bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A37: Activation of FGFR1 signaling in mammary tumors leads to STAT3 activation and chemoresistance
Authors: Chuntova Pavlina , Bohrer Laura , Bade Lindsey , Schwertfeger Kathryn 
Published: August 2014

Abstract
Recent studies have shown that the Fibroblast Growth Factor Receptor 1 (FGFR1) gene locus is amplified in approximately 10% of human breast tumors. Breast cancer patients with an FGFR1 amplification have significantly shorter overall survival potentially due to their increased risk of distant metastasis. Using an inducible FGFR1 system (iFGFR1), we have been working to identify the mechanisms involved in FGFR-induced tumorigenesis. Published studies have shown increased survival and proliferation of cells containing the activated iFGFR1. Examining both mouse and human FGF-responsive cell lines, we found that FGFR activation leads to a decrease in apoptosis, both basally and after treatment with chemotherapy agents. Further studies indicated that activation of FGFR signaling leads to indirect activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) both in vitro and in vivo. STAT3 is commonly activated as a result of IL-6 family member signaling. In our in vitro system, iFGFR1 activation leads to production of cytokines such as LIF and IL-6, which in turn signal in an autocrine fashion to activate the STAT3 pathway. Inhibition of FGFR activity in vivo using the small molecule inhibitor PD173034 in combination with the chemotherapeutic doxorubicin resulted in significant reduction of mouse tumor burden. These results provide evidence for the involvement of FGF receptors in the induction of chemoresistance and the potential benefit of combination therapy. Future studies will pursue the mechanism which drives the resistance to drug-induced apoptosis.
Citation Format: Pavlina Chuntova, Laura Bohrer, Lindsey Bade, Kathryn Schwertfeger. Activation of FGFR1 signaling in mammary tumors leads to STAT3 activation and chemoresistance. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A37.
Abstract A40: Cancer cells form in vivo-like tumors in Gelfoam histoculture
Authors: Yano Shuya , Mii Sumiyuki , Tome Yasunori , Hiroshima Yukihiko , Uehara Fuminari , Miwa Shinji , Hoffman Robert M. 
Published: August 2014

Abstract
Tumors in vivo are well known to behave quite differently from cancer cells cultured on plastic or glass plates (monolayer culture). Cell culture on agar (sphere culture) is used for three-dimensional culture, however tumor spheres on agar rarely invade the substrate. It has been previously demonstrated that 3-D Gelfoam histoculture of tumors enables the cancer cells to maintain in vivo properties, in contrast to monolayer or sphere culture. Cancer cell-cycle kinetics were visualized in Gelfoam histoculture using HeLa cells and MKN45 cells expressing fluorescence ubiquitination cell cycle indicator (FUCCI), whereby quiescent cancer cells express mKusabira-Orange fluorescent protein (red) and proliferating cells express mAzami-Green fluorescent protein (green). Gelfoam histoculture of FUCCI-expressing cancer cells results in tumor-like structures with quiescent cancer cells in the center and proliferating cells at the surface, similar to what occurs in vivo as visualized by confocal microscopy. These results have profound implications for cancer biology, since most cellular and molecular studies of cancer cells were performed on plastic monolayer culture where characteristics of the cells may be quite different from the tumor in vivo.
Citation Format: Shuya Yano, Sumiyuki Mii, Yasunori Tome, Yukihiko Hiroshima, Fuminari Uehara, Shinji Miwa, Robert M. Hoffman. Cancer cells form in vivo-like tumors in Gelfoam histoculture. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A40.
Abstract A41: Cancer cells invade or divide, not both
Authors: Yano Shuya , Mii Sumiyuki , Tome Yasunori , Hiroshima Yukihiko , Uehara Fuminari , Miwa Shinji , Hoffman Robert M. 
Published: August 2014

