bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B07: Gain of function activities of p53R245W in a conditional knock-in mouse model
Authors: Xiong Shunbin , Zhang Yun , Lozano Guillermina 
Published: May 2019

Abstract
Missense mutations of the p53 tumor suppressor gene are present in more than 50% of human tumors. Emerging evidence suggests that p53 missense mutations in human cancer patients are associated with the poor prognosis and drug resistance due to their gain-of-function (GOF) properties, rather than just the loss of normal p53 function. Interestingly, these missense mutations have been shown to contribute to tumor progression by different mechanisms: interactions with Smad and SREBPs, modulation of EGFR/integrin signaling, and inhibition of p63 and p73 tumor suppressors. Combined, these studies suggest that the GOF of p53 missense mutations may be dependent on cell contexts and mutation types. Of particular interest, the p53R248W mutation is one of the most frequent missense mutation among human cancer patients; yet to date a mouse model that faithfully mimics this mutation does not exist. Additionally, the majority of human cancers evolve from somatic inactivation of p53 and current mouse models do not mimic somatic mutation of p53. Thus, we generated a conditional p53WMR245/+ knock-in mouse model, which normally expresses wild type p53, but produces p53R245W by Cre-mediated deletion of wild type p53 sequences. Germ line mutation of p53R245W/+ can rescue the early embryonic lethality of Mdm2 and Mdm4 null alleles like p53 null. Preliminary analyses of p53R245W/+ cohorts indicate differences in tumor spectrum in comparison to p53+/- and p53R172H/+ mice. Somatic mutation of p53R245W has also been performed to examine germ line versus somatic differences in tumor development. This study will help us understand the in vivo contributions of different p53 missense mutations to tumorigenesis, as well as the genetic alterations that occur during tumor evolution initiated by both germ line and somatic p53 mutations.
Citation Format: Shunbin Xiong, Yun Zhang, Guillermina Lozano. Gain of function activities of p53R245W in a conditional knock-in mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B07.
Abstract B30: Rnaseh2c is a candidate metastasis susceptibility gene in breast cancer
Authors: Deasy Sarah , Hunter Kent 
Published: May 2019

Abstract
Breast cancer is a leading cause of cancer-related female deaths in the United States, the majority of which are due to distant metastases. Elucidating novel genes that drive metastasis is critical to improving patient outcome. Our laboratory has extensively shown that germline variants impact an individual's susceptibility for metastasis, and we have used this to identify novel metastasis modifier genes. Here we applied a mouse model of spontaneous metastasis to a mouse breeding scheme to screen for strain-specific haplotypes associated with metastatic phenotype. Additional filtering of the haplotype-containing genes was performed for those that were highly expressed in tumors. This screen identified Rnaseh2c, a scaffolding subunit of the Ribonuclease H2 complex which degrades RNA from DNA:RNA heteroduplexes such as those generated during replication and transcription, thus helping maintain genomic stability. Though mutations in RNASEH2C are known to cause the neurological autoinflammatory disorder Aicardi-Goutières Syndrome (AGS), it has not previously been linked to cancer. Given the known pathology of AGS, we hypothesize that differential expression of Rnaseh2c in tumor cells alters tumor progression and metastasis potentially via interaction with the immune system. We directly assessed the effect of tumor cell Rnaseh2c expression on metastasis using in vivo metastasis assays. We implanted into the mammary fat pad tumor cells expressing shRNAs that reduced Rnaseh2c expression and observed significantly fewer pulmonary metastases and reduced tumor burden. To complement this approach, we performed the same metastasis assay with cells overexpressing exogenous Rnaseh2c. In agreement with our initial result, overexpression generated significantly more metastases without affecting primary tumor size, confirming Rnaseh2c as a metastasis modifier. The results thus far validate our approach of employing germline variation in mice to identify novel metastasis modifier genes. Current and future work will focus on elucidating the mechanism by which Rnaseh2c expression impacts metastasis. Specifically, we will determine where Rnaseh2c functions in the metastatic cascade, whether modulated expression disrupts Rnase H2 complex formation, and whether the immune system is involved in mediating this gene's effect on metastasis. Elucidating the mechanism by which this gene acts can contribute to both the development of novel metastasis biomarkers as well as potential therapeutic targets.
Citation Format: Sarah Deasy, Kent Hunter. Rnaseh2c is a candidate metastasis susceptibility gene in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B30.
Abstract B33: Beyond apoptosis, Bcl-xL in metastasis
Authors: Choi Soyoung , Chen Zhengming , Tang Laura , Fang Yuanzhang , Li Yi , Jiang Xuejun , Du Yi-Chieh Nancy 
Published: May 2019

