bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A40: Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer cells
Authors: Wise Randi , Duhachek-Muggy Sara , Qi Yue , Zolkiewski Michal , Zolkiewska Anna 
Published: May 2019

Abstract
Cancer cells that separate from primary tumors and migrate to metastatic sites are exposed to stress caused by detachment from the extracellular matrix (ECM). Cultured breast cancer cells that survive this stress and are capable of anchorage-independent proliferation form mammospheres. Biological mechanisms responsible for maintaining the mammosphere-growth competence are not fully understood. We hypothesized that mammosphere growth requires elevated ECM secretion, which demands efficient folding quality control in the endoplasmic reticulum (ER). We found that SUM159PT and MCF10DCIS.com breast cancer cells grown as mammospheres had elevated mRNA and protein levels of three protein disulfide isomerases: ERp57, ERp44, and PDI. We also found an increased phosphorylation of eIF2alpha in mammospheres, suggesting that the PERK arm of the unfolded protein response was activated. An inducible knock-down of ERp57 in SUM159PT cells resulted in impaired ability to form mammospheres. Analysis of a publicly available gene expression data for circulating tumor cells (CTCs) revealed that up-regulation of ECM genes and ER folding quality control genes occurred at the time of disease progression and surge in the number of CTCs. These data indicate that breast cancer cell survival and growth under detachment conditions require enhanced assistance of the ER folding machinery in the correct disulfide bond formation.
Citation Format: Randi Wise, Sara Duhachek-Muggy, Yue Qi, Michal Zolkiewski, Anna Zolkiewska. Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer 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 A40.
Abstract A61: A novel image-guided genomics approach to dissect the mechanisms of collective cancer cell invasion
Authors: Konen Jessica , Dwivedi Bhakti , Kowalski Jeanne , Marcus Adam 
Published: May 2019

Abstract
During tumor metastasis, cancer cells invade as a collective pack to navigate the tumor microenvironment. In experimental models, this collective pack is phenotypically heterogenous and contains leader cells which pioneer invasion into the microenvironment and follower cells that immediately attach to and follow the leaders. To dissect the molecular mechanisms underlying this phenotypic heterogeneity, we developed a technique termed spatiotemporal genomic and cellular analysis (SAGA), which uses image-guided genomics to precisely select living, rare cell populations that are maintained within a physiologically relevant environment for downstream genomic and molecular analyses. In this manner, we can select, isolate, and amplify any living cell based upon phenotypic criteria. Using 3-D H1299 lung cancer cell spheroids, we precisely selected as few as 10 leader cells using the SAGA technique and extracted them from the bulk of a multicellular cancer spheroid embedded within a 3-D matrix. These isolated cells were used to create the first leader and follower purified cell cultures. The purified leader cell cultures continually show dynamic invasive patterns over time, while follower cells alone have limited invasive capabilities. Reintroducing limited numbers of leader cells, or even leader cell conditioned media, into follower cell cultures promoted invasion and motility in the follower cells. Genomic analysis comparing leader versus follower cell lines show significant enrichment in cell adhesion and vascular endothelial growth factor (VEGF) signaling pathways in leader cells. This was confirmed by protein analysis showing that leader cells secrete significantly higher levels of VEGF compared to follower cells, and VEGF inhibition abolished leader-follower collective invasion. Overall, our data show that SAGA can precisely select living cells based upon dynamic behaviors for genomic analysis and can amplify rare cell populations for subsequent molecular, cellular, and proteomic analyses. Therefore, this image-guided method has the potential to impact the field of tumor heterogeneity by uncovering genomic signatures of rare yet dynamic subpopulations within a heterogeneous cancer population.
Citation Format: Jessica Konen, Bhakti Dwivedi, Jeanne Kowalski, Adam Marcus. A novel image-guided genomics approach to dissect the mechanisms of collective cancer cell invasion. [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 A61.
Abstract A65: A novel small-molecule IAP antagonist, AZD5582, draws Mcl-1 down-regulation for induction of apoptosis through targeting of cIAP1 and XIAP in human pancreatic cancer
Authors: Gong Eun-Yeung , Lee Eun Young , Moon Jai-Hee , Shin Jae-Sik , Hong Seung-Woo , Jung Soo-A , Hwang Ih-Yeon , Kim Jeong Hee , Jin Dong-Hoon , Kim Tae Won 
Published: May 2019

