bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 834: Serine protease hepsin regulates tumor growth via TGFbeta-EGFR signaling axis
Authors: Tervonen Topi A. , Belitškin Denis , Munne Pauliina , Pant Shishir M. , Suleymanova Ilida , Belitškina Kati , Pouwels Jeroen , Klefström Juha 
Published: June 2022

Abstract
Hepsin (encoded by HPN gene) is a type II transmembrane serine protease, which is commonly overexpressed in carcinomas of prostate and breast. Hepsin protein is known to be stabilized by Ras-MAPK pathway signaling, and downstream, this protease regulates the degradation of extracellular matrix (ECM) components and activates growth factor pathways, including hepatocyte growth factor (HGF) and transforming growth factor beta (TGF beta) pathway. However, the impact of the hepsin-dependent signaling on cell proliferation and tumor growth is not well-understood. Therefore, we sought to clarify the role of hepsin during these events using engineered breast cancer cell lines, Hpn CRISPR knockout mouse model crossed with Wap-Myc breast cancer mouse model, and patient-derived explant cultures (PDEC)s from human breast tumors. We isolated Wap-Myc; Hpn-/- mammary tumor cells and made orthotopic transplantation into syngeneic wild-type recipient mice. The resulting Wap-Myc tumors that lack hepsin had reduced size both in primary and metastatic site compared to tumors derived from Wap-Myc; Hpn+/+ tumor cells. This decrease in growth was accompanied by downregulation in TGF beta and EGFR signaling as well as substantial reduction in total EGFR protein level. We further demonstrated that in 3D culture conditions overexpression of hepsin induced cell proliferation, which was TGF beta 1 and EGFR signaling-dependent, while PDECs treated with hepsin inhibitory antibodies and small molecules had decreased EGFR and TGF beta signaling activity and reduction in proliferation marker expression. Taken together, this study demonstrates a role for hepsin as a regulator of cell proliferation and tumor growth through TGF beta and EGFR pathways and may provide an interesting druggable upstream target to inhibit TGF beta and EGFR pathways in breast cancer.
Citation Format: Topi A. Tervonen, Denis Belitškin, Pauliina Munne, Shishir M. Pant, Ilida Suleymanova, Kati Belitškina, Jeroen Pouwels, Juha Klefström. Serine protease hepsin regulates tumor growth via TGFbeta-EGFR signaling axis [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 834.
Abstract 849: Characterization and prevention of radiation-induced malignancies in Li-Fraumeni Syndrome
Authors: Psarianos Pamela , Fischer Nicholas , Giovino Camilla , Ong Noel , Malkin David 
Published: June 2022

Abstract
PURPOSE: Li-Fraumeni Syndrome (LFS) is a genetic disorder associated with a significant risk of early-onset cancer. This condition is largely driven by germline mutations in the TP53 tumor suppressor, which has a broad spectrum of functions including the transcriptional regulation of radiation response. Termed the guardian of the genome, TP53 serves as a critical checkpoint which coordinates DNA repair, cell cycle progression and apoptosis following DNA damage, ultimately controlling the fate of the cell.
Aberrant or deficient TP53 function, such as occurs in LFS, contributes to radiation vulnerability. As a result, there is particular caution in the use of radiotherapy to treat primary LFS tumors, in order to prevent the formation of secondary, radiation-induced malignancies. To this end, therapeutic options for LFS are often limited to surgery and chemotherapy, posing substantial constraints for the treatment of patients who may otherwise benefit from primary tumor radiation.
Metformin, a commonly prescribed anti-diabetic drug, is associated with lower cancer incidence in populations worldwide. Recent studies have shed light on the potential utility of metformin as a pharmacopreventive agent for primary tumors in LFS; hence, we hypothesize that the utility of metformin can be extended to the prevention of secondary malignancies following radiotherapy in LFS.
METHODS/RESULTS: To explore the chemopreventive potential of metformin in LFS, we completed tumor challenges using a p53R172H/+ LFS mouse model. Mice treated prophylactically with metformin showed slower xenograft tumor growth compared to vehicle-treated mice. Ongoing work in our lab aims to characterize the effects of metformin on tumor growth following the administration of localized ionizing radiation (IR) to LFS mice. Briefly, these mice are treated with either vehicle or metformin, and IR is administered to the left hindlimbs to induce tumor formation. The timing and rates of tumor growth are monitored using magnetic resonance imaging. At endpoint, excised tumors are subjected to global profiling via RNA sequencing, proteomic analysis, and single-cell sequencing of discrete cell populations to characterize the effects of metformin on the development of radiation-induced malignancies. Results of these studies will be presented.
SIGNIFICANCE: Overall, this work will advance our understanding of the chemopreventive effects of metformin, with the potential to broaden the treatment options available to LFS patients.
Citation Format: Pamela Psarianos, Nicholas Fischer, Camilla Giovino, Noel Ong, David Malkin. Characterization and prevention of radiation-induced malignancies in Li-Fraumeni Syndrome [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 849.
Abstract 864: Ophiopogonin D increase apoptosis by activating p53 via ribosomal protein L5 and L11 and inhibiting the expression of c-Myc via CNOT2
Authors: Ko Hyun Min , Jee Wona , Park Do-il , Park Somi , Park Ye-Rin , Jang Hyeung-Jin , Jung Ji Hoon 
Published: June 2022

