bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1574: Neuropilin 2 regulates lung disseminated tumor cell escape from dormancy and progression into metastasis
Authors: Bragado Domingo Paloma , Alonso Raul , Fuster Gemma , Mancino Mario , Fernandez-Nogueira Patricia , Aguirre-Ghiso Julio , Gascon Pere 
Published: July 2016

Abstract
Despite considerable advances in the treatment of cancer, about 50% of patients will still eventually develop metastatic disease which remains the main cause of cancer-related death. Disseminated tumor cells (DTCs) are the precursors of metastasis and understanding their biology is one of the most important challenges for the future of cancer research. Our previous studies have shown that TGFβ2 through binding to TGFβR3 regulates DTCs quiescence through the activation of p38αMAPK and induction of the dormant genes DEC2 and p27. However, these DTCs dormancy may be reversed when micro-environmental conditions shift to support DTCs expansion. Nerve fibers and neural mediators are present in organs that serve as key targets for breast and head and neck cancer metastasis, including lungs and bone. In addition, neuropeptides and neurotransmitters receptors are expressed by both, nerve and cancer cells, which suggests that neurotrophic factors can act as messengers between the nervous system and DTCs and influence metastasis progression. Therefore, we hypothesized that in situations of chronic stress or inflammation, neural mediators might influence DTCs fate at secondary organs. Using bioinformatics tools we have found that the semaphorins receptor Neuropilin 2 (NRP2), a co-receptor for TGFβ ligands, is overexpressed in basal and HER2+ breast cancer patient samples and its expression in primary tumors correlate with worst prognosis. In basal breast cancer cell lines, NRP2 expression correlates with lower levels of DEC2 and p27 dormancy genes. Furthermore, we have found that NRP2 is downregulated in dormant cells and overexpressed in proliferative lung DTCs derived cell lines that express low levels of P-p38, DEC2 and p27 dormancy markers. Our results show that in lung DTCs derived cell lines, NRP2 inhibits TGFβR3 expression favoring TGFβ1 signaling and promoting DTCs growth. In agreement with this, breast cancer lung metastasis express higher levels of NRP2 than quiescence lung DTCs in vivo, suggesting that NRP2 might play a role in lung DTCs proliferation. Therefore, we conclude that NRP2 can regulate breast cancer lung DTCs progression from a dormant state to a proliferative state and promote metastasis formation.
Citation Format: Paloma Bragado Domingo, Raul Alonso, Gemma Fuster, Mario Mancino, Patricia Fernandez-Nogueira, Julio Aguirre-Ghiso, Pere Gascon. Neuropilin 2 regulates lung disseminated tumor cell escape from dormancy and progression into metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1574.
Abstract 1580: Cancer-associated fibroblasts potentiates tumor relapse after radiotherapy
Authors: Mi Jun , Wang Yongbin , Gan Guifang , Zhao Jiangmin 
Published: July 2016

Abstract
Cancer-associated fibroblasts (CAFs) are a major component of cancer stromal cells, about 40∼50% of total cell population in cancer. Our data show that CAFs are distributed into larger area than tumor image revealed by MRI or CT since MRI- or CT- images only represent the core region containing cancer cells. Although the image-guided stereotactic body radiation therapy (SBRT) can precisely deliver radiation does to cancers and decreases radiation side effects, compared to the conventional external beam radiotherapy (EBRT), the data from our retrospective study showed that cancer recurrence including local and remote in patients with conventional EBRT was more frequent than patients with SBRT, and the survival time of patients with EBRT was also longer than patients with SBRT. We also demonstrated that CAFs could promote cancer cells recovery from radiation-induced damage through secreting cytokines/chemokines and exporting intermediate metabolites, which induce cancer cell dormancy and enhance DNA damage repair capacity.
Citation Format: Jun Mi, Yongbin Wang, Guifang Gan, Jiangmin Zhao. Cancer-associated fibroblasts potentiates tumor relapse after radiotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1580.
Abstract 1581: Crosstalk of androgen sensitive prostate cancer cells and insensitive prostate cancer cells
Authors: Takezawa Yuta , Mizokami Atsushi , Machioka Kazuaki , Izumi Kouji , Iwamoto Hiroaki , Aerken Maolake , Ariunbold Natsagdorg , Namiki Mikio 
Published: July 2016