Abstract
Inhibitor of apoptosis proteins (IAPs) plays an important role in controlling cancer cell survival. IAPs have therefore attracted considerable attention as potential targets in anticancer therapy. In this study, we investigated the anti-tumor effect of AZD5582, a novel small-molecule IAP inhibitor, in human pancreatic cancer cells. Treating human pancreatic cancer cells with AZD5582 differentially induced apoptosis, dependent on the expression of p-Akt and p-XIAP. Moreover, the knockdown of endogenous Akt or XIAP via RNA interference in pancreatic cancer cells, which are resistant to AZD5582, resulted in increased sensitivity to AZD5582, whereas ectopically expressing Akt or XIAP led to resistance to AZD5582. Additionally, AZD5582 targeted cIAP1 to induce TNF-α-induced apoptosis. More importantly, AZD5582 induced a decrease of Mcl-1 protein, a member of the Bcl-2 family, but not that of Bcl-2 and Bcl-xL. Interestingly, ectopically expressing XIAP and cIAP1 inhibited the AZD5582-induced decrease of Mcl-1 protein, which suggests that AZD5582 elicits Mcl-1 decrease for apoptosis induction by targeting of XIAP and cIAP1. Taken together, these results indicate that sensitivity to AZD5582 is determined by p-Akt-inducible XIAP phosphorylation and by targeting cIAP1. Furthermore, Mcl-1 in pancreatic cancer may act as a potent marker to analyze the therapeutic effects of AZD5582.
Citation Format: Eun-Yeung Gong, Eun Young Lee, Jai-Hee Moon, Jae-Sik Shin, Seung-Woo Hong, Soo-A Jung, Ih-Yeon Hwang, Jeong Hee Kim, Dong-Hoon Jin, Tae Won Kim. A novel small-molecule IAP antagonist, AZD5582, draws Mcl-1 down-regulation for induction of apoptosis through targeting of cIAP1 and XIAP in human pancreatic 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 A65.
Abstract B01: Lymphangiogenic gene expression is associated with lymph node recurrence and poor survival after hepatectomy for colorectal liver metastases
Authors: Vellinga Thomas , Marvin Dieuwke , Rinkes Inne Borel , Hagendoorn Jeroen , Kranenburg Onno 
Published: May 2019

Abstract
Expression of the lymphangiogenic growth factors, in particular VEGF-C, are correlated with disease-free and overall survival in primary colorectal cancer (CRC). Moreover, in patients with metastatic CRC (mCRC) lymphatic invasion and lymph node metastases are correlated with worse outcome, but the biology underlying these correlations remains unknown.
To study a potential relationship between tumor biology, lymphatic spread from liver metastases and outcome, we compiled a lymph-endothelium gene set the lymphangiogenesis signature comprised of six genes specifically expressed by lymph endothelial cells, or growth factors stimulating them. In primary colorectal cancer, expression of this signature correlated with increased risk of distant metastasis. When used to cluster a cohort of 119 colorectal liver metastases (CRLM) based on gene expression profiles, the signature identified an aggressive poor prognosis subtype of CRLM with mesenchymal gene expression and a stem-like tumor phenotype. RTqPCR analysis of CRLMs with and without lymph node recurrence during follow up showed that VEGF-C and neuropilin-2 were significantly higher expressed by CRLM with onward spread to the lymph nodes.
We conclude that CRLM expressing high levels of lymphangiogenic genes are more likely to develop lymph node metastases during follow up and that this correlates with a general aggressive tumor biology (i.e. the mesemcnymal/stem-like phenotype) and poor survival. Post liver resection adjuvant therapy targeting onward spread to the lymph nodes may be beneficial for patients with mesenchymal-type mCRC.
Citation Format: Thomas Vellinga, Dieuwke Marvin, Inne Borel Rinkes, Jeroen Hagendoorn, Onno Kranenburg. Lymphangiogenic gene expression is associated with lymph node recurrence and poor survival after hepatectomy for colorectal liver metastases. [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 B01.
Abstract B14: The expression landscape of pancreatic cancer recurrence following resection
Authors: Dudgeon Crissy , Rosenfeld Jeffrey , Collisson Eric , Carpizo Darren 
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 (PR13) of the Conference Proceedings.
Citation Format: Crissy Dudgeon, Jeffrey Rosenfeld, Eric Collisson, Darren Carpizo. The expression landscape of pancreatic cancer recurrence following resection. [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 B14.
Abstract B18: Role of the tumor suppressor gene DLC-2 in ERBB2 induced mouse mammary tumorigenesis and metastasis
Authors: Basak Pratima , Basak Pratima , Leslie Heather , Leslie Heather , Raouf Afshin , Raouf Afshin , Mowat Michael RA , Mowat Michael RA 
Published: May 2019