Abstract
Bcl-xL, a negative regulator of mitochondria-mediated apoptosis, is frequently overexpressed in cancer to promote survival. Bcl-xL can also promote migration and/or metastasis. However, it is unclear whether this metastatic function is mediated via – or independent of – its anti-apoptotic activity and its residence at mitochondria. Here, we show that Bcl-xL promotes migration of cells defective in mitochondria-mediated apoptosis. Importantly, Bcl-xL mutants lacking anti-apoptotic activity still induce epithelial-mesenchymal transition (EMT), upregulate TGFβ, and increase metastasis of pancreatic neuroendocrine tumor (panNET) cells. In the RIP-Tag; RIP-tva mouse model, infection of pancreatic lesions with avian retroviruses carrying such Bcl-xL mutants promotes metastasis as potently as wild-type Bcl-xL does. Furthermore, engineered Bcl-xL targeted to the nucleus, but not mitochondria or outside of nucleus, promotes EMT and alters EMT-associated factors. In addition, nuclear Bcl-xL can be found in human metastatic panNET samples. Taken together, these data demonstrate that the metastatic function of Bcl-xL is independent of its anti-apoptotic activity and its residence at mitochondria.
Citation Format: Soyoung Choi, Zhengming Chen, Laura Tang, Yuanzhang Fang, Yi Li, Xuejun Jiang, Yi-Chieh Nancy Du. Beyond apoptosis, Bcl-xL in metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B33.
Abstract B34: CDKL2 promotes epithelial-mesenchymal transition and breast cancer progression
Authors: Li Linna , Hulsurkar Mohit , Amato Robert , Chang Jeffrey , Du Guangwei , Li Wenliang 
Published: May 2019

Abstract
The epithelial-mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by epithelial cancer cells. To identify novel regulators of EMT, we carried out cDNA screens that covered 500 human kinases. Subsequent characterization of candidate kinases led us to uncover cyclin-dependent kinase-like 2 (CDKL2) as a novel potent promoter for EMT and breast cancer progression. CDKL2-expressing human mammary gland epithelial cells displayed enhanced mesenchymal traits and stem cell-like phenotypes, which was acquired through activating a ZEB1/E-cadherin/beta-catenin positive feedback loop and regulating CD44 mRNA alternative splicing to promote conversion of CD24-high cells to CD44-high cells. Furthermore, CDKL2 enhanced primary tumor formation and metastasis in a breast cancer xenograft model. Notably, CDKL2 is expressed significantly higher in mesenchymal human breast cancer cell lines than in epithelial lines, and its over-expression/amplification in human breast cancers is associated with shorter disease-free survival. Taken together, our study uncovered a major role for CDKL2 in promoting EMT and breast cancer progression.
Citation Format: Linna Li, Mohit Hulsurkar, Robert Amato, Jeffrey Chang, Guangwei Du, Wenliang Li. CDKL2 promotes epithelial-mesenchymal transition and breast cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B34.
Abstract B36: Rab25 aggravates cancer cell invasion through Snail expression
Authors: Jeong Bo Young , Cho Kyung Hwa , Kim Seung Hwa , Kim Yu Na , Park Chang Gyo , Lee Hoi Young 
Published: May 2019

