bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 89: The microRNA-3622b-3p contributes to tumor progression and metastasis through an miR-3622-AIFM2 axis in prostate cancer
Authors: Wang Lizhong , Zhang Chao , Ye Ping 
Published: June 2022

Abstract
microRNA (miR)-3622 family is composed of two members, miR-3622a/b, but their roles remain debatable. In the present study, we found that expression of miR-3622a was lower, whereas expression of miR-3622b-3p was higher in human prostate cancer tissues than in normal prostate tissues. miR-3622a-3p inhibited cell migration and invasion of human prostate cancer cells, whereas miR-3622b-3p facilitated cell proliferation, migration, and invasion. To address the opposing roles of miR-3622 family members in various human prostate cancer cell lines, we knocked out endogenous miR-3622, including both miR-3622a/b. Our results showed that miR-3622 knockout reduced cell proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. Furthermore, we found that AIFM2, a direct target of miR-3622b-3p, is responsible for miR-3622 knockout-induced apoptosis, identifying an miR-3622-AIFM2 axis that contributes to oncogenic function during tumor progression. The results show that miR-3622b-3p is upregulated in human prostate cancers and has an oncogenic function in tumor progression and metastasis through an miR-3622-AIFM2 axis.
Citation Format: Lizhong Wang, Chao Zhang, Ping Ye. The microRNA-3622b-3p contributes to tumor progression and metastasis through an miR-3622-AIFM2 axis 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 89.
Abstract 912: A novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation of PRC2 target genes
Authors: Abdallah Aalaa , Cardona Herminio J. , Picketts David J. , Brat Daniel J. , Li Xiao-Nan , Becher Oren J. 
Published: June 2022

Abstract
Pediatric High Grade Glioma (pHGG) is a collection of molecularly distinct subtypes with different prognoses depending on the genetic drivers. One particularly aggressive subtype is H3.3G34R mutant gliomas, which are currently incurable and in need of improved therapies. Interestingly, H3.3G34R mutant gliomas commonly harbor TP53mutations, ATRX mutations, and alterations in PDGFRA signaling. The mechanism by which H3.3G34R promotes gliomagenesis is still somewhat unclear and additional models are needed to dissect its role in tumorigenesis. We used the RCAS Tv-a system to model H3.3G34R pHGG in mice. Nestin expressing progenitors in the frontal cortex of Nestin-Tva (Ntva); p53 fl/fl; ATRX fl/fl or Ntva; p53 fl/fl mice were infected with H3.3G34R or H3.3WT, PDGFA, and Cre, and monitored for signs and symptoms of tumor formation. RNAseq analysis and immunophenotype were used to characterize the tumors. We observed that H3.3G34R did not significantly impact tumor latency independent of ATRX status. ATRX loss significantly increased tumor latency independent of H3.3G34R (P &lt; 0.01) from 90 days to 143 days. H&E analysis revealed that the majority of tumors in all groups were high grade and that mice with ATRX loss were more likely to develop low grade tumors though this trend did not reach significance (P = 0.075). Expression of Ki67, GFAP and Olig2 was present in all groups, as shown by Immunophenotypic analysis. RNAseq analysis of murine tumor tissue revealed that ATRX loss in the context of G34R led to significant differential expression of 113 genes (78 upregulated and 35 downregulated) including upregulation of PRC2 target genes including HoxA genes. These findings highlight the cooperation between ATRX loss and H3.3G34R in gliomagenesis.
Citation Format: Aalaa Abdallah, Herminio J. Cardona, David J. Picketts, Daniel J. Brat, Xiao-Nan Li, Oren J. Becher. A novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation of PRC2 target genes [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 912.
Abstract 913: Tert mutant promoter mouse model induces cancer progression in BrafV600E-driven thyroid tumors: A novel tool to understand the biology of telomerase-reactivated cancers
Authors: Landa Inigo , Hao Jingzhu , Xu Bin , Giacalone Joseph , Herbert Zach , Blasco Maria A. , Knauf Jeffrey A. , Ghossein Ronald , Fagin James A. 
