bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4630: In vivo characterization of the Duffy antigen receptor for chemokines (DARC/ACKR1) in breast cancer tumor progression
Authors: Martini Rachel N. , Jenkins Brittany D. , Newman Lisa A. , Manley Nancy , Davis Melissa B. 
Published: August 2019

Abstract
In studies of the tumor microenvironment (TME), factors that influence immune cell infiltration are of great interest, as these populations can influence disease prognosis, and potential treatment for patients. Through in silico analysis of TCGA breast cancer (BC) cohort data, we have identified the Duffy antigen receptor for chemokine/atypical chemokine receptor 1 (DARC/ACKR1) as a potential driver of immune cell infiltration in the BC TME. DARC/ACKR1 is an atypical chemokine receptor that modulates levels of chemokine both in circulation through expression on red blood cells, and participates in chemokine transcytosis in tissues through expression on both post-capillary venules of endothelial cells and epithelial cells. As chemokines establish gradients to recruit specific immune cell types, we hypothesize that the function of DARC/ACKR1 in chemokine level modulation also influences tumor-associated immune cell levels. In the TCGA BC cohort, we observe a strongly positive and significant correlation between DARC/ACKR1 expression and total number of tumor-associated leukocytes, specifically populations of B cells, T cell, monocytes and macrophages. To further characterize the role of DARC/ACKR1 in vivo, we have established a novel DARC knock-out BC transgenic mouse model to study DARC/ACKR1 in the BC TME. To develop our target experimental mice, Ackr1-/- female mice were crossed with Ackr1 +/-; C3(1)Tag +/0 to generate the target Ackr1 -/-; C3(1)Tag +/0 experimental mice. Experimental mice and the littermate controls were aged to 3.5 months, at which point they were euthanized. Blood was collected from the mice to characterize the circulating chemokine profile. Mammary glands containing tumors were fixed and paraffin embedded, followed by IHC and immunofluorescent staining for expression of DARC/ACKR1, target chemokines, immune cells, epithelial cells and endothelial cells. The remaining glands were dissociated, followed by fluorescent-activating cell sorting analysis (FACS) to quantify abundance of immune cells in the gland. Using these methods, we have defined the circulating chemokine profile alongside patterns of immune cell infiltration in our target DARC/ACKR1 knockout BC mice compared to littermate controls in mouse mammary tumors.
Citation Format: Rachel N. Martini, Brittany D. Jenkins, Lisa A. Newman, Nancy Manley, Melissa B. Davis. In vivo characterization of the Duffy antigen receptor for chemokines (DARC/ACKR1) in breast cancer tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4630.
Abstract 4631: Modeling the vascular sarcoma spectrum with genetically engineered mice
Authors: Hanna Jason A. , Langdon Casey G. , Garcia Matthew R. , Finkelstein David , Rehg Jerold E. , Hatley Mark E. 
Published: August 2019

Abstract
Angiosarcomas are highly aggressive vascular sarcomas with an extremely poor prognosis. Angiosarcomas can develop spontaneously or are associated with prior radiation, chronic lymphedema, or exposure to toxic chemicals such as vinyl chloride. Sequencing efforts have identified a number of genetic alterations in angiosarcoma, however the genetic drivers and actionable targets remain unclear. Despite the poor outcome for patients, there are limited resources for studying angiosarcoma, highlighting the need for genetic, in vivo models to better elucidate the underlying biology of the disease. In studying the role of DICER1 and microRNAs in mouse models of tumorigenesis, we found that Dicer1 deletion with aP2-Cre leads to aggressive and metastatic angiosarcoma development with 100% penetrance. ERK and S6 hyperphosphorylation in the aP2-Cre;Dicer1cKO (AD) tumors suggest Dicer1 loss results in activation of the RAS-MEK-ERK and mTOR pathways. To determine if direct activation of the these pathways could similarly transform aP2-Cre expressing cells we first interrogated the combination of oncogenic KrasG12D with Cdkn2a inactivation. We found that aP2-Cre;LSL-KrasG12D;Cdkn2acKO (AKC) mice rapidly develop angiosarcomas providing an accelerated model for assessing cooperating alleles and therapies. To activate the mTOR pathway we tested conditional Tsc1 deletion with aP2-Cre and found that all aP2-Cre;Tsc1cKO (AT) animals develop vascular tumors in the paws. In contrast to the AD and AKC tumors, AT tumors express markers of lymphatic endothelial cells such as PROX1. In addition, the tumors display a distinct nodular spindle cell-like morphology that is consistent with a low grade angiosarcoma resembling human kaposiform hemangioendotheliomas, a vascular tumor occurring predominantly in the extremities of infants. The distinct onset, growth kinetics, anatomic locations, and histologic presentation of the tumors from AD, AT, and AKC mice provide a mechanism to interrogate the drivers of angiosarcoma in less aggressive AT paw tumors and more aggressive AD and AKC tumors. Furthermore, the aP2-Cre driven mouse models provide a platform to study angiosarcoma initiation, progression, and metastasis for the identification of novel therapeutics to improve outcomes for this understudied and devastating disease.
Citation Format: Jason A. Hanna, Casey G. Langdon, Matthew R. Garcia, David Finkelstein, Jerold E. Rehg, Mark E. Hatley. Modeling the vascular sarcoma spectrum with genetically engineered mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4631.
Abstract 4653: Melanocyte specific deletion of Map3k1 reveals its role in BRAFV600E-driven melanoma
Authors: Trucco Lucas D. , Mundra Piyushkumar A. , Garcia-Martinez Pablo , Hogan Kate , Dhomen Nathalie , Pavet Valeria , Marais Richard 
Published: August 2019