Abstract
Extracted from the root tuber of Ophiopogon japonicas, ophiopogon is well known to have an anti-cancer effect. However, the underlying mechanisms are still largely unknown. Here, we report that Ophiopogon D (OP-D) can inhibit colon cancer cell proliferation and induce apoptosis by inhibiting c-Myc expression through activation of p53 and CNOT2 regulation. Our results showed that OP-D induced p53 expression via ribosomal protein L5 or L11 and inhibited c-Myc expression through CNOT2 in a dose-dependent manner. Additionally, OP-D regulated cyclin D1 and CDK4 which are well known as cell cycle regulatory proteins. Consistently, OP-D inhibited the phosphorylation of AKT expression in a dose-dependent manner. Furthermore, OP-D shortened c-Myc’s half-life in a time-dependent manner. Furthermore, CNOT2 knockdown enhanced the inhibitory effect of OP-D on c-Myc in colon cancer cells. Interestingly, OP-D has increased the apoptotic effect of colon cancer cells when combined with doxorubicin or 5-FU, a treatment already used clinically. Altogether, our results suggested that OP-D regulates colon cancer cell survival and induces apoptosis by inhibiting c-Myc expression via activation of p53 and CNOT2 regulation.
Citation Format: Hyun Min Ko, Wona Jee, Do-il Park, Somi Park, Ye-Rin Park, Hyeung-Jin Jang, Ji Hoon Jung. Ophiopogonin D increase apoptosis by activating p53 via ribosomal protein L5 and L11 and inhibiting the expression of c-Myc via CNOT2 [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 864.
Abstract 899: Effects of innate immune deaminase deregulation on initiation and progression of myeloproliferative neoplasms
Authors: Isquith Jane Marie , Mark Adam , Pham Jessica , Donohoe Mary , Ladel Luisa , Jamieson Catriona 
Published: June 2022

Abstract
Inflammatory cytokine responsive APOBEC3 cytidine deaminases have been studied extensively with regard to innate immunity and more recently during cancer evolution. However, the mechanisms by which the APOBEC3 enzymes promote cancer initiation and progression in the malignant microenvironment remains to be investigated, especially in hematopoietic malignancies. Through whole genome and whole transcriptome sequencing analyses of MPN patient samples FACS sorted into stem and progenitor populations, we have found a cell type and context specific nature of these enzymes, notably the upregulation of APOBEC3C (A3C) in the high-risk Myelofibrosis (MF) stem cell population as compared to normal aged counterparts. Through lentiviral overexpression of each APOBEC3 enzyme, we can now study the effects of changes in APOBEC3 transcript level in relation to the known changes in expression seen in many cancers, focusing on the upregulation of A3C. Using these techniques, we have identified novel RNA and DNA editing targets, as well as differential gene expression patterns of each APOBEC3 in normal CD34+ cord blood and aged normal bone marrow. Gene set enrichment analysis (GSEA) performed on this dataset has exposed numerous deregulated pathways brought on by exaggerated levels of APOBEC3, including changes in splicing pathways. In addition, novel identification of the relationship between A3C and ADAR1, another innate immune deaminase, has important implications in initiation and prognosis of MPNs. Both A3C and ADAR1 transcript levels are elevated in high risk MF stem cells, and co-immunoprecipitation studies reveal a direct binding of the enzymes. Furthermore, we are able to study the detailed effects of editing by both A3C and ADAR1 using editase-deficient mutant constructs, allowing for a mechanistic look into the role of these deaminases and their deregulation in vitro and in vivo using patient samples and humanized mouse models. This novel connection, as well as the role of A3C in initiation and progression of hematopoietic malignancies will continued to be studied using this system to elucidate effects on proliferation, differentiation, self-renewal, and changes to the cell cycle, in hopes of creating both a marker of early detection and potentially a druggable target.
Citation Format: Jane Marie Isquith, Adam Mark, Jessica Pham, Mary Donohoe, Luisa Ladel, Catriona Jamieson. Effects of innate immune deaminase deregulation on initiation and progression of myeloproliferative neoplasms [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 899.
Abstract 915: C/EBPβis required for mouse mammary tumorigenesis
Authors: Burke Caitlin M. , Rojo Michelle D. , Rosen Jeffery M. , Ackermann Tobias , Muller Christine , Calkhoven Cornelis F. , Machado Heather L. 
Published: June 2022