Published: June 2022

Abstract
Hotspot mutations in the proximal promoter of the telomerase reverse transcriptase (TERT) gene are the first cross-cancer alterations lying in a gene regulatory region. TERT promoter mutations (TPMs) are enriched in advanced thyroid tumors and constitute markers of disease severity. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bone fide oncoprotein. To study TERT deregulation and its downstream consequences in a biologically accurate model, we generated a Tert-mutant promoter mouse model via CRISPR/Cas9 editing of the equivalent murine locus and crossed these animals with thyroid-specific BrafV600E-mutant mice. BrafV600E animals develop highly penetrant papillary thyroid tumors (PTC) by week 5, but do not progress. In contrast, BrafV600E+TertMUT animals showed an increased incidence of poorly differentiated thyroid cancers (PDTC) by 20 weeks (30% vs. 0% in BrafV600E; chi-squared P= 0.03), mimicking those exhibited by an alternative transgenic model of Tert overexpression (BrafV600E+K5-Tert; 36% PDTCs). Mouse Tert promoter mutation increased Tert transcription in vitro and in vivo, as reported in patients’ tumors carrying TPMs. Braf+Tert animals partially responded to MAPK pathway inhibition (dabrafenib plus trametinib), showing that MAPK signaling remains relevant in these specimens. Interestingly, RNA sequencing of Tert-reactivated murine thyroid tumors showed unique transcriptomic profiles (compared to BrafV600E alone), suggesting that downstream effects, other than the canonical Tert-mediated telomere maintenance, operate in cancers harboring TPMs. These cancer models of telomerase reactivation provide excellent pre-clinical settings to understand the regulatory mechanisms and biological underpinnings of TPM-induced progression of thyroid and other tumors, and to explore novel therapeutic strategies.
Citation Format: Inigo Landa, Jingzhu Hao, Bin Xu, Joseph Giacalone, Zach Herbert, Maria A. Blasco, Jeffrey A. Knauf, Ronald Ghossein, James A. Fagin. Tert mutant promoter mouse model induces cancer progression in BrafV600E-driven thyroid tumors: A novel tool to understand the biology of telomerase-reactivated cancers [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 913.
Abstract 926: IIKKa deletion amplifies renal transitional epithelial stem cells and initiates lethal invasive papillary urothelial cell carcinoma development
Authors: Li Xin , Zhu Feng , Jiang Chengfei , Zhao Yongmei , Tran Bao , Butcher Donna , Wu Xiaolin , Debra Tross , Hu Yinling 
Published: June 2022

Abstract
Urothelial cell carcinoma is the most common cancer of the renal pelvis or ureter in humans. Due to a lack of animal models, its pathogenic causes remain elusive. Here, we generated IkkαΔKsp mice lacking Ikkα specifically in epithelial cells of the developing kidney and genitourinary tract as well as renal tubules. The mutant mice developed invasive papillary urothelial cell carcinomas initiated from the pelvis, leading to hydronephrosis, and the animals eventually died. Depleting neutrophils or antibiotic treatment slowed down the development of phenotypes but did not rescue them, suggesting that epithelial-cell-autonomous aberrant alterations induced by Ikkα loss are critical for the initiation of urothelial cancer. Moreover, We found that the urothelial cell carcinomas in the mutant mice highly expressed cancer stem-cell markers such as Sox2, K15, p63, Nanog, and CD44, as well as FGFR3 and osteopontin (OPN). Thus, we hypothesize that Ikkα ablation-mediated OPN and FGFR3 overexpression regulates and amplifies CD44+ renal cancer-stem cells for tumor initiation. These alterations are shared with human papillary urothelial cell carcinomas.
Citation Format: Xin Li, Feng Zhu, Chengfei Jiang, Yongmei Zhao, Bao Tran, Donna Butcher, Xiaolin Wu, Tross Debra, Yinling Hu. IIKKa deletion amplifies renal transitional epithelial stem cells and initiates lethal invasive papillary urothelial cell carcinoma development [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 926.
