and fluorescence activated cell sorting analyses to ascertain these effects. We found that induction of wt-APC expression decreased WNT/β-catenin signaling and reduced protein expression of WNT-target genes. Notably, inducing wt-APC decreased ATRA-induced expression of the WNT target gene CYP26A1 (by 50%), which is predicted to, in turn, increase RA signaling by lowering degradation of RA. Indeed, inducing wt-APC increased sensitivity of CRC cells to ATRA-induced apoptosis and inhibition of cell proliferation in a dose-dependent manner. Expression of ALDH1A1 decreased (3-fold) with ATRA treatment and inducing wt-APC extended the decrease by an additional 2-fold. Furthermore, upon inducing wt-APC, we found an increase in the protein expression of several NEC markers including CHGA, GLP2R, NSE (ENO2), and SSTR1, and an increased number of GLP2R+ NECs. We also discovered a very highly regulated protein network of 248 proteins and identified a cell signaling mechanism that links the WNT and retinoic acid pathways via CYP26A1. Thus, by inducing wt-APC expression and exogenously activating RA signaling, we found a way to increase differentiation of SCs along the NEC (and other) lineage(s). Translating this strategy in vivo might lead to new, more effective treatments involving retinoids for CRC patients.
Citation Format: Caroline O. B. Facey, Victoria O. Hunsu, Brian T. Osmond, Chi Zhang, Lynn M. Opdenaker, Bruce M. Boman. Restoring the balance between WNT and retinoic acid signaling to promote differentiation of cancer stem cells in treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2457.
Abstract 2462: AXL-WRNIP1 mediated replication stress response aids metastatic latency and relapse
Authors: Marquez-Palencia Mauricio , Malladi Srinivas 
Published: April 2023

Abstract
Metachronous brain metastases, the primary cause of morbidity and mortality in HER2+ breast cancer patients arise from latent residual cells that resist systemic therapies. AXL, a receptor tyrosine kinase, is enriched in metachronous brain metastatic lesions from HER2+ breast cancer patients and in latent metastatic models. In contrast to its known function at the cell surface, AXL is localized to the nucleus and interacts with WRNIP1. Moreover, we show AXL depletion results in an increased replication stress and reduced survival of brain-tropic latent residual and metastatic cells. Furthermore, administration of BGB324 as a neoadjuvant sensitives brain metastatic lesions to targeted therapy. Our findings suggest targeting AXL is a viable option to eradicate residual brain metastatic cells and limit relapses in HER2+ breast cancer patients.
Citation Format: Mauricio Marquez-Palencia, Srinivas Malladi. AXL-WRNIP1 mediated replication stress response aids metastatic latency and relapse [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 2462.
Abstract 2468: Overcoming the leptomeningeal seeding of medulloblastoma by targeting HSP70
Authors: Choi Seung Ah , Ha Saehim , Lee Hee-Young , Kim Joo Whan , Paeng Jin Chul , Phi Ji Hoon 
Published: April 2023

Abstract
Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor and the development of leptomeningeal dissemination (LM seeding) through the cerebrospinal fluid (CSF) circulation is a major cause of treatment failure. We have previously established the MB LM seeding mouse model. In this study, we aimed to determine molecules that can target seeding (metastatic) cells by analyzing their specific genetic and functional characteristics.
Methods: Seeding and non-seeding cells were isolated and cultured, respectively, and microarray analysis was carried out. Proliferation and wound-healing assays were performed through the HCS system, and viability, migration and adhesion assays were accomplished. In addition, the therapeutic effect of the selected inhibitor was analyzed by region of interest (ROI) analysis of bioluminescence in vivo.
Results: The gene expression and functional characteristics of the successfully obtained seed cells and non-seed cells were compared and analyzed. Differentially expressed genes (DEGs) analysis indicated that heat shock protein 70 (Hsp70) was in the highest rank in seeding cells, and pathway enrichment analysis revealed that the metabolism was the main pathway enriched in seeding cells. Proliferation of seeding cells was slower than that of non-seeding cells, but there was no significant difference in viability. Notably, the wound-healing of seeding cells was delayed, but the adhesion ability on collagen was higher. Among the six HSP70 inhibitors, VER155008 was efficiently sensitive to seeding cells, and suppression of expression of MRP proteins along with HSP70 was also confirmed. In addition, it was observed that the treatment of VER155008 reduced seeding through the spinal cord in vivo.
Conclusion: Our study suggests that VER15008 can be a promising treatment option, targeting LM seeding of MB.
Citation Format: Seung Ah Choi, Saehim Ha, Hee-Young Lee, Joo Whan Kim, Jin Chul Paeng, Ji Hoon Phi. Overcoming the leptomeningeal seeding of medulloblastoma by targeting HSP70 [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 2468.
Abstract 247: Twist pan-cancer synthetic RNA fusion control for assay development
Authors: Cherry Patrick Daniel , Corwin Jason , Fuhrman Kit , Challacombe Jean , Murphy Derek , Toro Esteban 
Published: April 2023

