bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A36: Function of GPR56 in metastasis dormancy of melanoma
Authors: Corson Nancy , Warren Michelle , Xu Lei 
Published: May 2019

Abstract
Dormancy imposes significant challenges for cancer diagnosis and prognosis. We use pairs of metastatic melanoma cell lines that have different abilities to form metastases to investigate the molecular mechanisms of metastatic dormancy. We found that a novel receptor, GPR56, was down-regulated in highly metastatic melanoma cells compared with the poorly metastatic parental line. Re-expression of GPR56 in five different melanoma cell lines resulted in inhibition of metastasis formation in mouse lung. RNAseq analyses revealed that GPR56 might regulate the expression of genes involved in cellular homeostasis. Furthermore, our preliminary data show that GPR56 internalizes and degrades its ligand, TG2 from cell surface. TG2 is an ECM protein and functions to stabilize ECM and facilitate its signaling. The loss of TG2 resulting from GPR56 expression would disrupt ECM deposition and signaling in melanomas, ultimately leading to disturbance of cellular homeostasis of melanoma cells and their growth arrest. Taken together, we propose a model in which the novel receptor GPR56 sequesters metastatic melanomas at dormant states by down-regulating TG2 from cell surface and modulating cellular homeostasis.
Citation Format: Nancy Corson, Michelle Warren, Lei Xu. Function of GPR56 in metastasis dormancy of melanoma. [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 A36.
Abstract A38: A PERK inhibitor that blocks HER2-driven tumorigenesis and suppresses metastasis by targeting single disseminated tumor cells
Authors: Calvo Veronica , Staschke Kirk A. , Paredes Maria Cristina Garcia , Avivar-Valderas Alvaro , Cheung Julie , Wild Robert , Rigby Alan C. , Farias Eduardo F. , Aguirre-Ghiso Julio 
Published: May 2019

Abstract
The unfolded protein response (UPR) is a critical survival and adaptation pathway in cancer cells. The endoplasmic reticulum kinase PERK serves as a survival UPR factor for different tumor types, including those driven by the oncogene HER2, and it can also promote survival of dormant cancer cells. We wanted to evaluate the effect of a potent and selective new PERK inhibitor (LY4) on MMTV-HER2-driven tumorigenesis that, through genetic experiments, was shown to depend on a full complement of PERK for progression. Here we show that, from ductal carcinoma in situ (DCIS) through invasive cancer, MMTV-HER2-driven tumors and also HER2+ human cancer cell lines are exquisitely sensitive to this novel PERK inhibitor. We found that early MMTV-HER2+ lesions require PERK for HER2-driven alterations in ductal epithelial organization, and that LY4 impairs the expansion of established HER2+ tumor cells in 3D organotypic cultures and in vivo. Importantly, PERK inhibition blunted metastasis development. This effect was linked to the ability of the PERK inhibitor to eradicate solitary HER2+ disseminated tumor cells that, in their majority, are dormant or slow-cycling, but that represent the seeds for further metastases. Mechanism analyses revealed that PERK inhibition indirectly blocked the phosphorylation of HER2 and EGFR and their downstream signaling activation in response to EGF, possibly by altering receptor protein quality control. Our data suggest that in HER2-driven cancers PERK inhibition might be a novel therapeutic strategy to treat primary and metastatic lesions.
Citation Format: Veronica Calvo, Kirk A. Staschke, Maria Cristina Garcia Paredes, Alvaro Avivar-Valderas, Julie Cheung, Robert Wild, Alan C. Rigby, Eduardo F. Farias, Julio Aguirre-Ghiso. A PERK inhibitor that blocks HER2-driven tumorigenesis and suppresses metastasis by targeting single disseminated tumor 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 A38.
Abstract A41: Elucidating candidate biomarkers of breast cancer progression and dormancy using a 3D model of metastasis
Authors: Clark Amanda M. , Wheeler Sarah E. , Young Carissa L. , Pillai Venkateswaran C. , Stolz Donna B. , Lauffenburger Douglas A. , Venkataramanan Raman , Griffith Linda G. , Wells Alan 
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 (PR11) of the Conference Proceedings.
Citation Format: Amanda M. Clark, Sarah E. Wheeler, Carissa L. Young, Venkateswaran C. Pillai, Donna B. Stolz, Douglas A. Lauffenburger, Raman Venkataramanan, Linda G. Griffith, Alan Wells. Elucidating candidate biomarkers of breast cancer progression and dormancy using a 3D model of 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 A41.
Abstract A60: Loss of α3 integrin expression promotes α6 integrin internalization to Rab4 vesicles and migration of human prostate cancer cells
Authors: Das Lipsa , Anderson Todd A. , Gard Jaime M. , Sroka Isis C. , Strautman Stephanie R. , Nagle Raymond B. , Morrissey Colm , Knudsen Beatrice S. , Cress Anne E. 
Published: May 2019