Abstract 938: Characterization of a murine pancreatic ductal adenocarcinoma (PDAC) model with tamoxifen inducible pancreas-specific blockade of transforming growth factor-β (TGF-β) signaling with KrasG12D expression
Authors: Pandey Sanjay , Bell Brett , Chavez Claudia G. , Koba Wade , Savage Talicia , Asp Patrik , Basu Indranil , Guha Chandan 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a five-year overall survival of less than 10%. The lack of effective therapeutic strategies for PDAC necessitates the development of models to better understand the disease. Transforming growth factor-β (TGFβ)-SMAD4 signaling plays a critical role in PDAC development with more than half of all patients either have mutated SMAD4 (loss of function) or altered type II TGF TGFβ -receptor (Tgfbr2) gene. Here we present a murine model of PDAC with Tamoxifen induced conditional deletion of the TGFβ-receptor 2 (Tgfbr2) gene and expression of an activating KrasG12D mutation in pancreatic acinar cells. LSL-KrasG12D/+; Tgfbriifl/fl; Ptf1a-CreER mice were generated by crossing Ptf1aCre-ERTM mice with LSL-KrasG12D mice in which expression of KrasG12D is restrained by a lox-stop-lox cassette until Cre activation by tamoxifen injection. These mice were then bred with Tgfbr2fl/fl mice with loxP sites flanking exon 4 of the Tgfbr2 allele to block TGFβ-SMAD4 signaling. 18Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography was performed to detect tumors and measure their metabolic volumes and standard uptake values over time. This model showed a latency of approximately 16-20 weeks following 5 i.p. injections of tamoxifen (~75 mg/kg in corn oil). Follow-up on the survival of the mice post tamoxifen injections showed the median survival of 252 days in male and 234 days in female mice. Histological evaluation showed multifocal nodules of neoplasia composed of tubules and acini with cuboidal to polygonal cells. Carcinoma cells were positive for cytokeratin 19 and for mucins identified by Alcian blue staining, both confirming the ductal phenotype of these tumors. Picrosirius red staining demonstrated dense stromal desmoplasia which recapitulates human disease. Flow cytometric evolution of the immune microenvironment was also done to evaluate the infiltration of immune cells. Additional characterization of our novel mouse model of pancreatic cancer is underway to understand PDAC progression and develop effective therapeutic approaches.
Citation Format: Sanjay Pandey, Brett Bell, Claudia G. Chavez, Wade Koba, Talicia Savage, Patrik Asp, Indranil Basu, Chandan Guha. Characterization of a murine pancreatic ductal adenocarcinoma (PDAC) model with tamoxifen inducible pancreas-specific blockade of transforming growth factor-β (TGF-β) signaling with KrasG12D 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 938.
Abstract 956: Role of E-cadherin in progression of invasive breast lobular carcinoma
Authors: Savariau Laura , Tasdemir Nilgun , Elangovan Ashuvinee , Ding Kai , Tallapaneni Pooja Sree , Hooda Jagmohan , Atkinson Jennifer M. , Lee Adrian V. , Oesterreich Steffi 
Published: June 2022

Abstract
Invasive lobular carcinoma (ILC) is the second most frequently diagnosed histologic subtype of invasive breast cancer following invasive ductal carcinoma (IDC) and accounts for 15% of all cases. The hallmark of ILC is the genetic loss of E-cadherin (CDH1) causing the disruption of adherens junctions and resulting in discohesive, linear growth of ILC cells in tissues. Beyond its effects on this unique histology, there is limited data on the role of E-cadherin loss in ILC metastasis. Therefore, we generated three ILC cell lines (MDA-MB-134, SUM44PE and BCK4) with inducible E-cadherin overexpression. Using immunoblotting and immunofluorescence microscopy we confirmed E-cadherin expression, re-expression of other adherens junction proteins including α and β-catenin, and re-localization of cytoplasmic p120-catenin to the membrane. Successful cell adhesion to E-cadherin coated plates suggested formation of functional junctions. E-cadherin expression had no effect on 2D growth but did diminish cell growth in ultra-low attachment (ULA) conditions consistent with its previously described role in anoikis. We confirmed increased cell death of MM134 with E-cadherin overexpression compared to control cells when grown in ULA. Overexpression of E-cadherin failed to rescue poor migratory and invasive ability of ILC cell lines as measured by transwell assays. However, E-cadherin expression in SUM44PE lead to decreased haptotaxis to collagen I, and altered morphology from loose grape-like structure to tight sphere-like formation when embedded in collagen I.In vivo analyses revealed reduced primary tumor formation in E-cadherin-overexpression SUM44PE cells after mammary fat pad injection. Additional studies aimed at understanding E-cadherin’s effect on in vivo metastasis are ongoing.Collectively, our studies using novel cell line models will lead to an improved understanding of the hallmark loss of E-cadherin and disease mechanisms in ILC, which we hope will ultimately enable the development of more effective therapies and improve the outcome of patients with this understudied histological subtype of breast cancer.