Abstract
Fusion genes are structural variants that arise when the coding region of two previously independent genes become joined together; fusion genes can be a major driving cause of cancer development. Many gene fusion events have been classified as clinically-relevant and are targets for both diagnostic applications, such as TMPRSS2-ERG in prostate cancer, and therapeutic applications, such as CD74-ROS1 and EML4-ALK in non-small cell lung cancer. Given the potential clinical benefits of early detection, there is significant interest in developing highly sensitive and accurate diagnostic assays to detect cancer using these gene fusions as biomarkers. A significant barrier to the development of these diagnostic assays is the lack of a reliable and renewable sample source harboring gene fusions of interest for use in assay development and analytical validation.
Here, we describe the development and performance of a new fusion reference material: the Twist Pan-cancer RNA Fusion Control, a highly-multiplexed positive control designed to be spiked into a selected RNA background or as a stand-alone positive control. The Twist Pan-cancer RNA Fusion Control provides a wide selection of 80+ common and curated cancer targets for analytical validation and assay development. The synthetic RNAs are designed centered around the known and documented fusion sites with 750 nt of RNA 5′- of and 3′- of the fusion junction, suitable for short read sequencing and qPCR experiments. Pooled synthetic fusion RNAs are quantified at known molar ratios, NGS QC’d for uniformity, and ddPCR’d to establish a highly precise pool concentration. Finally, in fusion detection NGS experiments, we observe over a 95% recall rate of fusion events.
The Pan-cancer RNA Fusion Control is designed to serve as a spike-in or stand-alone positive control and specifically pairs well with a clinically-relevant target enrichment (TE) panel within the Twist Targeted Enrichment for Gene Expression solution. This control sample positive for RNA fusions can be applied in both qPCR and NGS workflows to validate panel/probe sets, establish limits of detection, and monitor ongoing assay performance. The Twist Pan-cancer RNA Fusion Control provides a valuable one-stop solution to assay developers seeking reference materials for a wide array of cancer-associated fusion transcripts.
For Research Use Only. Not for use in diagnostic procedures.
Citation Format: Patrick Daniel Cherry, Jason Corwin, Kit Fuhrman, Jean Challacombe, Derek Murphy, Esteban Toro. Twist pan-cancer synthetic RNA fusion control for assay development [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 247.
Abstract 2475: Bromodomain inhibitor: MT1 and its potential role in modulation of prostate cancer progression
Authors: Shukla Sanjeev , Al-Toubat Mohammed , Feibus Allison H. , Elshafei Ahmed , Riveros Carlos , Meurice Nathalie , Gleba Justyna , Chardon-Robles Jonathan , Kase Adam M. , III John A. Copland , Petit Joachim L. , Osumi Teruko , Balaji K.C. 
Published: April 2023