Abstract
Background: Rab25 is a member of the Rab11 subfamily and exclusively expressed in epithelial cells. As a small GTP-binding protein, Rab25 has been known to mediate recycling of proteins from the endosome to the plasma membrane. Cancer metastasis is multi-step events including epithelial-to-mesenchymal transition (EMT). Various transcription factors mediate EMT through downregulation of E-cadherin. In the present study, we investigate whether Rab25 induces EMT transcription factors, thereby increasing cancer invasiveness.
Methods: Immunoblotting, quantitative RT-PCR and immunofluorescence assay were used to examine the expression of Rab25 and EMT factors. siRNAs of Rab25 and Snail were transfected to determine their role in Rab25-induced cancer cell EMT and invasiveness. Transwell invasion assay were used to determine cancer cell invasiveness.
Results: Ectopic expression of Rab25 marked reduced E-cadherin expression, while Snail expression was upregulated. In addition, Rab25 significantly aggravated cancer cell invasiveness. However, silencing Snail expression by utilizing specific siRNA significantly attenuated cancer cell invasion. In addition, Rab25 induced phosphorylation of Akt and GSK-3beta. However, pharmacological inhibition of Akt and GSK-3beta marked attenuated Rab25-induced Snail expression. Further, we observed that a beta1integrin located upstream of an Akt/GSK-3beta signaling is important for Rab25-induced Snail expression and cancer cell invasion.
Conclusion: Our results show for the first time that Snail mediates Rab25-induced cancer cell EMT and invasiveness through a beta1 integrin /Akt/GSK-3beta signaling cascade, providing novel biomarkers, and potential therapeutic targets for deadly cancers.
Citation Format: Bo Young Jeong, Kyung Hwa Cho, Seung Hwa Kim, Yu Na Kim, Chang Gyo Park, Hoi Young Lee. Rab25 aggravates cancer cell invasion through Snail expression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B36.
Abstract B51: Extracellular matrix control of metastasis and dormancy
Authors: Barney Lauren E. , Gilman Ari , Mercurio Arthur , Peyton Shelly R. 
Published: May 2019

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR14) of the Conference Proceedings.
Citation Format: Lauren E. Barney, Ari Gilman, Arthur Mercurio, Shelly R. Peyton. Extracellular matrix control of metastasis and dormancy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B51.
Abstract B58: CELF1 is a central node in post-transcriptional regulatory programs underlying EMT and metastasis in breast epithelial cells
Authors: Chaudhury Arindam , Kongchan Natee , Fachini Joseph M. , Simon Lukas M. , Wang Tao , Mao Sufeng , Rosen Daniel G. , Ittmann Michael M. , Hilsenbeck Susan G. , Shaw Chad A. , Neilson Joel R. 
Published: May 2019

Abstract
The importance of translational regulation in tumorigenesis and metastasis is increasingly appreciated. We have leveraged polyribosomal profiling to prospectively and functionally define translational regulatory programs underlying the epithelial to mesenchymal transition (EMT), one of the early manifestations of metastasis, in breast epithelial cells. Our approach identified scores of mRNAs both enriched and depleted from polyribosomal fractions in mesenchymal cells as compared to their epithelial counterparts. Computational analysis of the 3′ untranslated regions (UTRs) of mRNAs enriched in polysomal fractions derived from the mesenchymal state revealed enrichment of a distinct GU-rich cis-element within these mRNA transcripts. Strikingly, while relative representation of these GU-rich-containing transcripts at the level of bulk mRNA were generally decreased in mesenchymal cells, the protein encoded by each of these mRNAs was dramatically increased. 3′ UTRs from affected transcripts conferred similar regulation upon a fluorescent reporter gene dependent upon the presence of the GU-rich element within the 3′ UTR sequence. Several of the translationally upregulated transcripts were necessary and/or sufficient for the EMT program. We next identified the CELF1 protein as a common regulator of these mRNA transcripts, demonstrating direct binding of the CELF1 protein to affected transcripts dependent upon the presence of the GU-rich element within their 3′ UTRs. CELF1 was itself necessary and sufficient for EMT in several distinct in vitro models as well as for metastatic colonization in vivo. Analysis of publicly available transcriptomic data revealed no increase in the relative expression of CELF1's regulatory targets or CELF1 itself in human breast cancer. We demonstrate that the CELF1 gene product is itself post-translationally regulated during EMT, and that CELF1 protein, but not mRNA, is significantly overexpressed in human breast cancer tissues and correlates with disease progression. Cumulatively, our data present a distinctive model of gene regulation, invisible to traditional transcriptional profiling, in which the CELF1 protein serves as a central node controlling translational activation of the EMT program and ultimately tumor metastasis in human breast cancer.
Citation Format: Arindam Chaudhury, Natee Kongchan, Joseph M. Fachini, Lukas M. Simon, Tao Wang, Sufeng Mao, Daniel G. Rosen, Michael M. Ittmann, Susan G. Hilsenbeck, Chad A. Shaw, Joel R. Neilson. CELF1 is a central node in post-transcriptional regulatory programs underlying EMT and metastasis in breast epithelial cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B58.
Abstract B59: Control of invasion by PKC theta in triple-negative breast cancer
Authors: Chadelle Lucie , Cadamuro Valérie , Liu Jiaying , Wang Xiaobo , Belguise Karine 
Published: May 2019