Citation Format: Laura Savariau, Nilgun Tasdemir, Ashuvinee Elangovan, Kai Ding, Pooja Sree Tallapaneni, Jagmohan Hooda, Jennifer M. Atkinson, Adrian V. Lee, Steffi Oesterreich. Role of E-cadherin in progression of invasive breast lobular 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 956.
Abstract 96: A novel virus-drug combination to enhance oncolysis in colorectal cancer (crc)
Authors: Chavez Valery A. , Bustamante Floritza , Murray Abner , Saluja Ashok , Merchan Jaime 
Published: June 2022

Abstract
Background: While advances in immune and targeted therapies improve outcomes in selected cancers, only a minority of colorectal cancer (CRC) patients benefit from them. Oncolytic viruses (OVs) represent novel cancer biotherapies, and among them, the oncolytic measles virus (MV) has demonstrated safety and antitumor activity in early clinical studies. MV alone does is not associated with cancer cures. Triptolide, a diterpenoid epoxide extracted from the thunder god vine (Tripterygium wilfordii), has been reported to have potent antitumor effects via multiple mechanisms, including anti-proliferative, pro-apoptotic, antiangiogenic, and induction of ER stress. The effects of triptolide on viral colon cancer oncolysis have not been previously investigated.
Objectives: To characterize the in vitro and in vivo mechanisms of novel stromal retargeted oncolytic MVs and improve efficacy by combining MVs with triptolide.
Methods: The in vitro effects of triptolide alone, MV-GFP (Edmonston strain of Measles virus expressing eGFP, for human cancer cells), MV-m-uPA (MV retargeted against the murine uPA receptor, for murine cancer cells), or virus-triptolide combinations on tumor cell cytotoxicity were assessed by cell count (Vi cell counter) or xCelligence assays, on HT-29, HCT116, SW620, CT26, and MC38 cells. Molecular and mechanistic characterization of Triptolide’s effects alone and combination with MV in HT29 cells will be analyzed by the (Reverse Phase Protein Array (RPPA) and validated by western blot analysis (experiment undergoing). In vivo effects (tumor progression and survival) of minnelide (M) (water-soluble version of Triptolide) alone and in combination with Measles Virus were assessed in Balb/C mice bearing CT26.
Results: While MV and T had dose-dependent cytotoxic activity as single agents, significant augmentation of MV oncolysis was induced by co-treatment with triptolide. In vivo experiments showed similar effects observed in vitro, with potent antitumor activity of triptolide and enhanced in vivo antitumor activity when minnelide was combined with MV vectors.
Conclusions: our results strongly suggest that triptolide or minnelide enhances measles virus oncolysis in vitro and in vivo models of colorectal cancer. In vitro and in vivo mechanistic studies are underway to characterize the molecular mechanisms by which triptolide enhances MV oncolysis and will be presented at the meeting.
Citation Format: Valery A. Chavez, Floritza Bustamante, Abner Murray, Ashok Saluja, Jaime Merchan. A novel virus-drug combination to enhance oncolysis in colorectal cancer (crc) [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 96.
Abstract 966: All stressed out: Phenoytpe plasticity and therapy resistance in melanoma
Authors: Giles Jasmin , Biancaniello Maria , Fane Mitchell , Alicea Gretchen , Kossenkov Andrew , Kaur Amanpreet , Rebecca Vito , Xu Xiaowei , Herlyn Meenhard , Murphy Maureen , Weeraratna Ashani , Webster Marie R. 