Abstract
Breast tumorigenesis relies on complex interactions between tumor cells and their surrounding environment, orchestrated by tightly regulated transcriptional networks. While much is known about the signaling pathways affecting breast cancer cell growth and apoptosis, the transcriptional programs driving these responses are less understood. C/EBPβ is a transcription factor essential for proper cellular proliferation, differentiation, tissue function, metabolism, and the immune response, and is deregulated in breast cancer. C/EBPβ and its protein isoform LIP have long been postulated to promote breast cancer progression, however, the precise mechanisms and gene regulatory networks induced by C/EBPβ are less understood. Analysis of available human patient gene expression data reveals that increased Cebpb mRNA is associated with poor overall survival amongst all breast cancer subtypes, and analysis of available liquid chromatography with tandem mass spectrometry data shows that increased C/EBPβ total protein is associated with poor overall survival in triple-negative breast cancer patients. To test the function of C/EBPβ in tumor initiation and progression, several genetic mouse models were generated. Genetic ablation of tumor C/EBPβ in mouse models of basal-like [C3(1)TAg] and luminal (MMTV-Neu) breast cancers results in a complete block in mammary tumorigenesis. Interestingly, C/EBPβ-null tumor cells upregulate genes involved in antigen presentation and interferon gamma response in vitro, while overexpression of the C/EBPβ-LIP induces chemokines involved in immune cell recruitment and immunosuppression, such as CCL5. In support, RNA sequencing of human breast cancer cells shows that deletion of Cebpb in BT-20 cells causes de-repression of immune genes. Specifically, genes associated with interferon α and γ signaling (JAK1, TNFA, CCRL16, CSF2, IL32) as well as genes involved in antigen processing and presentation (MHC class I and class II molecules) are upregulated in the absence of Cebpb. These data suggest that C/EBPβ may repress genes important for immune visibility. Ongoing studies are aimed at identifying gene regulatory programs induced by C/EBPβ and specifically by C/EBPβ-LIP. These studies will have critical implications for whether C/EBPβ-induced pathways can be targeted in combination with other drugs, such as immune checkpoint inhibitors, improving patient outcome. These studies are supported by NIH RO1CA212518 (H.L.M.).
Citation Format: Caitlin M. Burke, Michelle D. Rojo, Jeffery M. Rosen, Tobias Ackermann, Christine Muller, Cornelis F. Calkhoven, Heather L. Machado. C/EBPβis required for mouse mammary tumorigenesis [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 915.
Abstract 927: Developing new mouse models of metastatic lung cancer
Authors: Wells Julie , Maser Richard , Tucker Ashley , McGee Teresa , Memishian Wendy , Doty Rosalinda , Bult Carol J. 
Published: June 2022