Abstract
Introduction: Overexpression of dominant oncogenes and the loss of tumor suppressor genes are basic genetic events in acquisition of the malignant phenotype. The ERBB-2 proto-oncogene is overexpressed in 20% - 30% of human breast cancers. The tumor suppressor gene Deleted in liver cancer 2 (DLC-2, also known as STARD13) maps to chromosome 13q12.3 and is frequently downregulated by 72% in human breast cancer. It encodes a RhoGAP protein containing a START lipid binding domain. It is not known what role DLC-2 silencing plays in breast carcinogenesis. The purpose of our study is to assess the biological significance of inactivation of DLC-2 in ERBB2 induced mammary tumorigenesis mouse model. For this, we used MMTV-NIC mice, which carry an activated NEU oncogene (ERBB2) under control of the MMTV-LTR promoter that also co-expresses Cre recombinase. These mice were crossed to a conditional DLC-2 knockout mouse (floxed exon 3).
Objectives: To determine if heterozygous or homozygous DLC-2 loss plays a role in mouse mammary tumor progression in MMTV-NIC mice.
Results: Our preliminary results showed that heterozygous deletion of DLC-2 in the mammary epithelium of the MMTV-NIC mouse model resulted in increased tumor burden with accelerated tumor growth. Metastases to the lungs were quantified by scanning H&E stained step sections (4X150uM). We observed a significant increase in the incidence of lung metastases in heterozygous DLC-2 exon3floxed/+ MMTV-NIC mice. The lung metastases showed a homogenous morphology and histopathologically similar phenotype to the MMTV-NIC strain. DLC-2 heterozygous tumor cells showed increased tumorosphere formation under low-attachment conditions with minimal growth factor supplementation. These tumor cells also showed increased expression of mesenchymal cell markers, as determined by quantitative real time RT-PCR, suggesting an Epithelial to Mesenchymal transition is occurring. Experiments with homozygous floxed DLC-2 mice are ongoing and will be presented.
Conclusion: These results indicate that loss of one allele of DLC-2 is sufficient to accelerate NEU oncogene induced tumorigenesis.
Citation Format: Pratima Basak, Pratima Basak, Heather Leslie, Heather Leslie, Afshin Raouf, Afshin Raouf, Michael RA Mowat, Michael RA Mowat. Role of the tumor suppressor gene DLC-2 in ERBB2 induced mouse mammary tumorigenesis and 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 B18.
Abstract B27: Identification of novel anti-metastatic drugs targeting oncogenic E2F1:coregulator complexes by applying a systems pharmacology approach
Authors: Goody Deborah , Engelmann David , Mikkat Stefan , Gupta Shailendra K. , Pützer Brigitte M. 
Published: May 2019