Abstract
Invasive cancer cells are a critical target for chemotherapy. However most chemotherapeutic agents in clinical use target dividing cancer cells. Cancer cell-cycle kinetics were visualized in Gelfoam histoculture using a fluorescence ubiquitination cell cycle indicator (FUCCI), whereby quiescent cancer cells express mKusabira-Orange fluorescent protein (red) and proliferating cells express mAzami-Green fluorescent protein (green). Real-time imaging demonstrated that cancer cells in G0/G1 phase are invasive and disseminate in Gelfoam histoculture. In vivo, FUCCI-expressing cancer cells were in G0/G1 phase when they metastasized to the liver. Disseminated cancer cells in the peritoneal cavity were also in G0/G1 phase. Most drugs currently in use target cells in S/G 2/M, which may not be capable of invasion. Color-coded cell-cycle imaging in Gelfoam histoculture should provide a novel platform for the rapid screening of candidate therapeutic agents against quiescent invasive cancer cells.
Citation Format: Shuya Yano, Sumiyuki Mii, Yasunori Tome, Yukihiko Hiroshima, Fuminari Uehara, Shinji Miwa, Robert M. Hoffman. Cancer cells invade or divide, not both. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A41.
Abstract A52: Vimentin serves as a signaling scaffold at focal adhesion sites to regulate lung cancer cell adhesion
Authors: Havel Lauren , Marcus Adam I. 
Published: August 2014

Abstract
Vimentin is a dynamic type III intermediate filament that is overexpressed in various cancers including non-small cell lung cancer (NSCLC). It is a classic biomarker for highly invasive tumors and is associated with increased likelihood of metastasis and poor survival. Vimentin filaments are dynamic and localize to focal adhesions, where they assemble and disassemble to promote cell migration. Our data show that vimentin depletion reduces cell adhesion and phosphorylated focal adhesion kinase (pFAK); therefore, we hypothesize that vimentin acts through FAK to regulate cell adhesion and metastasis. We show that vimentin filaments enter pFAK- and pSrc-positive focal adhesion sites, and upon vimentin depletion, pFAK, pSrc and total FAK levels decrease. To explore the mechanism behind this observation, we performed a phospho-proteomic screen for proteins whose phosphorylation is altered upon vimentin loss. One of the identified proteins was a guanine nucleotide exchange factor (GEF) that regulates rac1. We show that vimentin loss leads to GEF mis-localization and downstream rac1 inactivation. Furthermore, inactivation of the GEF itself resulted in aberrant cellular adhesion and loss of pFAK. Based upon this data, we propose that vimentin serves as a signaling scaffold to regulate FAK via a rac1-GEF interaction. This work provides insight into the mechanism by which vimentin affects cell adhesion and potentially NSCLC metastasis.
Citation Format: Lauren Havel, Adam I. Marcus. Vimentin serves as a signaling scaffold at focal adhesion sites to regulate lung cancer cell adhesion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A52.
Abstract A54: TACE-regulated TGF-alpha shedding drives GRB7-dependent invasion in triple-negative breast cancer cell lines
Authors: Calvo Veronica , Giricz Orsi , Kenny Paraic A. 
Published: August 2014

Abstract
The Epidermal Growth Factor Receptor (EGFR) is frequently expressed in triple-negative breast cancer and is a marker of poor prognosis. We have also recently identified an EGFR-associated adaptor protein, GRB7, as being associated with reduced relapse-free survival in triple-negative breast cancer. In this study we have sought to define the mechanisms underlying the contributions of EGFR and GRB7 to triple-negative breast cancer progression.
Because activating mutations in EGFR are very rare events in breast cancer, we screened breast tumor gene expression profiles to examine the distribution of EGFR ligand expression. Of the six known EGFR ligands, TGFalpha was expressed more highly in triple-negative breast tumors than in tumors of other subtypes. TGFalpha is synthesized as a transmembrane precursor requiring TACE/ADAM17-dependent proteolytic release in order to activate its receptor. In this study we show that an inhibitor of this proteolytic release blocks invasion, migration and colony formation by several triple-negative breast cancer cell lines. Each of these effects of the drug was reversed upon expression of a soluble TGFalpha mutant which does not require TACE activity to function, implicating this one metalloproteinase substrate as playing a critical role in these metastasis-related phenotypes. A cyclic peptide inhibitor of GRB7, G718-NATE, also blocked tumor cell invasion and colony formation in 3D culture. Importantly, cell lines overexpressing the soluble TGFalpha mutant remained sensitive to the effects of the GRB7 inhibitor, suggesting that a linear TACE-TGFalpha-EGFR-GRB7 signaling module is involved. We additionally demonstrate that GRB7 overexpression upregulates several pathways with roles in tumor cell proliferation, migration and survival.
Taken together, these data demonstrate that TGFalpha is the key ligand for EGFR in triple-negative breast cancer and that it drives invasion and proliferation via GRB7. This work suggests that triple-negative breast tumors in which this pathway is active might benefit clinically from either EGFR or TACE inhibitors.
Citation Format: Veronica Calvo, Orsi Giricz, Paraic A. Kenny. TACE-regulated TGF-alpha shedding drives GRB7-dependent invasion in triple-negative breast cancer cell lines. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A54.
Abstract A57: Characterization of novel regulators of epithelial-mesenchymal transition in human cancer cells
Authors: Li Linna , Ai Nanping , Hulsurkar Mohit , Li Wenliang 
Published: August 2014

