bluuebunny/crossref_metadata_2025_split huggingface dataset:
Secreted Frizzled-Related Protein 4 Is Silenced by Hypermethylation and Induces Apoptosis in β-Catenin–Deficient Human Mesothelioma Cells
Authors: He Biao , Lee Amie Y. , Dadfarmay Sina , You Liang , Xu Zhidong , Reguart Noemi , Mazieres Julien , Mikami Iwao , McCormick Frank , Jablons David M. 
Published: June 2022

Abstract
The secreted frizzled-related proteins (SFRPs) function as negative regulators of Wnt signaling and have important implications in tumorigenesis. Frequent promoter hypermethylation of SFRPs has been identified in human cancer. Restoration of SFRP function attenuates Wnt signaling and induces apoptosis in a variety of cancer types. Wnt signaling is known to inhibit apoptosis through activation of β-catenin/Tcf–mediated transcription. Recently, we identified aberrant Wnt activation as a result of Dishevelled overexpression in malignant mesothelioma. Here, we report that silencing of SFRP4 is correlated with promoter hypermethylation in β-catenin–deficient mesothelioma cell lines. Reexpression of SFRP4 in these β-catenin–deficient mesothelioma cell lines blocks Wnt signaling, induces apoptosis, and suppresses growth. Conversely, knocking down SFRP4 by small interfering RNA in cell lines expressing both SFRP4 and β-catenin stimulates Wnt signaling, promotes cell growth, and inhibits chemodrug-induced apoptosis. Our results suggest that methylation silencing of SFRP4 may play an important role in aberrant Wnt activation in mesothelioma even in the absence of β-catenin. Our data also suggest that β-catenin–independent noncanonical pathway(s) may be involved in the apoptotic inhibition caused by activation of Wnt signaling.
Homeobox Msx1 Interacts with p53 Tumor Suppressor and Inhibits Tumor Growth by Inducing Apoptosis
Authors: Park Kyoungsook , Kim Kwangbae , Rho Seung Bae , Choi Kyusam , Kim Dojin , Oh Sun-Hee , Park Jinhee , Lee Seung-Hoon , Lee Je-Ho 
Published: June 2022

Abstract
The stability of wild-type p53 is critical for its apoptotic function. In some cancers, wild-type p53 is inactivated by interaction with viral and cellular proteins, and restoration of its activity has therapeutic potential. Here, we identify homeobox Msx1 as a p53-interacting protein and show its novel function as a p53 regulator. Overexpression of homeobox Msx1 induced apoptosis of cancer cells harboring nonfunctional wild-type p53 and suppressed growth of human tumor xenografts in nude mice. The homeodomain of Msx1 functions as a protein-protein interacting motif rather than a DNA-binding domain and is essential for stabilization, nuclear accumulation, and apoptotic function of wild-type p53. The identification of a novel function of Msx1 as a p53 regulator may open new avenues for developing improved molecular therapies for tumors with a nonmutational p53 inactivation mechanism.
Suppression of Melanotroph Carcinogenesis Leads to Accelerated Progression of Pituitary Anterior Lobe Tumors and Medullary Thyroid Carcinomas in Rb+/− Mice
Authors: Zhou Zongxiang , Flesken-Nikitin Andrea , Levine Corinna G. , Shmidt Elena N. , Eng Jessica P. , Nikitina Ekaterina Yu. , Spencer David M. , Nikitin Alexander Yu. 
Published: June 2022