Abstract
Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of protooncogene cellular myelocytomatosis (c- Myc) and other genes. Because c-Myc cannot be directly targeted by small molecular inhibitors due to disordered alpha helical structure, epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for diseases such as prostate cancer (PC) associated with increased c-Myc upregulation with advancing disease. We studied the efficacy of MT1, a novel bivalent BD inhibitor that is 100-fold more potent than the first in class BD inhibitor JQ1, at inhibiting PC growth. We tested the effect on viability by MT-1 on PC cell lines, 3D spheroids derived from clinically annotated drug resistant patient derived xenografts (PDX), mice PDX models and corroborated the molecular mechanism of MT1 down regulation of Myc leading to downstream Myc-dependent up regulation of Protein Kinase D1 (PrKD) substrate phosphorylation by western blot. MT-1 inhibited growth of PC in castration sensitive (LNCaP) and resistant PC cells (PC-3). MT-1 treatment upregulated PrKD expression and phosphorylation of known PrKD substrates: threonine 120 (Thr-120) residues in beta-catenin and the serine 216 in Cell Division Cycle 25 (CDC25C) in PC-3 cells. Moreover, MT-1 was effective in inhibition of 3D spheroids growth at IC 50 between 0.27-0.92µM in Abiraterone, Enzalutamide, Docetaxel, Cabazitaxel metastatic castrate resistant PCa patient-derived tumor 3D spheroids. Additionally, MT1 was effective in inhibiting the tumor growth in PDX mice model. A combined intra-peritoneal administration of MT-1 with another c-Myc inhibitor (3JC48-3), an obligate c-Myc and MYC-associated protein X (MAX) heterodimerization inhibitor, increased the efficacy of inhibiting the PDX growth in mice. This study provides strong pre-clinical in vitro and in vivo evidence for advancing MT- 1 as a novel c-Myc targeting drug in PC. The MT-1 drug development will likely be highly impactful as c-Myc is dysregulated in three fourths of men with advanced PC.
Citation Format: Sanjeev Shukla, Mohammed Al-Toubat, Allison H. Feibus, Ahmed Elshafei, Carlos Riveros, Nathalie Meurice, Justyna Gleba, Jonathan Chardon-Robles, Adam M. Kase, John A. Copland III, Joachim L. Petit, Teruko Osumi, K.C. Balaji. Bromodomain inhibitor: MT1 and its potential role in modulation of prostate cancer progression [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 2475.
Abstract 2476: Nischarin is a potential druggable target in both epithelial and stromal compartments of pancreatic ductal adenocarcinoma
Authors: Grahovac Jelena , Živić Kristina , Pavlović Marijana , Ostojić Marija , Đurić Ana , Srdić-Rajić Tatjana , Pavić Aleksandar , Galun Danijel 
Published: April 2023

Abstract
Nischarin is a scaffolding protein involved in the regulation of cell cytoskeletal organization and metabolic homeostasis. In breast and ovarian cancers, nischarin has been demonstrated to have tumor suppressive functions. We have found that nischarin was expressed in both the epithelial and stromal compartments of the PDAC patient tissue, in cancer cell lines and patient-derived stellate cells. Of interest, nischarin is a functional imidazoline 1 receptor for which there are several FDA-approved agonists used for treatment of hypertension. The aim of this study was to examine the effects of nischarin agonists on PDAC cancer cells and stellate cells, separately and in co-culture and determine the potential for their repurposing in treatment of PDAC. mRNA sequencing revealed that cancer cell treatment with nischarin agonist rilmenidine induced transcriptional changes associated with regulation of cell adhesion, EMT and vesicular transport. In vitro, rilmenidine treatment of cancer cells decreased their migration and invasion potential and treatment of stellate cells decreased the αSMA-positive fraction. Treatment of cancer cell-stellate cell co-cultures decreased the production of pro-inflammatory cytokines IL-6, IL-8 and CCL-2, known drivers of the metastatic progression. Ultimately, rilmenidine treatment decreased PDAC cell invasion in Tg(fli1: EGFP) zebrafish model. Taken together, nischarin agonist rilmenidine has a potential for limiting the processes involved in PDAC metastatic cascade and may be a good candidate for drug repurposing.
Citation Format: Jelena Grahovac, Kristina Živić, Marijana Pavlović, Marija Ostojić, Ana Đurić, Tatjana Srdić-Rajić, Aleksandar Pavić, Danijel Galun. Nischarin is a potential druggable target in both epithelial and stromal compartments of pancreatic ductal adenocarcinoma [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 2476.