Abstract
Background: Metastatic prostate cancer express laminin binding integrins α6 and α3 while losing the expression of a variety of integrins present in normal prostate gland.
Results: In human xenograft tissues, at least 70% of bone and soft tissue metastasis of prostate cancer (185 samples from 45 patients) had cytoplasmic expression of the α6 integrin that correlated to increased expression of intracellular trafficking proteins. Given the reported link between cytoplasmic integrin distribution and integrin endocytosis, surface labelled integrin α6 were quantified for internalization kinetics using flow cytometry. The integrin α6 was internalized 3-fold faster than α3 integrin (CD49c) (1.0 min-1), 1.5-fold faster than the vitronectin binding αv integrin (CD51) (2.2 min-1), and significantly slower than the unrelated transferrin receptor (TfR, CD71) (15 min-1).
Silencing α3 expression increased α6 integrin internalization by 1.45 fold without affecting internalization of non-integrin control receptor, TfR. The internalized α6 integrin was targeted to early endosomes and Rab4 recycling vesicles and redistributed to a cell-cell staining pattern similar to human prostate cancer specimens. This was accompanied by a 1.8-fold increase in cancer cell migration that was dependent on α6 integrin. Silencing integrin α6 however, didn't affect the internalization rate or intracellular endocytic distribution of the α3 integrin.
Conclusion and Significance: We conclude that internalization of the α6 and α3 integrins is coordinated in a unidirectional fashion and their relative expression can significantly modulate cancer cell migration. The observed loss of α3 integrin expression in high grade cancer is predicted to increase the internalization and pro-migratory features of α6 integrin in high grade cancer.
Acknowledgements: Research was supported in part by NIH research grants R01 CA 159406, CA 23074 and CA09213. Patient tissue studies were supported by Biobank and Translational Research Core, Cedars Sinai Medical Center, CA, Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grants (PO1CA085859) and the Richard M. LUCAS Foundation.
Citation Format: Lipsa Das, Todd A. Anderson, Jaime M. Gard, Isis C. Sroka, Stephanie R. Strautman, Raymond B. Nagle, Colm Morrissey, Beatrice S. Knudsen, Anne E. Cress. Loss of α3 integrin expression promotes α6 integrin internalization to Rab4 vesicles and migration of human prostate 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 A60.
Abstract B05: Repurposing FDA-approved drugs for anti-metastatic therapy: Results of an integrated genome wide screen for metastasis modifiers
Authors: Shukla Anjali , Hunter Kent W. 
Published: May 2019

Abstract
Metastasis remains the primary cause of patient morbidity and mortality in solid tumors. Recent advances in genomic technologies have provided major insights into the etiology of tumors. However, significantly less is known about factors that contribute to metastasis. Here we report the results of a genome-wide integrated genetic, transcriptional, and epigenetic analysis in a mouse mammary tumor model to identify factors associated with tumor progression. This strategy identified a prognostic transcription signature and several upstream transcriptional regulators for metastatic disease. Interestingly, this analysis also identified novel or other FDA-approved drugs as potentially useful for anti-metastatic therapy. As predicted by this screen, administration of antidiabetic thiazolidones Rosiglitazone and Pioglitazone suppressed metastasis in an orthotopic breast cancer mouse model. Similarly, ciprofloxacin, an antibiotic, also decreased breast cancer metastasis. This strategy is thus not only of prognostic value but also presents the opportunity to rapidly repurpose drugs with proven safety and efficacy profiles for control and treatment of advanced neoplastic disease.
Citation Format: Anjali Shukla, Kent W. Hunter. Repurposing FDA-approved drugs for anti-metastatic therapy: Results of an integrated genome wide screen for metastasis modifiers. [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 B05.
Abstract B19: The histone demethylase KDM3A in Ewing sarcoma metastasis
Authors: Sechler Marybeth , Parrish Janet , Jedlicka Paul 
Published: May 2019