Abstract
Triple-negative breast cancers (TNBC: negative for oestrogen-receptor, progesterone-receptor and human-epidermal-growth-factor receptor 2 [HER2]) account for 15-20% of breast cancers and are characterized by an extremely aggressive phenotype. Currently, there is no efficient targeted therapy that can prevent the metastatic dissemination of TNBC. The serine threonine kinase PKCθ has recently been identified as a potential new marker of TNBC and as a strong inducer of cancer invasion. However, how PKCθ controls tumour invasion in TNBC is still unclear. Here our results suggest that PKCθ can promote invasion by activating the focal adhesion kinase (FAK) signalling that regulates the cycle of focal contact formation and disassembly. As a consequence of this activation, PKCθ enhances the dynamic of adhesion turnover, Rho GTPases activity and protrusions formation. We also have unravelled the molecular mechanisms by which PKCθ controls FAK: PKCθ interacts with and phosphorylates FAK thus leading to its opening and activation. We believe that the identified phosphorylation sites are implicated in the PKCθ controlled invasion. In the long term, this study could help develop new targeted therapy for TNBC such as PKCθ specific inhibitors that would limit metastasis formation.
Citation Format: Lucie Chadelle, Valérie Cadamuro, Jiaying Liu, Xiaobo Wang, Karine Belguise. Control of invasion by PKC theta in triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B59.
Abstract IA20: Quantifying patterns of tumor evolution
Authors: Markowetz Florian 
Published: May 2019

Abstract
Cancer has long been understood as a somatic evolutionary process, but many details of tumor progression remain elusive. Here, I will talk about computational methods to infer evolutionary pathways leading to tumor heterogeneity. I will start by discussing how to quantify intra-patient heterogeneity by rigorous analysis of copy-number profiles from multiple patient samples. Using a study in ovarian cancer I will describe how summary statistics of phylogenetic quantification of genetic heterogeneity can predict patient survival. Then, I will present a probabilistic framework to reconstruct intra-tumor evolution from data obtained by bulk bisulfite sequencing of mixed tumor samples or single cell genomes. Our approach jointly estimates the number and composition of clones in the sample as well as the most likely tree connecting them. I will finish by describing ongoing work to reconstruct patterns of clonal evolution from single cell sequencing data.
Citation Format: Florian Markowetz. Quantifying patterns of tumor evolution. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA20.
Abstract IA24: The role of CCL18 signaling in breast tumor associated macrophages promoting cancer progression
Authors: Song Erwei 
Published: May 2019