Abstract
The epithelial-mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by cancer cells of several cancer types. Recently, a few kinases, such as FYN and c-Met, were reported to participate in regulating EMT. However, the roles of the majority of &gt;700 human kinases in EMT and cancer progression are still unknown. Here we carried out human kinase cDNA screens to identify novel regulators of EMT. Many unknown EMT regulators and a few known ones such as PI3K, PDGFRA, FYN and c-Met, were found to up-regulate mesenchymal marker vimentin. Some also increase expression of fibronectin and N-cadherin, as well as EMT transcriptional regulators, such as ZEB1/2, Snail and Slug. At the same time, the cells acquired mesenchymal phenotypes, such as increased migration/invasion activity, enhanced capability to survive and proliferate in growth factor deprivation condition or under drug treatments. Interestingly, FACS analysis also showed a substantial increase in CD44hiCD24low population in kinase-transducted mammary gland epithelial cells. The increase of CD44hi population could be attributed to increase of a CD44 mesenchymal variant — the standard form CD44s and decrease of the epithelial variant CD44 v8-10. And this alternation was associated with down-regulation of ESRP1 and ESRP2, two splicing factors that regulate CD44 splicing and EMT. Furthermore, the mammary gland epithelial cells undergoing EMT showed increase capability of forming mammosphere and differentiating into other lineage, such as osteoblast and adipocyte. Importantly, some of these novel EMT regulators are associated with tumor progression and stemness of human cancers. Further study of these novel EMT regulators promises to provide new mechanisms of cancer progression, and may also lead to development of new prognostic markers and therapeutics for metastasis.
Citation Format: Linna Li, Nanping Ai, Mohit Hulsurkar, Wenliang Li. Characterization of novel regulators of epithelial-mesenchymal transition in human cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A57.
Abstract A58: Loss of Par3 promotes metastasis of ErbB2 transformed mammary epithelial cells by inhibiting E-cadherin adhesion junction maturation
Authors: Xue Bin , Muthuswamy Senthil 
Published: August 2014

Abstract
The mechanisms by which tumor cells metastasize and the role cell polarity proteins play in this process are not well understood. We report that Partitioning defective protein 3 (Par3) is dysregulated in metastasis in human breast cancer, and is associated with higher tumor grade and ErbB2-positive status. Downregulation of Par3 cooperated with ErbB2 to induce cell invasion and metastasis in vivo. Interestingly, the metastatic behavior was not associated with an overt mesenchymal phenotype. However, loss of Par3 inhibited E-cadherin junction maturation, disrupted membrane and actin dynamics at cell-cell junctions and decreased cell-cell cohesion in a Tiam1/Rac-GTP pathway dependent manner. Inhibition of this pathway restores E-cadherin junction maturation and blocked invasive behavior of cells lacking Par3 suggesting that loss of Par3 promotes metastatic behavior of ErbB2-induced tumor epithelial cells by decreasing cell-cell cohesion.
Citation Format: Bin Xue, Senthil Muthuswamy. Loss of Par3 promotes metastasis of ErbB2 transformed mammary epithelial cells by inhibiting E-cadherin adhesion junction maturation. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A58.
Abstract A59: Dixdc1 links the LKB1 tumor suppressor to Snail, noncanonical Wnt signaling, and metastasis
Authors: Goodwin Jonathan M. , Svensson Robert U. , Shackelford David B. , Winslow Monte M. , Shaw Reuben J. 
Published: August 2014