Abstract
Mice with a single copy of the retinoblastoma gene (Rb+/−) develop a syndrome of multiple neuroendocrine neoplasia. They usually succumb to fast-growing, Rb-deficient melanotroph tumors of the pituitary intermediate lobe, which are extremely rare in humans. Thus, full assessment of Rb role in other, more relevant to human pathology, neoplasms is complicated. To prevent melanotroph neoplasia while preserving spontaneous carcinogenesis in other types of cells, we have prepared transgenic mice in which 770-bp fragment of pro-opiomelanocortin promoter directs expression of the human RB gene to melanotrophs (TgPOMC-RB). In three independent lines, transgenic mice crossed to Rb+/− background are devoid of melanotroph tumors but develop the usual spectrum of other neoplasms. Interestingly, abrogation of melanotroph carcinogenesis results in accelerated progression of pituitary anterior lobe tumors and medullary thyroid carcinomas. A combination of immunologic tests, cell culture studies, and tumorigenicity assays indicates that α-melanocyte–stimulating hormone, which is overproduced by melanotroph tumors, attenuates neoplastic progression by decreasing cell proliferation and inducing apoptosis. Taken together, we show that cell lineage–specific complementation of Rb function can be successfully used for refining available models of stochastic carcinogenesis and identify α-melanocyte–stimulating hormone as a potential attenuating factor during progression of neuroendocrine neoplasms.
Growth Stimulation of COX-2–Negative Pancreatic Cancer by a Selective COX-2 Inhibitor
Authors: Eibl Guido , Takata Yasunori , Boros Laszlo G. , Liu Joey , Okada Yuji , Reber Howard A. , Hines Oscar J. 
Published: June 2022

Abstract
Cyclooxygenase 2 (COX-2) inhibitors are promising antiangiogenic agents in several preclinical models. The aim of the present study was to evaluate the effect of selective COX-2 inhibitors on vascular endothelial growth factor (VEGF) production in vitro and angiogenesis and growth of pancreatic cancer in vivo, focusing on putative differences between COX-2–negative and COX-2–positive tumors. VEGF production and angiogenesis in vitro were determined by ELISA and endothelial cell migration assay. To determine whether the effect of COX-2 inhibitors was mediated by peroxisome proliferator–activated receptor γ (PPAR-γ), we used a dominant-negative PPAR-γ and a pharmacologic inhibitor. In vitro findings were validated in a pancreatic cancer animal model. Microvessel density was assessed by CD31 immunostaining. Intratumoral prostaglandin and VEGF levels were measured by mass spectroscopy and ELISA. Selective COX-2 inhibitors had a concentration-dependent effect on VEGF production in vitro. Higher concentrations increased VEGF levels and stimulated angiogenesis by activating PPAR-γ. In vivo, nimesulide increased VEGF production by cancer cells in COX-2–positive and COX-2–negative pancreatic tumors. In COX-2–negative pancreatic cancer, this effect was associated with an increase in angiogenesis and growth. In COX-2–positive pancreatic cancer, the nimesulide-induced increase of VEGF production by the cancer cells was offset by a decrease in VEGF production by the nonmalignant cell types leading to reduced tumor angiogenesis and growth. Selective COX-2 inhibitors had opposite effects on growth and angiogenesis in pancreatic cancer depending on COX-2 expression. These findings imply that assessing the COX-2 profile of the pancreatic tumor is mandatory before initiating therapy with a selective COX-2 inhibitor.
Expression-Based Discovery of Variation in the Human Glutathione S-Transferase M3 Promoter and Functional Analysis in a Glioma Cell Line Using Allele-Specific Chromatin Immunoprecipitation
Authors: Liu Xuemei , Campbell Michelle R. , Pittman Gary S. , Faulkner Eric C. , Watson Mary A. , Bell Douglas A. 
Published: June 2022