Abstract
Tumor-associated macrophages (TAMs) play critical roles in cancer progression. We focus on dissecting their underlying molecular mechanisms by applying human sample-based approaches, which include humanized mice, clinical samples and online clinical databases. Our data showed that CCL18, one of the most abundantly produced cytokines from human breast TAMs, is closely associated with advanced histopathological grading, triple negative breast cancer subtype, lymphovascular invasion, distant metastasis and poor prognosis of breast cancer patients. Mechanistic studies revealed that CCL18 induces epithelial-mesenchymal transition (EMT) and inflammatory cytokine secretion of tumor cells by activating NFkB pathway. Among the cytokines induced by CCL18, GM-CSF released from tumor cells undergone EMT in turn enhances the CCL18 production from TAMs and forms a positive feedback loop, which is essential to breast cancer metastasis, especially in the triple negative subtype. In addition, our recent study demonstrated that CCL18 could also mediate the activation and functions of other stromal cells in tumor microenvironment, leading to angiogenesis, recruitment of naïve T cells and activation of a special subset of chemoresistance-inducing fibroblasts. Previously, the receptor of CCL18 remained unknown. By using immunoprecipitation and mass spectra of the membrane extracts, cell-free isotope binding assays, [Ca2+]I mobilization and cAMP assays, we identified PITPNM3 as a functional receptor for CCL18. RNAi silencing of PITPNM3 in either cancer cells or stromal cells significantly inhibited the tumor progression in vivo. In conclusion, we define CCL18 from TAMs as the axis of a novel inflammatory signaling network in tumor microenvironment and imply the potential clinical application by targeting its receptor.
Citation Format: Erwei Song. The role of CCL18 signaling in breast tumor associated macrophages promoting cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA24.
Abstract PR02: Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of pro-metastatic tumor-associated macrophages
Authors: Rabe Daniel C. , Frankenberger Casey , Bainer Russell , Sankarasharma Devipriya , Chada Kiran , Krausz Thomas , Gilad Yoav , Becker Lev , Rosner Marsha Rich 
Published: May 2019

Abstract
Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. While physiological inhibitors of metastasis (metastasis suppressors) play key roles in regulating tumor growth, invasion and metastasis, their role in regulating the tumor microenvironment and immune system is unknown. We hypothesized that the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP) regulates stromal cells, which then affect tumor invasiveness.
Using species-specific RNAseq we determined that expression of RKIP in tumors markedly reduces the number and metastatic potential of infiltrating TAMs. While TAMs isolated from TNBC xenografts drive in vitro invasion, RKIP+ derived TAMs did not drive invasion and had decreased secretion of pro-metastatic factors including SLPI, OPN, MMP-12, Galectin-3, VEGF-A, VEGF-D, TNFR2, and PGRN. We determined that RKIP regulates TAM recruitment by blocking HMGA2, which activates CCL5 expression. CCL5 rescued pro-metastatic TAM infiltration as well as tumor intravasation. We additionally showed that factors decreased in RKIP-derived TAMs were restored in CCL5-derived TAMs. CCL5 derived TAMs were also able to promote metastasis when co-injected with MDA-MB-231 tumors. These tumor cells demonstrated permanent increases in both growth and invasive potential after co-injection with highly pro-metastatic CCL5 derived TAMs.
To determine the clinical utility of these TAM genes we combined their expression with RKIP signaling in the tumor to create a signature that strikingly separates TNBC patients based on outcome. Our results demonstrate for the first time that metastasis suppressors can regulate the microenvironment, regulating invasion through TAMs. Our results also suggest aggressive triple negative breast cancers could be controlled by attacking CCL5 derived TAMs crucial for promoting metastasis.
Citation Format: Daniel C. Rabe, Casey Frankenberger, Russell Bainer, Devipriya Sankarasharma, Kiran Chada, Thomas Krausz, Yoav Gilad, Lev Becker, Marsha Rich Rosner. Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of pro-metastatic tumor-associated macrophages. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr PR02.
Law and Norms in the Market Response to Discrimination in the Sharing Economy
Authors: Schoenbaum Naomi 
Published: May 2019

Abstract
Sharing-economy firms have opposed the application of antidiscrimination law to their transactions. At the same time, these firms have heralded their ability to achieve antidiscrimination aims without the force of law, and have adopted various measures to address discrimination. This Article documents and assesses these measures, focusing on the relationship between law and norms. Relying on the sharing economy as a case study, this Article shows how law can play a crucial role in spurring antidiscrimination efforts by firms that it does not regulate, but also how antidiscrimination law might nonetheless be undermined by these voluntary efforts.