Abstract
The kinase LKB1 is a tumor suppressor mutated in familial and sporadic human cancers, whose loss is uniquely coupled with metastatic progression. Although LKB1 controls growth and metabolism through phosphorylation of AMPK, it also phosphorylates the related MARK/ Par1 kinases, which play conserved roles in cell polarity and cytoskeletal dynamics. In a screen for novel targets of LKB1-dependent signals, we identified the scaffold protein DIXDC1 as a substrate of MARK1 which controls cell migration and invasion. DIXDC1 localizes to focal adhesions, and like LKB1, its depletion results in hyperactivation of focal adhesion kinase and subsequent increases in the EMT-transcription factors Snail and Slug. Depletion of LKB1 or DIXDC1 results in Snail-dependent induction of the noncanonical Wnt5a and Wnt5b, which are required for the increased invasive behavior of these cells. Studies on a panel of murine lung adenocarcinoma cell lines from defined stages of metastatic progression reveals that DIXDC1 depletion was sufficient to promote metastasis, while Wnt5a and Wnt5b are required for metastatic behavior in these cells. DIXDC1 is frequently downregulated in human cancers, and inversely correlates with Snail and Wnt5 family members expression. This study reveals the first downstream effector of LKB1 in tumor suppression that is independent of AMPK and identifies a novel signaling pathway that provides a molecular explanation for how LKB1 controls EMT and metastasis.
Citation Format: Jonathan M. Goodwin, Robert U. Svensson, David B. Shackelford, Monte M. Winslow, Reuben J. Shaw. Dixdc1 links the LKB1 tumor suppressor to Snail, noncanonical Wnt signaling, and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A59.
Abstract A60: Foxf1 transcription factor drives progression of benign lung adenomas to malignant adenocarcinomas
Authors: Wang Xinjian , Balli David , Le Tien , Kalinichenko Vladimir V. , Kalin Tatiana V. 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer-related deaths in the United States with current 5-year survival only 8—12%. Patients with non-small cell lung cancer (NSCLC) develop metastases prior to clinical symptoms, which reduces successful treatment outcomes. The new therapeutic approaches targeting progression and metastasis of NSCLC are needed. Foxf1 transcription factor is expressed in mesenhyme-derived cells, such as fibroblasts, smooth muscle cells and endothelial cells, but absent from epithelial-derived cells, such as alveolar and airway epithelial cells, and benign lung adenoma cells. In present study, we used immunohistochemistry to demonstrate that Foxf1 expression is up-regulated in the invasive front of human lung adenocarcinomas. Foxf1 expression is also induced in mouse lung adenocarcinomas, caused by either activation of K-Ras G12D transgene or transplantation of Lewis Lung Carcinoma (LLC) cells. In vitro, shRNA-mediated depletion of Foxf1 from LLC cells decreased migration, invasion and colony formation of LLC cells on soft agar. Depletion of Foxf1 reduced mRNA and protein levels of Twist1, and prevented TGFbeta-induced EMT. In vivo, Foxf1-depleted LLC cells failed to form lung metastasis in the transplantation model of lung cancer. Furthermore, we generated transgenic mice with Doxycycline-inducible expression of Foxf1 under control of epithelial-specific SPC-promoter (epFoxf1 mice). Lung adenomas in these mice were induced by urethane. Activation of the Foxf1 transgene in pre-existing lung adenomas promoted their progression towards adenocarcinomas that invaded adjacent bronchiolar lumens and pleural surfaces. Transgenic expression of Foxf1 in tumor cells resulted in the loss of cell polarity, decreased E-cadherin, and increased expression of aSMA, Twist1 and other EMT associated genes. Foxf1 directly bound to promoter region of Twist1, implicating the Foxf1 in the regulation of the Twist1 gene. The present study provides the first genetic evidence that aberrant expression of Foxf1 induces EMT in lung tumors and promotes the progression of lung adenomas to invasive adenocarcinomas, suggesting that Foxf1 is a promising target for anti-cancer therapy.
Citation Format: Xinjian Wang, David Balli, Tien Le, Vladimir V. Kalinichenko, Tatiana V. Kalin. Foxf1 transcription factor drives progression of benign lung adenomas to malignant adenocarcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A60.
Abstract A64: Identification of p75NTR/TrkB-BDNF axis in breast cancer brain metastasis
Authors: Chen Wenhong , McMahan Christine N. , Barlow Keith D. , Juarez Dennis , Metheny-Barlow Linda J. 
Published: August 2014