Abstract
This study aims to explore the roles and mechanisms of new candidates for therapeutic targeting in Ewing Sarcoma. Ewing Sarcoma is an aggressive pediatric malignancy of the bone and soft tissue, driven by EWS/Ets oncogenic fusions and characterized by high propensity for metastasis and poor clinical outcomes. We have identified the histone demethylase KDM3A as a novel tumor and metastasis promoter downstream of EWS/Fli1, the most common driver in this disease. Moreover, we have identified the cell surface protein, Melanoma Cell Adhesion Molecule (MCAM), as a potential important mediator of KDM3A action. Our data show that both KDM3A and MCAM depletion can inhibit metastatic phenotypes. Additionally we explore the regulation of MCAM, showing that KDM3A may upregulate MCAM expression both through a direct as well as an indirect mechanism via the Ets1 transcription factor. Since both KDM3A and MCAM are pharmacologically targetable, understanding of this pathway could provide at least two new therapeutic targets in Ewing Sarcoma, and, importantly alternatives to drugging of EWS/Ets fusions, which to date has proven very difficult.
Citation Format: Marybeth Sechler, Janet Parrish, Paul Jedlicka. The histone demethylase KDM3A in Ewing sarcoma 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 B19.
Abstract B22: Loss of LncRNA XIST induces Epithelial to Mesenchymal Transition in Breast Cancer
Authors: Liu Yin , Xing Fei , Wu Kerui , Sharma Sambad , Watabe Kounosuke 
Published: May 2019

Abstract
Brain is one of the major sites of metastasis of breast cancer, and approximately 20% of patients with aggressive breast cancer eventually develop the metastatic disease in the brain. Long non-coding RNAs (lncRNA) have recently drawn much attention due to their wide functional variations and potential roles in tumor progression. By performing lncRNA array analysis comparing non-metastatic primary tumors with brain metastatic tumors from breast cancer patients, we identified that lncRNA XIST expression was significantly down-regulated in brain metastatic tumors. The result of Taqman PCR validated the results in tumor samples and also indicated that XIST expression was down-regulated in brain metastatic cell lines compared to non-brain metastatic cell lines. Moreover, we found that the XIST expression was negatively correlated with breast cancer stage and brain metastasis-free survival. XIST is located on the q arm of the X chromosome (Xq13-2) and plays a critical role in the X inactivation, thus providing dosage equivalence between males and females. Importantly, XIST has been found to be down-regulated in several types of tumors including breast cancer. Loss of XIST facilitates escape of some X chromosome genes from inactivation. To further study the effect of XIST down-regulation on tumor cells, we knocked down XIST expression in MCF7 by siRNA. We found that the knockdown of XIST drastically altered the morphology of MCF7 cell from epithelial to mesenchymal type. Furthermore, several epithelial-mesenchymal transition (EMT)-related genes including ZEB2 and SNAIL were upregulated in the XIST knockdown cells. In addition, the results of qPCR, western blot and immunocytochemical analysis showed that the epithelial marker E-cad was significantly down-regulated, while mesenchymal markers N-cad and Vimentin were upregulated in MCF7-siXIST, SKBR-siXIST and ZR751-siXIST cells compared to the control cells. To further examine the effect of XIST knockdown in vivo, we transplanted MCF7-siXIST, SKBR3-siXIST and their control cells by intra-cardiac injection into nude mice. We found that knockdown of XIST significantly enhanced tumor metastasis, especially in the brain. Our results strongly suggest that lncRNA XIST plays a critical role in tumor progression and metastasis by inducing EMT.
Citation Format: Yin Liu, Fei Xing, Kerui Wu, Sambad Sharma, Kounosuke Watabe. Loss of LncRNA XIST induces Epithelial to Mesenchymal Transition 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 B22.
Abstract B35: NR2F1 limits early dissemination and phenotypic plasticity of early-progressed ErbB2+ tumor cells by maintaining luminal differentiation
Authors: Sosa Maria Soledad , Cheung Julie , Aguirre-Ghiso Julio A. 
Published: May 2019