Abstract
Discovery and functional evaluation of biologically significant regulatory single nucleotide polymorphisms (SNP) in carcinogen metabolism genes is a difficult challenge because the phenotypic consequences may be both transient and subtle. We have used a gene expression screening approach to identify a functional regulatory SNP in glutathione S-transferase M3 (GSTM3). Anttila et al. proposed that variation in GSTM3 expression was affected by exposure to cigarette smoke and inheritance of the GSTM1-null genotype. To investigate the mechanism of GSTM3 expression was affected by exposure to cigarette smoke and inheritance of the GSTM1-null genotype. To investigate the mechanism of GSTM3 expression variation, we measured GSTM3 expression in lymphoblast cells from a human Centre d'Etude du Polymorphisme Humain family and observed a low expression phenotype. Promoter sequencing revealed two novel GSTM3 promoter SNPs: A/C and A/G SNPs, 63 and 783 bp upstream of the codon 1 start site, respectively. In this pedigree, the two children homozygous for the −63C/C genotype had 8-fold lower GSTM3 expression relative to the two children with the −63A/A genotype, with no association between A−783G SNP and GSTM3 expression. Further evaluation using genotyped glioma cell lines and with luciferase reporter constructs showed that the −63C allele was associated with lower GSTM3 expression (P &lt; 0.0001 and P &lt; 0.003). RNA pol II chromatin immunoprecipitation was combined with quantitative probed-based allelic discrimination genotyping to provide direct evidence of a 9-fold reduced RNA pol II binding capacity for the −63C allele. These results show that the GSTM3 −63C allele strongly affects gene expression in human cell lines and suggests that individuals who carry the low expression allele may be deficient in glutathione transferase catalyzed biological functions.
Abstract 6298: The novel long noncoding RNA lncNeur promotes neuroblastoma by up-regulating AURKA and Myc expression
Authors: Wu Jing , Liu Pei Yan , Cheung Belamy , Marshall Glenn , Dinger Marcel , Liu Tao 
Published: June 2022

Abstract
Background: Neuroblastoma is the most common solid tumor in early childhood, and accounts for approximately 15% of childhood cancer death. We have recently analyzed RNA sequencing data from 493 human neuroblastoma tissues, and identified the long noncoding RNA lincNeur as one of the transcripts, high expression of which most considerably correlated with poor prognosis in both MYCN oncogene-amplified and MYCN non-amplified neuroblastoma patients.
Aims: To determine the tumorigenic role of lincNeur in neuroblastoma, and to identify the mechanism of action through which lincNeur exerts oncogenic function, also to screen for small molecule compound inhibitors of lincNeur.
Methods and results: We performed RNA-binding protein pull-down assay and RNA-immunoprecipitation assay. RALY was identified and validated as one of the binding proteins of lincNeur. We also identified down-stream targets of lincNeur via genome-wide differential gene expression analysis. E2F1 and AURKA were identified as among the transcripts significantly down-regulated after lincNeur knockdown. RT-PCR and western blot analysis showed that lincNeur knockdown reduced E2F1 and AURKA mRNA and protein expression, and reduced N-Myc and c-Myc protein but not mRNA expression. In addition, lincNeur or RALY knockdown reduced, while over-expression of lincNeur or RALY promoted, neuroblastoma cell proliferation. We also demonstrated lincNeur knockdown significantly suppressed RALY protein binding to E2F1 and AURKA mRNAs. Mouse xenograft model experiment showed that lincNeur knockdown suppressed neuroblastoma tumor progression in vivo. Importantly, we have confirmed the binding site between lincNeur and RALY, and are screening small molecule compound libraries for inhibitors of lincNeur and RALY interaction for neuroblastoma therapy.
Conclusions: The novel long noncoding RNA lincNeur promotes neuroblastoma by interacting with RALY to up-regulate E2F1 and AURKA mRNA and protein, as well as N-Myc and c-Myc protein expression. Small molecule compound inhibitors of lincNeur and RALY interaction is a promising therapeutic approach.
Citation Format: Jing Wu, Pei Yan Liu, Belamy Cheung, Glenn Marshall, Marcel Dinger, Tao Liu. The novel long noncoding RNA lncNeur promotes neuroblastoma by up-regulating AURKA and Myc 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 6298.
Abstract PL01-05: Genomic medicine meets cancer interception
Authors: Domchek Susan M. 
Published: June 2022