Abstract
BRAF is the most common driver oncogene in cutaneous melanoma. Activating mutations in the BRAF gene are enriched in melanomas associated with intermittent sun exposure, with the most frequent mutations occurring at codon 600, leading to a constitutive activation of the RAF/MEK/ERK signaling pathway. In previous studies, we demonstrated that ultraviolet radiation (UVR) accelerates melanomagenesis in a mouse model of melanoma driven by BRAFV600E. From whole exome sequencing analysis of the tumors we found that Map3k1 was the most recurrently mutated gene across different experimental cohorts. MAP3K1 is unique in having both a kinase and E3 ligase function, allowing it to regulate protein phosphorylation and ubiquitin-mediated proteasome degradation. The vast majority of the mutations in Map3k1 occurred within the RING domain, which contains the E2 binding site for ubiquitin-conjugating enzymes. The most prevalent non-synonymous mutations where present in codon 484 and arose as a consequence of C-to-T transitions at a dipyrimidine site, characteristic of UVR-induced DNA damage. To understand better the role of MAP3K1, we generated Tyr::CreERT2+/o;Map3k1f/f mice allowing us to conditionally delete Map3k1 specifically in the melanocytes upon topical application of tamoxifen to the dorsal skin of juvenile mice. These mice did not develop tumors, but when crossed to mice carrying a Braf+/LSL-V600E allele, all mice develop melanoma, with a shorter latency and an increased multiplicity compared to Tyr::CreERT2+/o;Braf+/LSL-V600E mice. Tumors showed similar histopathological features, but melanomas carrying Map3k1 floxed or mutant variants presented higher levels of phosphorylated ERK1/2 than those with wild-type Map3k1. In addition, analysis of expression data of human cutaneous melanomas from The Cancer Genome Atlas showed an inverse correlation between the expression of MAP3K1 and ERK2 protein levels. Taken together, our results suggest that MAP3K1 loss-of-function cooperates with BRAFV600E to drive melanoma development by increasing MEK-ERK pathway activation.
Citation Format: Lucas D. Trucco, Piyushkumar A. Mundra, Pablo Garcia-Martinez, Kate Hogan, Nathalie Dhomen, Valeria Pavet, Richard Marais. Melanocyte specific deletion of Map3k1 reveals its role in BRAFV600E-driven melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4653.
Abstract 4656: TRAF1 is critical for regulating the BRAF/MEK/ERK pathway in non-small cell lung carcinogenesis
Authors: Wang Qiushi , Zhang Tianshun , Gao Ge , Bode Ann , Dong Zigang 
Published: August 2019