Abstract
INTRODUCTION: The focus of this work is to develop new mouse models for metastatic lung cancer. Lung cancer is the leading cause of cancer deaths worldwide and greater than 75% of human lung cancer deaths can be attributed to metastasis. Metastatic disease in most existing mouse models of pulmonary adenocarcinoma is typically sporadic and often requires aging mice for several months. These factors limit the usefulness of mouse models for basic and pre-clinical research aimed at identifying effective treatments of metastatic disease.
METHODS AND RESULTS: We have developed new mouse models of pulmonary adenocarcinoma in which we added mutations in Dicer1, an RNAse III enzyme within the microRNA (miRNA) biosynthesis pathway to a mouse model of Kras-driven pulmonary adenocarcinoma. For both models, we induced tumorigenesis by conditionally expressing an oncogenic allele of Kras (KrasG12D), deleting of both alleles of Trp53 and deleting one allele of Dicer1 in one cell population then expressing truncated Dicer1 in a different cell population. In the absence of Dicer1 truncation, mice expressing KrasG12D and deleting Trp53 in Club cells have a reported median survival of 28.6 weeks after tumor induction. When we also deleted one allele of Dicer1 in Club cells and truncated Dicer1 in alveolar type II cells of these mice, they exhibited respiratory distress and began dying 12.1 weeks after tumor induction. In our initial pilot study, all animals (12/12) developed pulmonary adenocarcinoma and 30% (3/10) had lymph node metastasis. We did not observe accelerated tumorigenesis, however, when we switched cell types, inducing tumorigenesis in alveolar type II cells and truncating Dicer1 in Club cells, or when induced tumorigenesis and truncating Dicer1 within the same cell populations.
CONCLUSIONS: Through cell type specific truncation/deletion of Dicer1 we have generated a new mouse model that rapidly develops pulmonary adenocarcinomas and metastatic disease. Our findings support our hypothesis that tumorigenesis and metastasis are influenced by miRNA regulated communication between different cell types. These models have potential for both understanding the basic processes of metastasis and for pre-clinical studies aimed at preventing and/or treating metastatic lung cancer.
Citation Format: Julie Wells, Richard Maser, Ashley Tucker, Teresa McGee, Wendy Memishian, Rosalinda Doty, Carol J. Bult. Developing new mouse models of metastatic lung 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 927.
Abstract 945: Gab2 deficiency protects against Flt3-ITD driven acute myeloid leukemia in vivo
Authors: Spohr Corinna , Poggio Teresa , Andrieux Geoffroy , Schönberger Katharina , Cabezas-Wallscheid Nina , Börries Melanie , Halbach Sebastian , Illert Anna L. , Brummer Tilman 
Published: June 2022

Abstract
Internal tandem duplications (ITD) of the FMS-like tyrosine kinase 3 (FLT3) frequently co-exist with inactivating DNMT3A mutations and predict poor prognosis in acute myeloid leukemia (AML). In vitro studies implicated the docking protein Grb2-associated binder 2 (GAB2) as FLT3-ITD effector. By utilizing a Flt3-ITD knock-in, Dnmt3a haploinsufficient mouse model, we demonstrate that Gab2 is essential for the development of Flt3-ITD driven AML in vivo, as Gab2 deficient mice survived significantly longer, had reduced blast counts and exhibited an attenuated spleen and liver pathology as compared to their Gab2-proficient littermates. Further, leukemic bone marrow isolated from Gab2 deficient mice displayed a reduced colony forming unit capacity and an increased sensitivity towards the Flt3 inhibitor quizartinib. Using RNA sequencing, we identify the genes encoding for Axl and the Ret co-receptor Gfra2 as targets of the Flt3-ITD/Gab2/Stat5 axis. We propose a pathomechanism in which Gab2 increases signaling of these receptors as it induces their expression and additionally serves as a downstream effector. Consequently, Gab2 promotes AML aggressiveness as well as drug resistance by incorporating the receptor tyrosine kinases Axl and Ret into the Flt3-ITD signaling network. Therefore, our data identify GAB2 as a promising biomarker as well as a therapeutic target in human AML.
Citation Format: Corinna Spohr, Teresa Poggio, Geoffroy Andrieux, Katharina Schönberger, Nina Cabezas-Wallscheid, Melanie Börries, Sebastian Halbach, Anna L. Illert, Tilman Brummer. Gab2 deficiency protects against Flt3-ITD driven acute myeloid leukemia in vivo [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 945.
Abstract 974: Genome-wide analysis of estrogen receptor b binding sites: Implications for endogenous anti-metastatic activity in inflammatory breast cancer
Authors: Karagounis Ilias V. , Tastsoglou Spyros , Karavangeli Anna , Maity Amit , Chatzigeorgiou Artemis , Thomas Christoforos 
Published: June 2022