Abstract
Tumor cells derived from MMTV-Neu primary tumors (tumor-derived cells, TDC) are known to be able to complete all steps of the metastatic cascade. However, new evidence shows that cells derived from early stages of tumor progression (before detection of palpable tumors, ErbB2+ early-progressed tumor cells, EPTC) can disseminate and, as disseminated tumor cells (early DTCs), enter a non-proliferative state for prolonged periods at secondary organs. When EPTC are co-cultured with TDC, the tumor sphere formation capacity of the later is increased suggesting a synergistic contribution of early-progressed tumor cells to the growth of TDC. Thus, early DTCs are proposed to contribute to metastasis, but the mechanisms that would allow these cells, considered sessile and with few genetic alterations, to complete all steps of metastasis are unknown. Here we report that the orphan nuclear receptor NR2F1 is downregulated in human pre-malignant and malignant lesions and mouse ErbB2+ EPTC and TDC when compared with normal mammary tissue. In ErBb2+ EPTC further downregulation of NR2F1 activates a motile phenotype and this is coincident with the detection of circulating tumor cells (CTCs) and DTCs in lungs and bone marrow. Knock down of basal NR2F1 levels in ErBb2+ EPTC induced cell motility, loss of laminin-V deposition, β-catenin delocalization from the membrane and dramatic loss of E-cadherin junctions. Interestingly, TWIST, SMAD2, CK14 and ROR1 levels became upregulated upon NR2F1 depletion. This anti-EMT NR2F1-regulated program is ErbB2 oncogen-dependent. These results suggest that NR2F1 expression maintains epithelial identity and suppresses epithelial-mesenchymal transition (EMT), possibly by blocking WNT signaling. Knock down of NR2F1 in ErBb2+ EPTC also enhanced mammosphere formation efficiency and this was accompanied by upregulation of the pluripotency transcription factor NANOG and TWIST. These findings suggest that NR2F1 limits the spreading of ErBb2+ EPTC cells and it promotes a luminal differentiation-associated program by limiting the activation of a stem cell-like program. Our findings provide for the first time evidence that NR2F1 functions in mammary epithelial cells as a suppressor of pluripotency and dissemination during early stages of tumor progression. We propose that therapies that might restore expression of NR2F1 might limit early dissemination and the progression to metastasis of already disseminated tumor cells.
Citation Format: Maria Soledad Sosa, Julie Cheung, Julio A. Aguirre-Ghiso. NR2F1 limits early dissemination and phenotypic plasticity of early-progressed ErbB2+ tumor cells by maintaining luminal differentiation. [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 B35.
Abstract B41: Haptotaxis and direct remodeling of the extracellular matrix by tumor cells is important for metastasis
Authors: Oudin Madeleine J. , Jonas Oliver , Kosciuk Tatiana , Broye Liliane , Wyckoff Jeff , Klazen Joelle , Lamar John , Asokan Sreeja , Whittaker Charlie , Langer Robert , Cima Michael , Wisinski Kari , Hynes Richard , Lauffenburger Douglas , Keely Patricia , Bear James , Gertler Frank 
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 (PR15) of the Conference Proceedings.
Citation Format: Madeleine J. Oudin, Oliver Jonas, Tatiana Kosciuk, Liliane Broye, Jeff Wyckoff, Joelle Klazen, John Lamar, Sreeja Asokan, Charlie Whittaker, Robert Langer, Michael Cima, Kari Wisinski, Richard Hynes, Douglas Lauffenburger, Patricia Keely, James Bear, Frank Gertler. Haptotaxis and direct remodeling of the extracellular matrix by tumor cells is important for 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 B41.
Abstract B43: ADAM12 is a novel regulator of stem-like cells in triple-negative breast cancer
Authors: Qi Yue , Duhachek-Muggy Sara , Li Hui , Alyahya Linda , Wise Randi , Zolkiewska Anna 
Published: May 2019