Abstract
Tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) is a unique TRAF protein that can interact directly or indirectly with multiple TNFR family members, regulatory proteins, kinases, and adaptors that contribute to its diverse functions in specific tissues. However, the role of TRAF1 in non-small cell lung cancer (NSCLC) remains unknown. In this study, we report that TRAF1 is overexpressed in human lung cancer cells and tissues. TRAF1 expression level inversely correlated with patient survival probability. Loss of TRAF1 decelerated tumor invasion in a urethane-induced lung carcinogenesis mouse model. Furthermore, TRAF1 expression affected TRAF2-mediated BRAF Lys48-linked ubiquitination, which was followed by the inhibition of growth and differentiation, and the induction of death in lung cancer cells. Overall, our work suggests that TRAF1 plays a novel role in the regulation of the BRAF/MEK/ERK signaling pathway in NSCLC and offers a candidate molecular target for lung cancer prevention and therapy.
Citation Format: Qiushi Wang, Tianshun Zhang, Ge Gao, Ann Bode, Zigang Dong. TRAF1 is critical for regulating the BRAF/MEK/ERK pathway in non-small cell lung carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4656.
Abstract 4657: MB21D2 amplification and recurrent mutation exhibit oncogenic activity through centrosome and cilia alteration
Authors: Gracilla Daniel Esguerra , Korla Praveen Kumar , Lai Louis , Sheu Jim Jinn-Chyuan 
Published: August 2019

Abstract
MB21D2 (Mab-21 containing domain 2), a member of the Mab family, is predicted to form protein complexes with different partners, thus performs diverse functions in cells. In silico analyses using TCGA data revealed MB21D2 amplification/overexpression in various types of human cancer and correlated with poor survivals in patients with head and neck and endometrial cancer. More interestingly, a recurrent Q311E mutation was found in the Mab-21 domain critical for protein-protein interactions and downstream signaling. When expressed in oral cancer TW206 and CAL27 cells (low endogenous MB21D2), wild-type MB21D2 moderately increased cell proliferation, migration, and invasion as compared to the vector control. Significantly, the mutant variant (Q311E) showed stronger oncogenic effects on those processes and formed bigger spheres in a 3-D culture condition. Data mining, functional network predictions, and Western blotting confirmed the involvement of MB21D2 in centrosome-associated ciliogenesis via a crosstalk between PIK3CA and PKA (GSK and CREB) signaling pathways. Blockage of such interactome by specific inhibitors against PIK3CA or PKA reduced oncogenic activities mediated by MB21D2. Our data therefore suggest MB21D2 amplification/overexpression or the Q311E mutation as cancer drivers promoting cancer development through alteration of centrosome and primary cilia activity.
Citation Format: Daniel Esguerra Gracilla, Praveen Kumar Korla, Louis Lai, Jim Jinn-Chyuan Sheu. MB21D2 amplification and recurrent mutation exhibit oncogenic activity through centrosome and cilia alteration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4657.
Abstract 4664: Massively parallel sequencing-based analysis of synchronous gastric cancer and lung cancer
Authors: Wu Nandie , Li Rutian , Shao Yang , Wang Lifeng , Liu Baorui , Wei Jia 
Published: August 2019

Abstract
Synchronous gastric cancer(GC) and lung cancer(LC) have been suggested to represent independent primary tumors rather than metastatic disease. We subjected sporadic synchronous GC/LC from five patients to whole-exome massively parallel sequencing, which revealed a median of and 1174 and 830 nonsynonymous somatic mutations in the synchronous GC and LC repectively. DNA mutations range between 292 to 2421 in lung samples and 287 to 1995 in stomach sample. Common mutations varies between 41 and 145. The substitution of C&gt;A, C&gt;T and T&gt;C accounts for the most common mutations in both lung and stomach cancers. Tumor mutation burden (TMB ) varies from 2.7 to 11.0 Mut/Mb in Lung cancer and from 1.8 to 30.4 Mut/Mb in gastric cancer. We further did pathway analysis based on the list of mutant genes. Top 20 pathways enriched in each patient were analyzed. We found MAPK signaling pathway was most commonly enriched pathways in lung cancer patients, whereas PI3K-Akt signaling and Hedgehog signaling pathway were most commonly enriched pathways in stomach cancer patients. This result suggests the potential benefit of targeted therapeutic treatments involved in these pathways.
Citation Format: Nandie Wu, Rutian Li, Yang Shao, Lifeng Wang, Baorui Liu, Jia Wei. Massively parallel sequencing-based analysis of synchronous gastric cancer and lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4664.
Abstract 4666: p21CIP1 promotes mammary cancer initiating cells via activation of Wnt/TCF1/CyclinD1 signaling
Authors: Hazan Rachel B. 
Published: August 2019