Abstract
Tumour metastasis is considered to be one of the most important problems in cancer research and the identification of mechanisms that drive this multistep process provides urgently needed opportunities for therapeutic interventions. Many cancer types are driven by the dysfunction of transcriptional coregulators which interact with transcription factors such as E2F1 that has been associated with cancer aggressiveness and poor patient survival prognosis. Although the role of E2F1 in malignant progression is not fully understood, its physical interaction with oncogenic coregulators is clearly linked to the activation of prometastatic gene expression programs. In order to identify metastatic E2F1:coregulator complexes that determine occurrence of metastases and clinical outcome, we employed co-immunoprecipitation assays in advanced-stage metastatic cancer cells combined with high throughput mass spectrometry. We identified a hitherto unknown regulatory network of E2F1 interaction partners, which were validated by Western blotting, confocal laser scanning microscopy, ChIP and promoter reporter assays. Knockdown and overexpression studies in a large panel of metastatic cell lines originating from various tumor entities showed a clear impact of these proteins on cancer motility and invasiveness. Genome-wide transcriptome analyses were applied to uncover the metastasis gene signature regulated by the E2F1-coregulator complexes that predicts aggressive behavior. Finally, we developed a pharmacophore model of E2F1 interacting proteins and predicted potential drug molecules which can be used as inhibitors of E2F1:coregulator complexes based on a computer-assisted virtual screening of FDA-approved compounds. Taken together, our straight forward approach on finding new prometastatic E2F1 coregulators and potential inhibitors to disrupt these complexes may shed new light into future cancer therapy.
This research was funded by grants from the German Cancer Aid, Dr. Mildred Scheel Stiftung (109801 to B.M.P. and D.E.) and German Federal Ministry of Education and Research (BMBF) as part of the eBio:SysMet project (0316171 to B.M.P.).
Note: This abstract was not presented at the conference.
Citation Format: Deborah Goody, David Engelmann, Stefan Mikkat, Shailendra K. Gupta, Brigitte M. Pützer. Identification of novel anti-metastatic drugs targeting oncogenic E2F1:coregulator complexes by applying a systems pharmacology approach. [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 B27.
Abstract B52: PTK6 inhibition as a novel strategy to reverse EMT and suppress metastasis of triple negative breast cancer
Authors: Ito Koichi , Park Sun Hee , Irie Hanna Y. 
Published: May 2019

Abstract
Triple negative breast cancer (TNBC) poses clinical challenges due to intrinsic biological aggressiveness and lack of targeted therapies.
Hypothesis: Protein tyrosine kinase 6 (PTK6) regulates epithelial-mesenchymal transition (EMT) of TNBC, as well as their growth and metastatic potential. We evaluated PTK6 as a promising therapeutic target to prevent metastases of TNBC.
Experimental Procedures: Levels of PTK6 have prognostic significance; higher transcript levels are associated with poor outcomes for patients. We modulated the level of PTK6 in breast epithelial and TNBC cell lines, and determined effects on growth, migration, epithelial-mesenchymal transition and metastasis formation in vivo.
Results: PTK6 promotes EMT; overexpression of kinase active PTK6 (Y447F) in non-transformed MCF10A cells promotes migration, suppresses expression of epithelial markers (E-cadherin, claudin-1), and increases expression of N-cadherin and fibronectin, markers of mesenchymal cells. Promotion of EMT is dependent on PTK6 kinase activity as overexpression of catalytically inactive PTK6 (K219M) failed to induce EMT. Downregulation of PTK6 in mesenchymal TNBC cells (human MDA-MB231 or murine MMTV-myc) restores epithelial properties and suppresses migration and growth in 3-D MatrigelTM cultures. PTK6 inhibition-induced E-cadherin expression is due to decreased expression of Snail, a transcriptional repressor of E-cadherin. PTK6 downregulation promotes the proteasome-dependent degradation of Snail protein, via a mechanism that is independent of GSK3β activity. PTK6 inhibition promotes anoikis of TNBC cells in vitro and prevents metastases in vivo; decreased metastasis formation is directly linked to PTK6-dependent regulation of EMT and E-cadherin levels.
Conclusions: Our studies support PTK6 inhibition as a novel strategy to impair metastasis of TNBC cells via reversal of mesenchymal properties. The kinase dependency of EMT regulation by PTK6 highlight the potential for clinical translation of recently developed PTK6 kinase inhibitors as a therapeutic strategy for patients with triple negative breast cancers.
Citation Format: Koichi Ito, Sun Hee Park, Hanna Y. Irie. PTK6 inhibition as a novel strategy to reverse EMT and suppress metastasis of 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 B52.
Abstract IA08: Prostate cancer tumor dormancy and the development of metastases
Authors: Morrissey Colm 
Published: May 2019