Abstract
The increased identification of individuals with an elevated risk of developing cancer based on inherited genetic susceptibility allows for targeted cancer interception opportunities. Understanding the molecular basis for cancer susceptibility creates the potential to disrupt the oncogenic process even after it has started. Individuals with pathogenic variants in BRCA1 and BRCA2 are at increased risk for the development of breast, ovarian, pancreatic, and prostate cancers. Work over the past decade has allowed for an understanding of the cells of origin of BRCA1 - related breast cancer and has led to a Phase III study of denosumab vs placebo to examine the impact of denosumab on breast cancer risk. The adjuvant study of the PARP inhibitor olaparib in high risk BRCA-associated breast cancer demonstrated an improvement in event free survival along with a favorable safety profile, paving the way for further work in the prevention space. Immunologic approaches have led to clinical trials using vaccines which will include healthy BRCA1/2 carriers. As our molecular understanding of BRCA haploinsufficiency improves, so too will our options for cancer interception. All of this work could lead to a halo effect with impact on sporadic cancer interception.
Citation Format: Susan M. Domchek. Genomic medicine meets cancer interception [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 PL01-05.
Abstract PL04-03: Germline and microbiome variants impact immunotherapy efficacy through modulation of myeloid cells
Authors: Gajewski Thomas F. 
Published: June 2022

Abstract
Most cancers express tumor antigens that can be recognized by T cells of the host. The fact that cancers become clinically relevant and grow nonetheless implies that immune escape must occur to allow cancer outgrowth. We have observed two major phenotypes of human melanoma metastases based on gene expression profiling and confirmatory assays. One subgroup of patients has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and appears to display immune “exclusion”. Factors that influence the degree of spontaneous immune infiltration are being investigated, as sources of inter-patient heterogeneity. These include tumor cell-intrinsic oncogenic events, the composition of the gut microbiota, and polymorphisms in immune regulatory genes. We now know that each of these dimensions can be functionally important. The first tumor cell-intrinsic oncogenic pathway identified that mediates immune exclusion is the Wnt/β-catenin pathway. Tumors with active β-catenin fail to recruit Batf3-lineage dendritic cells into the tumor site. Regarding the commensal microbiota, mouse models identified commensal Bifidobacterium as one key component that augments spontaneous anti-tumor immunity and increases efficacy of anti-PD-L1 therapy in vivo. Similar analyses in human cancer patients revealed bacteria sequences enriched in anti-PD-1 responders, and also bacteria sequences enriched in non-responders. Fecal transfer into germ-free mice has confirmed a causal role for the gut microbiota in regulating immunotherapy efficacy. Recent experiments have revealed that one major mechanism by which gut microbes impact on distant ani-tumor immunity is through modulation of immune-regulatory myeloid cells, ie the M1/M2 ratio and MDSCs. Regarding germline variants, our first identified SNP connected to immune cell infiltration is in the PKCδ gene. Loss of function variants are associated with greater immune cell infiltration. PKCδ knockout hosts show improved immune-mediated tumor control and anti-PD-L1 efficacy, but with comparable T cell priming. However, activated T cell accumulation in the tumor microenvironment increases overtime, which is associated with a shift from M2 to M1. Myeloid cell-specific PKCδKO mice using LysM-Cre Tg mice recapitulate the phenotype. Thus, in each of these 3 instances, tumor and host factors impact on anti-tumor immunity by modulating myeloid cell participation—Batf3-DCs, MDSCs, and M1/M2 cells.
Citation Format: Thomas F. Gajewski. Germline and microbiome variants impact immunotherapy efficacy through modulation of myeloid cells [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 PL04-03.
Abstract SY03-02: Extrachromosomal DNA (ecDNA): Cancer's dynamic circular genome
Authors: Mischel Paul S. 
Published: June 2022

Abstract
Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumor-promoting genes and regulatory elements can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). ecDNA poses one of the greatest challenges for cancer patients, affecting children and adults and women and men, with a wide variety of cancer types. Although ecDNA was first observed more than 50 years ago, its critical importance has only recently come to light. ecDNA, because of its non-chromosomal inheritance, drives high-copy number oncogene amplification and enables tumors to evolve their genomes rapidly, contributing to treatment resistance and shorter survival for patients. Furthermore, the circular ecDNA architecture fundamentally alters gene regulation and transcription. In this talk, I will discuss recent collaborative discoveries that highlight how the higher order, spatial organization of ecDNA, and its mechanism of inheritance, contributes to aggressive tumorigenesis, accelerated evolution, and treatment resistance.
Citation Format: Paul S. Mischel. Extrachromosomal DNA (ecDNA): Cancer's dynamic circular genome [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 SY03-02.
Abstract SY23-03: Mesenchymal lineage heterogeneity as a determinant of matrix composition and tumor progression
Authors: Sherman Mara H. 
Published: June 2022