Abstract
Cancer stem cells (CSCs) generate and sustain tumors due to tumor initiating potential, resulting in recurrence or metastasis. We showed previously that knockout of the cell cycle inhibitor, p21CIP1, in the PyMT mammary tumor model, inhibits metastasis; however the exact mechanism remained unknown. Here, we show a pivotal role for p21 in potentiating a cancer stem cell-like phenotype. p21 knockout in PyMT mammary tumor cells suppressed tumorsphere formation, ALDH1 expression, and tumor initiating potential, that were in turn rescued by p21 overexpression. Consistent with these effects, p21 loss caused mesenchymal to epithelial transition that was accompanied by downregulation of Slug, Sox9, basal keratins and upregulation of luminal keratins and Claudin-3. Furthermore, p21 knockout suppressed Wnt/β-catenin signaling which was due to TCF1 downregulation. In turn, TCF1 knockdown in PyMT cells, attenuated Wnt signaling and tumorsphere formation. Interestingly, p21 rescue in p21 knockout cells, caused dramatic upregulation of Cyclin D1, consistent with known inhibition of Cyclin D1 nuclear export by p21. These data suggest that p21 promotes a cancer stem like phenotype via Wnt-TCF1 signaling along with direct upregulation of Cyclin D1 by p21.
Citation Format: Rachel B. Hazan. p21CIP1 promotes mammary cancer initiating cells via activation of Wnt/TCF1/CyclinD1 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4666.
Abstract 4672: WDR26 regulates an AKT-Gsk3-Wnt/b-catenin signaling cascade to maintain the breast cancer stem cell population and controls cancer metastasis
Authors: Bhargava Dharmendra K. , Wang Wei , Lensing Maddison , Chen Songhai 
Published: August 2019

Abstract
Cancer metastasis is the major cause of tumor mortality and has been attributed in part to the presence of a minority subpopulation of cancer stem cells (CSCs) in the bulk of tumor cells. We showed previously that WDR26, a scaffolding/adaptor protein that is highly upregulated in breast cancer, promotes breast cancer growth and metastasis. Here we show WDR26 was required for maintaining the CSC populations in breast cancer cells and the formation of lung metastases. Downregulation of WDR26 in breast cancer cells impaired the CSC-like activities and reduced the CSC population. Mammary gland-specific deletion of WDR26 in the MMTV-PyMT mouse model of breast cancer had a little effect on primary tumor formation but largely abolished spontaneous lung metastasis. WDR26 promoted β-catenin activation via AKT and GSK3, and the activity of AKT, GSK3 and β-catenin was required for maintaining the CSC population in breast cancer cells. Our results have identified a novel, WDR26-dependent pathway that links breast CSC activities to tumor metastatic potential.
Citation Format: Dharmendra K. Bhargava, Wei Wang, Maddison Lensing, Songhai Chen. WDR26 regulates an AKT-Gsk3-Wnt/b-catenin signaling cascade to maintain the breast cancer stem cell population and controls cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4672.
Abstract 4673: DCLK1 promotes hepatocellular carcinoma via atypical β-catenin-regulated signaling and immune suppression
Authors: Ali Naushad , Chandrakesan Parthasarathy , Bronze Michael S. , Houchen Courtney W. 
Published: August 2019