Abstract
Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor a (ERa) negativity. We previously explored the second ER subtype, (ERb) and reported expression in IBC tumors and its correlation with reduced metastasis in patients. We have also seen decreased metastasis of IBC tumors when ERb is expressed or activated by chemical agonists. In contrast, ablation of ERb in IBC cells increased migration and stimulated signaling pathways that activate Rho GTPases promoting actin reorganization. We have now mapped all ERb binding sites in IBC cells and by interrogating this information together with gene expression data we identified genomic targets that mediate its tumor repressive effects. Through a combined analysis of cells that express endogenous ERb and knockout cells engineered to re-express the receptor we have defined how a biologically relevant ERb interacts with the cancer cell genome to control metastatic signals in IBC. We reveal key binding motifs and cis-regulatory chromatin sites and associate target genes with clinical outcomes to strengthen the relevance of ERb signaling for the progression of IBC. Our findings thus offer an opportunity to better understand the mechanism of ERb action that is critical step in validating its tumor repressive role in breast cancer.
Citation Format: Ilias V. Karagounis, Spyros Tastsoglou, Anna Karavangeli, Amit Maity, Artemis Chatzigeorgiou, Christoforos Thomas. Genome-wide analysis of estrogen receptor b binding sites: Implications for endogenous anti-metastatic activity in inflammatory breast 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 974.
Abstract 99: Interplay between CDK5 and IRF2BP1 enhances breast cancer brain metastasis
Authors: Yuzhalin Arseniy E. , Lowery Frank , Saito Yohei , Zhang Patrick , Yu Dihua 
Published: June 2022

Abstract
Prognosis of patients with breast cancer brain metastasis is poor due to unavailability of effective treatments. Hence, more fundamental research is needed to broaden our understanding of mechanisms underlying the origin and development of brain metastasis. We have identified that expression of cyclin-dependent kinase 5 (CDK5) in cancer cells promotes brain metastasis growth in experimental mouse models through suppressing the antitumor immunity. Here, we interrogated the underlying mechanism that connects CDK5 with defective antitumor immunity. To understand the repertoire of CDK5 phosphorylation targets, we performed a quantitative stable isotope labeling by amino acids in cell culture (SILAC) phopshoproteomics analysis of cultured brain-seeking cell lines that have been genetically engineered to express shRNA targeting the CDK5 gene. The knockdown of CDK5 resulted in a dramatic dephosphorylation of multiple proteins, among which Interferon Regulatory Factor 2 Binding Protein 1 (Irf2bp1) is well recognized to function in mediating the immune response. Knockdown of CDK5 reduced the phosphorylation of Irf2bp1 at Ser66 in both 4T1 and T11 cells (Log10 fold change: -0.51 and -0.39, respectively, P less than 0.0001). These findings were further validated by co-immunoprecipitation of Irf2bp1 in cell lysates from shCtl and shCDK5 brain-seeking cancer cell lines, followed by immunoblotting for phosphoserine. Furthermore, analysis of Irf2bp1 protein band shifts and intensities using Phos-tag™ gels also demonstrated that CDK5 knockdown reduces the Irf2bp1 phosphorylation. In order to investigate the function of Irf2bp1, we established a stable knockdown of the Irf2bp1 gene in brain metastasis-derived cell lines 4T1.Br3 and T11.Br1. We observed that Irf2bp1-knockdown cells displayed a reduced expression of genes encoding the class I major histocompatibility complex (MHC-I) as well as Nlrc5, a key transcriptional regulator of MHC I. Thus, these findings indicate that CDK5 may regulate the expression of surface MHC-I in breast cancer brain metastasis cells through Irf2bp1 phosphorylation at Ser66, in the absence of Interferon gamma or other classically recognized MHC-I agonists. These findings reveal a previously unknown mechanism of MHC-I regulation in cancer cells, that might improve our knowledge about cancer cell immune evasion through MHC-I loss.
Citation Format: Arseniy E. Yuzhalin, Frank Lowery, Yohei Saito, Patrick Zhang, Dihua Yu. Interplay between CDK5 and IRF2BP1 enhances breast cancer brain 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 99.