Abstract
Metastasis of breast cancer to the brain is increasing and is a significant cause of morbidity and mortality for breast cancer patients. In order to understand the molecular mechanisms controlling metastasis to the brain, we have generated two mouse models of breast cancer brain metastasis (4T1.luc2.Br5, Eo771.Br5) via serial selection of these cells through the brains of syngeneic mice following carotid artery injection. In vitro, the 4T1.luc2.Br5 cells exhibit increased proliferation and invasion through basement membrane proteins, while both models demonstrate increased ability to adhere to brain microvascular endothelial cells. Transcriptional profiling followed by Western analysis determined that the p75NTR neurotrophin receptor and its ligand BDNF are highly upregulated in brain-metastatic 4T1.luc2.Br5 cells. The TrkB neurotrophin receptor for BDNF is expressed by these cells as well. Knockdown of p75NTR abolishes the increased invasive capacity of brain-selected 4T1.luc2.Br5 in vitro, confirming a role for p75NTR signaling in invasion. While p75NTR expression in primary breast epithelial cells is reportedly low, we observed that 8 of 12 (67%) human breast cancer brain metastasis specimens express high levels of p75NTR, further suggesting an important role in metastasis to brain. Interestingly, while the brain metastatic Eo771.Br5 cells do not express p75NTR in vitro, both the TrkB receptor and its BDNF ligand are upregulated compared to parentals. Together these data suggest a role for activation of p75NTR/TrkB-BDNF signaling in breast cancer brain metastatic cells, and that targeting this pathway may be a means to prevent or treat breast cancer brain metastasis.
Citation Format: Wenhong Chen, Christine N. McMahan, Keith D. Barlow, Dennis Juarez, Linda J. Metheny-Barlow. Identification of p75NTR/TrkB-BDNF axis in breast cancer brain metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A64.
Abstract A65: ShcA is required for the TGFβ-induced repression of Chordin-like-1 in ErbB2-expressing breast cancer cells
Authors: Northey Jason J. , Dong Zhifeng , Cyr-Depauw Chanele , Cory Sean , Siegel Peter M. 
Published: August 2014

Abstract
Clinical data and transgenic mouse models have provided clear evidence of a critical role for the adaptor protein ShcA in mammary tumor formation and metastasis downstream of several oncogenes. Indeed, we have demonstrated that stable silencing of ShcA expression in ErbB2-expressing breast cancer cells impairs tumor outgrowth and metastasis in vivo. In addition, we have identified a requirement for an intact PTB domain and the three tyrosine residues in ShcA for mediating TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells. Together, these observations position the ShcA adaptor as an important signaling node that facilitates cooperation between the ErbB2 and TGFβ signaling pathways in breast cancer progression. To understand how ShcA signaling contributes to TGFβ-induced gene expression changes, we generated a doxycycline-inducible system to deplete ShcA levels from ErbB2-expressing breast cancer cells. The inducible silencing of ShcA in pre-established ErbB2-positive tumors resulted in impaired tumor cell proliferation and survival in vivo. Gene expressing profiling was then performed on cells with an inducible loss of ShcA expression to identify ShcA-dependent transcriptional responses downstream of active TGFβ and ErbB2 signaling in breast cancer cells. ShcA was found to mediate the suppression of Chordin-like 1, a BMP antagonist. Conditioned media taken from TGFβ-stimulated ErbB2-expressing cells treated with doxycycline to achieve reduced ShcA levels was confirmed to contain increased levels of Chordin-like-1 compared with unstimulated controls. This same conditioned media was efficient at inhibiting the BMP-stimulated phosphorylation of Smad proteins 1/5/8 in ErbB2-expressing cells. Furthermore, this TGFβ upregulation of Chordin-like 1 production resulting from ShcA loss correlated with decreased activation of Smad1/5/8 in ShcA-deficient tumor cells in vivo, and may represent a transcriptional mechanism through which ShcA coordinates ErbB2 and TGFβ initiated tumor growth and invasion.
Citation Format: Jason J. Northey, Zhifeng Dong, Chanele Cyr-Depauw, Sean Cory, Peter M. Siegel. ShcA is required for the TGFβ-induced repression of Chordin-like-1 in ErbB2-expressing breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A65.