Abstract
High expression of metalloprotease ADAM12 is associated with increased metastasis in triple-negative breast cancers (TNBC) and is an independent prognostic factor of chemoresistance in TNBC. ADAM12 is up-regulated in the claudin-low subtype of breast tumors and in the mesenchymal stem-like subtype of TNBC. Furthermore, expression of ADAM12 is elevated in post-therapy tumors. The goal of our study was to examine whether ADAM12 may serve as a marker or a therapeutic target in cells with enhanced metastatic cancer stem cell phenotype, using two representative TNBC cell lines with aggressive and metastatic phenotype, SUM159PT and Hs578T. We found that sorted cell subpopulations with the highest cell surface expression of ADAM12 had increased expression of cancer stem cell markers, decreased proliferation rates in 2-D cultures, and increased ability to form mammospheres under suspension conditions. ADAM12 knockdown decreased mammosphere formation, increased apoptotic cell death upon detachment, and decreased cell migration and invasion. ADAM12 knockdown also decreased the population of CD44+/CD24- cells and ALDEFLUOR+ cells and reduced tumor formation in mice in vivo, suggesting that ADAM12 might be necessary for maintaining cancer stem cell phenotype of TNBC cells. To get insight into molecular pathways modulated by ADAM12, we performed RNA sequencing in cells with inducible knockdown of ADAM12 and identified several candidate pathways. Our results indicate that ADAM12 is a novel regulator of the plasticity of TNBC stem cells and it may serve as a future target in anti-metastatic breast cancer therapies.
Citation Format: Yue Qi, Sara Duhachek-Muggy, Hui Li, Linda Alyahya, Randi Wise, Anna Zolkiewska. ADAM12 is a novel regulator of stem-like cells 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 B43.
Abstract B47: Drug-induced EMT is fundamentally distinct from pathologic EMT
Authors: Akhand Saeed Salehin , Wendt Michael 
Published: May 2019

Abstract
Background: Receptor tyrosine kinase ErbB2 (Her2) is overexpressed in an estimated 25% of the breast cancer patients. A therapeutic regime of Her2 targeted therapies, consists of Trastuzumab followed by the dual EGFR/Her2 tyrosine kinase inhibitor, Lapatinib. These therapies continue to show success in blocking the progression of this breast cancer subtype. Of clinical concern, however, cancer cells eventually develop pathways to evade Lapatinib-mediated tumor inhibition and acquire drug resistance. In this study, we sought to understand the molecular mechanism of resistance towards Lapatinib.
Methods: We used Her2 overexpressing human mammary epithelial cells to generate Lapatinib resistant cell lines (LapR) in vitro. The LapR cells acquired growth persistence within the continued presence of Lapatinib for four weeks. We analyzed the resultant cell populations via cell viability assays, immunoblotting, flow cytometry, 3D cell culture and Nano-string gene expression analysis.
Results: Generated LapR cell lines showed robust epithelial-mesenchymal transition (EMT) phenotypes that included upregulated FGFR1 and preservation of their Her2 expression. We tested the viability of LapR cells using dose response assays with Afatinib, a second-generation covalent ErbB kinase inhibitor, and Trastuzumab emtansine (T-DM1), an anti-Her2 antibody drug conjugate. We also utilized recently developed covalent inhibitors of FGFR. LapR cells were highly resistant to Afatinib but did show sensitivity to T-DM1 and FGFR kinase inhibition. Importantly, resistance to ErbB inhibition was maintained in the LapR cells for several weeks following removal of Lapatinib. This stable phenotype was consistent with a maintained yet distinct regulation of the cancer stem cell markers (CD44/CD24) compared to a transient EMT induced by transforming growth factor β (TGF-β). Strikingly, we observed that unlike their parental counterparts LapR cells were unable to grow in a compliant 3D matrix. Furthermore, unlike TGF-β-treated cells, LapR cells were unable to metastasize in vivo. By using Nano-string pan cancer progression panel analysis, we characterized key differences in the LapR EMT phenotype as compared to a TGF-β induced EMT.
Future Directions: Currently, we are analyzing the expression data of LapR and TGF-β-induced EMT to identify key targets required for EMT-induced tumor progression. Overall, our studies seek to define what aspects of EMT are involved in cellular persistence in response to anti-cancer drugs versus those utilized by cells during metastatic progression.
Citation Format: Saeed Salehin Akhand, Michael Wendt. Drug-induced EMT is fundamentally distinct from pathologic EMT. [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 B47.