Published: June 2022

Abstract
Metastatic melanoma is an aggressive disease. Despite recent improvements in therapy, drug resistant populations emerge even in drug-sensitive tumors. The ability to adapt to multiple types of stress contributes to tumor progression and therapy resistance. We have found a subset of melanoma cells with high Wnt5A and wild type p53 expression can transition to a slow-cycling state, rendering them resistant to most targeted therapy. Multiple types of stress, including DNA damage, targeted therapy, and aging increase Wnt5A and p53 in these metastatic cells. Inhibiting p53 blocks the slow cycling phenotype and promotes sensitivity to targeted therapy. A single dose of a p53 inhibitor at the commencement of BRAF/MEKi therapy was sufficient to prolong sensitivity to BRAF/MEKi therapy in Yumm1.7 derived tumors grown in aged mice (&gt; 52 weeks). Upon analysis of PDX tumors with WTp53, treated with BRAF/MEKi combination or BRAFi therapy, we observed an increase in p53 positive cells as well as an increase in Wnt5A expression, further linking Wnt5A and p53 with resistance to targeted therapy. These data suggest that melanoma cells require p53 to survive multiple types of stress and that taking the paradoxical approach of inhibiting rather than activating WTp53 may sensitize previously resistant metastatic melanoma cells to therapy by temporarily driving them into a rapidly cycling state. WTp53 is typically thought of as a tumor suppressor due to its ability to regulate cell proliferation, stress response, and cell death. However, in metastatic melanoma cells, p53 promotes the expression of EDIL3, FAP, MMP3, and netrin G1, which are associated with poor prognosis, increased angiogenesis, and metastasis in multiple types of cancer. These data suggest that p53, typically thought of as a tumor suppressor, may be promoting the survival of a subset of highly resistant metastatic cells.
Citation Format: Jasmin Giles, Maria Biancaniello, Mitchell Fane, Gretchen Alicea, Andrew Kossenkov, Amanpreet Kaur, Vito Rebecca, Xiaowei Xu, Meenhard Herlyn, Maureen Murphy, Ashani Weeraratna, Marie R. Webster. All stressed out: Phenoytpe plasticity and therapy resistance in melanoma [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 966.
Abstract 968: Loss of glutathione peroxidase 2 promotes epithelial to mesenchymal transition and breast cancer metastasis
Authors: Ren Zuen , Liang Huizhi , Dharmaratne Malindrie , Morales-Gallego Miriam , Fard Atefeh Taherian , Mar Jessica , Suyama Kimita , Benard Outhiriaradjou , Prystowsky Michael B. , Norton Larry , Hazan Rachel B. 
Published: June 2022

Abstract
The processes regulating tumor metastasis are multivariate and complex. Redox regulation of the tumor phenotype by GPx2 knockdown (KD) in breast cancer led us to uncover dramatic effects on spontaneous metastasis. Analysis of single cell RNA sequencing (scRNAseq) data from GPx2 KD tumor and control tumor, revealed that both tumors were comprised of several luminal-like tumor cell clusters and one mesenchymal-like cell cluster (cluster 3). Notably, GPx2 KD promoted a significant increase in the size of mesenchymal cells (cluster 3) relative to control, which might be due to the stimulation of epithelial-to-mesenchymal transition (EMT) in response to GPx2 loss. In support of this view, GPx2 KD stimulated an increase in mRNA expression of basal/mesenchymal (KRT5, KRT14, KRT17, Vimentin, Twist1, Twist2, CDH2) genes and a decrease in mRNA expression of epithelial/luminal (Cldn7 and Epcam) genes, especially in cluster 3. Moreover, GPx2 KD upregulated mRNA expression of basal/mesenchymal (Twist2, CDH2, and KRT14) genes in most luminal-like clusters expressing epithelial/luminal (Epcam, Cldn3/7, CDH1, KRT8/18) genes, implying these clusters may be undergoing EMT transition in a hybrid epithelial/mesenchymal state in response to GPx2 loss. Validation of these data in cell lines and tumors showed that GPx2 KD dramatically enhanced EMT via activation of ROS/HIF1α-mediated signaling. Importantly, these effects were reversed by GPx2 re-expression or HIF1α inhibition, which was capable of suppressing EMT and metastasis. Collectively, these results indicate that GPx2 loss promotes breast cancer metastasis by stimulating EMT due to HIF1α signaling, highlighting the impact of GPx2 and HIF1 on therapeutic intervention in metastasis.
Citation Format: Zuen Ren, Huizhi Liang, Malindrie Dharmaratne, Miriam Morales-Gallego, Atefeh Taherian Fard, Jessica Mar, Kimita Suyama, Outhiriaradjou Benard, Michael B. Prystowsky, Larry Norton, Rachel B. Hazan. Loss of glutathione peroxidase 2 promotes epithelial to mesenchymal transition and breast cancer 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 968.