Abstract
The mechanisms underlying evolution of tumor-associated stroma remain poorly understood. In solid tumors featuring a prominent stromal reaction, an improved understanding of the functions and origins of abundant stromal cell types may facilitate the development of new and effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is the quintessence of a fibro-inflammatory malignancy, with 50-90% of tumor volume occupied by a dense, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are the key cell type which drives the stromal reaction in PDAC, and recent reports suggest that stromal CAFs represent a heterogeneous population of cells from diverse origins, potentially including cell types which support and others which suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas which can transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of fibroblasts in the PDAC tumor microenvironment. However, proper lineage tracing studies have never been performed, such that the relative contribution and specific functions of PSCs in the tumor microenvironment are unknown. We have developed a novel mouse model to track PSC differentiation and function during pancreatic tumor progression in vivo. This model revealed that PSC-derived CAFs in fact give rise to a numerically minor but functionally significant subset of PDAC CAFs, and may represent a viable therapeutic target. We adapted our mouse model to enable targeted ablation of PSCs and derivative CAFs within their host tissue for the first time. Functional studies in this model reveal non-redundant functions for PSC-derived CAFs in shaping the PDAC microenvironment, and highlight the significance of mesenchymal lineage heterogeneity for pancreatic tumorigenesis. Further, we find that tumor genotype with respect to p53 status dictates stromal evolutionary routes with respect to cell of origin, a finding that may extend to additional cancer cell-intrinsic genomic alterations. Together, these findings shed light on mechanisms that shape the tumor microenvironment during pancreatic cancer progression, and may hold relevance in additional solid tumor types.
Citation Format: Mara H. Sherman. Mesenchymal lineage heterogeneity as a determinant of matrix composition and tumor progression [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 SY23-03.
Abstract SY31-04: Uncovering targetable dependencies of latent brain metastatic cells
Authors: Malladi Srinivas 
Published: June 2022

Abstract
Uncovering Targetable Dependencies of Latent Brain Metastatic Cells
Srinivas Malladi, Department of Pathology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, 75390, USA
ABSTRACT
HER2+ breast cancer patients presenting with brain metastases have poor survival outcomes. Metachronous brain metastases or relapse are observed in approximately fifty percent of HER2+ breast cancer patients considered disease free after a variable length of time post primary diagnosis and treatment. Disseminated latent residual cells that survive current therapies are responsible for these relapses or metachronous metastasis. How disseminated tumor cells survive as latent/dormant entities for extended period before initiating metachronous metastasis is poorly understood. Moreover, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ is unknown and vital for better clinical management. Through a phenotypic screen in mice, we have isolated HER2+ latent (Lat) and brain metastatic (BM) cells.Transcriptomic and metabolic profiles of these brain-tropic breast cancer cells identified actionable dependencies and unique therapeutic opportunities. Brain-tropic Lat and metastatic cells have distinct metabolic profiles that determine their metastatic fitness. Both latent and metastatic cells survive in equilibrium with innate immune surveillance, oxidize glutamine and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Likewise, xCT expression was significantly higher in matched metachronous brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Genetic or pharmacological blockade of xCT eradicates residual disease and brain metastatic relapse in these preclinical models. Lactate secreted by aggressive metastatic cells limits innate immune surveillance and triggers overt metastasis. Furthermore, transcriptomic analysis identified augmented AXL expression. Depleting or inhibiting AXL in these HER2 targeted therapy resistant brain-tropic cells attenuates metastatic incidence. In sum, by investigating phenotypically distinct brain-tropic latent and metastatic cells, we uncovered the impact of metabolic diversity and adaptations on metastatic fitness and identified targetable vulnerabilities.
Citation Format: Srinivas Malladi. Uncovering targetable dependencies of latent brain metastatic cells [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 SY31-04.