Abstract
Cancer dormancy refers to the prolonged clinical disease-free time between removal of the primary tumor and recurrence, which is common in prostate cancer (PCa). PCa disseminated tumor cells (DTC) can be detected in the bone marrow of patients with no evidence of disease (NED) and advanced disease (ADV). However, the molecular and cellular nature of DTC is unknown. Single cell transcriptomic analyses comparing DTC in NED versus ADV PCa patients identified a molecular signature associated with the p38 stress activated kinase pathway and dormancy. Understanding the mechanism by which dormant tumor cells are triggered to proliferate may provide new targets for therapy. We have demonstrated that LuCaP PCa xenografts, which appear dormant in vitro, can be induced to proliferate through contact with each other and bone marrow stroma. Constitutive activation of myosin light chain kinase (MLCK), a downstream effector of integrin-β1 and TGFβ2, in non-proliferating cells promoted cell proliferation. Additionally, gene expression analyses and in vitro data support a role for TGFβ2 in suppressing proliferation. Taken together, these data point to a potential mechanism by which PCa cells are released from dormancy to form lethal metastases. The early dissemination of cells from the primary to other sites most likely involves epithelial-mesenchymal transition (EMT)-like behavior. It has been proposed that further dissemination can occur where a metastasis can seed further metastases. TGFβ is a known driver of EMT which is associated with tumor aggressiveness and metastasis. We assessed the natural history of tumor dissemination and EMT-related markers TGFβ, Twist, Slug, and Zeb1 in bone and visceral metastases from castration resistant PCa (CRPC) patients. Importantly, nuclear Twist, Slug, and Zeb1 were only present in a subset of epithelial cells that had an EMT-like phenotype, suggesting only a subset of cells display an EMT-like behavior in any given CRPC metastasis. These studies highlight the biological relevance of dormancy, cell-contact and EMT-like behavior in the seeding and establishment of CRPC metastases.
Citation Format: Colm Morrissey. Prostate cancer tumor dormancy and the development of metastases. [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 IA08.
A Ca2+-ATPase Regulates E-cadherin Biogenesis and Epithelial–Mesenchymal Transition in Breast Cancer Cells
Authors: Dang Donna K. , Makena Monish Ram , Llongueras José P. , Prasad Hari , Ko Myungjun , Bandral Manuj , Rao Rajini 
Published: May 2019

Abstract

Progression of benign tumors to invasive, metastatic cancer is accompanied by the epithelial-to-mesenchymal transition (EMT), characterized by loss of the cell-adhesion protein E-cadherin. Although silencing mutations and transcriptional repression of the E-cadherin gene have been widely studied, not much is known about posttranslational regulation of E-cadherin in tumors. We show that E-cadherin is tightly coexpressed with the secretory pathway Ca2+-ATPase isoform 2, SPCA2 (ATP2C2), in breast tumors. Loss of SPCA2 impairs surface expression of E-cadherin and elicits mesenchymal gene expression through disruption of cell adhesion in tumorspheres and downstream Hippo-YAP signaling. Conversely, ectopic expression of SPCA2 in triple-negative breast cancer elevates baseline Ca2+ and YAP phosphorylation, enhances posttranslational expression of E-cadherin, and suppresses mesenchymal gene expression. Thus, loss of SPCA2 phenocopies loss of E-cadherin in the Hippo signaling pathway and EMT–MET transitions, consistent with a functional role for SPCA2 in E-cadherin biogenesis. Furthermore, we show that SPCA2 suppresses invasive phenotypes, including cell migration in vitro and tumor metastasis in vivo. Based on these findings, we propose that SPCA2 functions as a key regulator of EMT and may be a potential therapeutic target for treatment of metastatic cancer.

Implications:
Posttranslational control of E-cadherin and the Hippo pathway by calcium signaling regulates EMT in breast cancer cells.