Abstract
[Background] The mechanisms that prostate cancer (PCa) progresses to castration-resistant PCa (CRPC) are adaptation and clonal selection. We hypothesized that PCa proliferated while each mechanism cooperated when PCa recurred.
[Materials and Methods] After LNCaP cells were transfected with luciferase reporter driven by PSA promoter, LNCaP were cocultured with androgen-insensitive DU145 or PC-3. Then DHEA or DHT were added to the medium and luciferase assay was performed. Also, we added DHEA or DHT in the medium and measured various androgens level by LC-MS/MS. As for proliferation, LNCaP were cocultured with DU145 or PC -3 in 2-layer chamber and number of LNCaP were counted. DU145 and PC-3 were also cocultured with LNCaP cells for 4 days. We also checked migration by using 2-layer chamber and migrated cells were counted.
[Results] Whereas DHEA was converted into DHT in DU145 and induced PSA promoter activity in LNCaP, the effect was not found in PC-3. Moreover, DU145 elevated DHT-induced PSA promoter activity. DU145 promoted LNCaP proliferation stimulated by DHT and DHEA, but PC-3 did not. LNCaP also promoted proliferation of DU145 and PC-3. LNCaP promoted migration of PC-3, but not DU145.
[Conclusion] Cross-talk between androgen-sensitive PCa cells and androgen-insensitive PCa cells might regulate progression of CRPC.
Citation Format: Yuta Takezawa, Atsushi Mizokami, Kazuaki Machioka, Kouji Izumi, Hiroaki Iwamoto, Maolake Aerken, Natsagdorg Ariunbold, Mikio Namiki. Crosstalk of androgen sensitive prostate cancer cells and insensitive prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1581.
Abstract 1583: SRI31215, a novel inhibitor of oncogenic HGF/MET signaling
Authors: Owusu Benjamin Y. , Venukadasula Phanindra K. , Galemmo Robert A. , Klampfer Lidija 
Published: July 2016

Abstract
Constitutive activation of MET signaling, frequently observed in cancer, triggers signaling by AKT, ERK 1/2 and STAT3, and promotes survival, proliferation, migration and invasion of cancer cells. Accordingly, MET amplification or overexpression of its ligand, hepatocyte growth factor (HGF), are associated with tumor aggressiveness, resistance to therapy and poor prognosis in many cancer patients. Cancer cells can secrete HGF which triggers autocrine HGF/MET signaling, however, fibroblasts are the predominant source of HGF and activate MET expressed on tumor cells in a paracrine manner. Cancer cells and fibroblasts secrete HGF as an inactive precursor, pro-HGF. A crucial step in the regulation of HGF/MET signaling is the proteolytic processing of the inactive precursor, pro-HGF, to its active form by one of the three serine proteases, matriptase, hepsin or HGF activator (HGFA). This is the rate-limiting step in the HGF/MET signaling pathway, controlled by the inhibitors of HGF activation, hepatocyte growth factor activator inhibitors 1 and 2 (HAI-1/2).
We synthesized a novel small molecule, SRI31215, a triplex inhibitor of matriptase, hepsin and HGFA, mimicking the biological activity of HA1-1/2. We confirmed that SRI31215 inhibits the proteolytic activation of pro-HGF and blocks HGF-induced MET activation and signaling by AKT, ERK 1/2 and STAT3. SRI31215 blocked fibroblast-induced epithelial-to-mesenchymal transition (EMT) and prevented scattering and migration of cancer cells. Finally, we demonstrated that SRI31215 sensitized HGF-producing colon cancer cells to epidermal growth factor receptor inhibitors (EGFRi) and inhibited fibroblast-mediated, HGF-dependent, resistance to EGFRi in colon cancer. Thus, SRI31215 blocks signaling between cancer cells and fibroblasts and inhibits the tumor-promoting activity of cancer associated fibroblasts.
Taken together, our data demonstrate that inhibitors of HGF activation, such as SRI31215, represent a novel approach to curb the growth and metastatic spread of tumor cells that are addicted to HGF/MET signaling and to overcome primary and acquired resistance to EGFR-targeted therapy.
Citation Format: Benjamin Y. Owusu, Phanindra K. Venukadasula, Robert A. Galemmo, Lidija Klampfer. SRI31215, a novel inhibitor of oncogenic HGF/MET signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1583.
Abstract 159: Analysis of resistance to the combination of a PI3K- and Parp-inhibitor using a genomic sequencing approach
Authors: Nabavi Sheida , Juvekar Ashish , Wang Nicholas , Cantley Lewis C. , Wulf Gerburg M. 
Published: July 2016