Abstract
Introduction: Genetic lineage tracing in mouse model has revealed that mature hepatocytes are the cell of origin of injury-induced hepatocellular carcinoma (HCC), the second most common cause of cancer-related deaths worldwide. Hepatocyte plasticity, defined as the ability to change cellular identity, plays a critical role in the repair process following liver injury. Inflammatory liver diseases often lead to cirrhosis and HCC. The molecular mechanisms that regulate the decision between hepatocyte injury repair and neoplastic initiation are unclear. Doublecortin-like kinase 1 (DCLK1), a microtubule-associated kinase, is expressed during liver injury, cirrhosis, and HCC, but not in normal liver. Here, we demonstrate a novel mechanism by which DCLK1 regulates injury-associated hepatocyte plasticity and immunosuppression in HCC.
Methods: Cell culture, DEN/CCl4-induced injury in mouse livers, and humanized mouse model were used for analyzing hepatocyte plasticity and DCLK1+ cells-induced changes in hepatic cells and macrophages.
Results: DCLK1-overexpressing primary human hepatocytes formed spheroids in 3D culture. DCLK1-overexpressing hepatoma cells exhibited a 48-kDa active β-catenin with preserved hypophosphorylated N-terminus, which interacted with TCF-4, resulting in enhanced luciferase reporter activity and cyclin D1 expression. Downregulation of DCLK1 using siRNAs inhibited expression of this β-catenin fragment. DCLK1 overexpression increased phosphorylation of GSK-3β at Ser9, thus preventing its complete proteasomal degradation. Liver tissues from patients with cirrhosis and HCC expressed the 48-kDa active β-catenin, DCLK1, cyclin D1, and 80-kDa E-cadherin ectodomain, suggesting a change in epithelial polarity. DCLK1-overexpressing primary human hepatocytes transplanted into FRG mice demonstrated β-catenin activation in the transplanted hepatocytes. Injury-induced DCLK1+ epithelial cells in mouse livers expressed PD-L1. DCLK1+ human hepatoma cells induced CD206 in macrophages in a dual co-culture assay.
Conclusions: DCLK1 enhances hepatocyte plasticity, clonogenicity, and tumorigenic signaling via atypical β-catenin-dependent mechanism. DCLK1+ cells show ability to suppress the host anti-tumor immunity by expressing PD-L1 and inducing macrophage polarization.
Citation Format: Naushad Ali, Parthasarathy Chandrakesan, Michael S. Bronze, Courtney W. Houchen. DCLK1 promotes hepatocellular carcinoma via atypical β-catenin-regulated signaling and immune suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4673.
Abstract 4685: Cancer associated fibroblasts promote ovarian cancer chemoresistance by inducing cancer stem cells through Wnt signaling
Authors: Fang Yiming , Aziz Mohamed A. Abd El , Tiwari Kartikeya , Mitra Anirban K. 
Published: August 2019

Abstract
Ovarian cancer is the most lethal gynecologic malignancy and the 5th leading cause of cancer related deaths among women in the USA. Most patients eventually succumb to chemoresistant disease and the purpose of this study is to understand the mechanism of development of chemoresistance and disease relapse. Cancer stem cells (CSCs) consist of a small subpopulation in the tumor that are resistant to cytotoxic chemotherapy and cause relapse. The tumor microenvironment can potentially provide an optimal cancer stem cell niche for cancer stem cell growth and maintenance. Cancer associated fibroblasts (CAFs) are one of the main constituents of the tumor microenvironment in ovarian tumors, promoting tumor progression and chemoresistance. We have studied the potential role of CAFs in maintaining CSC population and enhancing chemoresistance with an objective to develop effective approaches to overcome chemoresistance and tumor relapse. Co-culture of high grade serous ovarian cancer cells with CAFs resulted in increased resistance to carboplatin. ALDH1A1 is a well-established marker for ovarian cancer CSCs and the ALDH+ population was significantly increased upon co-culture with CAFs. Similarly, CAFs also enhanced spheroid formation of ovarian cancer cells seeded in ultralow adhesion plates in CSC medium. Interestingly, co-culturing ALDH- ovarian cancer cells with CAFs resulted in the induction of ALDH+ cells within 6 days. Analysis of the signaling pathways activated in ovarian cancer CSCs and the gene expression profiles of ovarian cancer CAFs indicated the potential role of Wnt signaling in the productive cross-talk between CAFs and ovarian cancer CSCs. Treatment with Wnt inhibitors abrogated the induction of CSCs by CAFs. By selectively silencing porcupine, a protein involved in Wnt ligand lipidation and secretion, we further confirmed that CAF derived Wnts are responsible for the induction of CSC. Studies are ongoing to identify the specific Wnt ligand involved in the cross-talk and downstream pathways activated during CSC induction and maintenance by CAFs. Our results indicate that CAF-derived Wnt ligands are instrumental in ovarian cancer CSC growth and maintenance. In the long term, our studies will broaden the understanding of CSC maintenance by the tumor microenvironment and contribute towards the development of novel therapeutic approaches to prevent ovarian cancer chemoresistance and relapse.
Citation Format: Yiming Fang, Mohamed A. Abd El Aziz, Kartikeya Tiwari, Anirban K. Mitra. Cancer associated fibroblasts promote ovarian cancer chemoresistance by inducing cancer stem cells through Wnt signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4685.