Abstract
The objective of this study is to investigate the genomic and transcriptonal changes that are associated with resistance to treatment with the combination of a PI3K-inhibitor (NVP-BKM120) and a PARP-inhibitor (Olaparib). Previous studies have shown that the combination of a PI3K-inhibitor and a PARP-inhibitor synergistically reduced the growth of BRCA-related xenograft tumors derived from patients with TNBC. However, in clinical practice, primary and secondary resistance to this combination is observed. We hypothesize that acquired resistance is the result of a genomic evolution resulting from the selection pressure exerted by the drug treatment.
We used a genetically engineered mouse model, K14-Cre BRCA1f/fp53f/f, where primary tumors had been propagated in Cre-negative littermates and treated to point of resistance with NVP-BKM120 or NVP-BKM120 plus Olaparib. For each of the three tumors, we analyzed exome sequencing and RNA-seq using Illumina technology at the stage of sensitivity (C), resistance to PI3K-inhibition (B) and resistance to the combination (BO); i.e. for each individual tumor a parental clone and its drug-resistant subclones, obtained in vivo, were analyzed. We used the Mutect software tool to call somatic mutations, VarScan2 to call somatic copy number variations, Cuffdiff for differential expression analysis, and TophatFusion. Data were integrated to identify genes for functional analyses using MetaCore and MSigDB software tools.
We found that tumors resistant to the combination drug treatment in general had fewer gross genomic alterations (CNVs) than parental tumors, indicative of evolution of a less variable subclone. However, these tumors also displayed a higher number of non-synonymous mutations than their parental clone. Pathway analysis showed that somatically mutated genes in PI3K-inhibitor resistant tumors were highly enriched for antigen processing and presentation, while those of tumors resistant to the combination treatment were enriched for histone modification pathways. Notably, the tumors resistant to PI3K-inhibitor alone were enriched for Insulin-processing pathways. Genomic losses in PI3K-inhibitor treated tumors enriched for the estrogen receptor pathway (ESR) in breast cancer and DNA damage pathways.
In conclusion, our experimental design of analyzing isogenic tumors resistant to PI3K- or combined PI3K- and Parp-inhibitors enabled us to identify genomic alterations and pathways that explain the evolution to drug resistance.
Citation Format: Sheida Nabavi, Ashish Juvekar, Nicholas Wang, Lewis C. Cantley, Gerburg M. Wulf. Analysis of resistance to the combination of a PI3K- and Parp-inhibitor using a genomic sequencing approach. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 159.
Abstract 1598: LncRNA AK001796 as a therapeutic target in aggressive breast cancers
Authors: Kumar Maneesh , Sinnott DeVaux Rebecca , Shen Julia J. , Davis Steven P. , Dinger Marcel E. , Mattick John S. , Perou Charles M. , Rosen Jeffrey M. , Mani Sendurai A. , Herschkowitz Jason I. 
Published: July 2016

Abstract
Breast cancer is a heterogeneous disease that can be classified into several distinct molecular subtypes based on gene expression. Like mRNAs and miRNAs, long noncoding RNAs (lncRNAs) differ dramatically in expression across subtypes and can be used for classification. While there has been considerable emphasis on miRNAs, our knowledge is still lacking about the role of lncRNAs that comprise the majority of the mammalian transcriptome. Recently, the importance of lncRNAs in cancer has been highlighted by several studies. We have examined the expression profiles of &gt;17,000 lncRNAs in a large set of breast tumors and have identified a lncRNA, AK001796, that is overexpressed in aggressive breast cancers. In particular, AK001796 is enriched in the aggressive claudin-low, HER-enriched, and luminal B subtypes. Furthermore, in four different models, we find that AK001796 is significantly upregulated in cell lines induced to undergo EMT and in putative mesenchymal-like cancer stem cells within cell lines suggesting this lncRNA as an inducer/facilitator of EMT. Similar results were obtained when a lung cancer cell line was induced to EMT through TGF beta treatment. Using cell fractionation, we have discovered that AK001796 is maintained predominantly in the nucleus. By RACE we have identified two isoforms of AK001796 in breast cancer cells that differ by the presence or absence of a 94 nucleotide intron. The short form (with intron spliced out) appears to be the variant enriched following EMT and may serve as a marker of aggressiveness. Interestingly, knockdown of AK001796 using antisense oligonucleotides lead to significantly increased apoptosis in EMT positive cell lines whereas in EMT negative cells knockdown had little effect. Preliminary studies for finding out the protein interacting partners identified some mesenchymal phenotype-associated proteins in pull-down studies using biotinylated oligos. To further investigate the molecular mechanisms regulated by AK001796 and its utility as a therapeutic target, we will determine the pathways induced by AK001796 by mapping its protein interaction network and downstream signaling pathways. These results nominate AK001796 as a promising therapeutic target in aggressive breast cancers.
Citation Format: Maneesh Kumar, Rebecca Sinnott DeVaux, Julia J. Shen, Steven P. Davis, Marcel E. Dinger, John S. Mattick, Charles M. Perou, Jeffrey M. Rosen, Sendurai A. Mani, Jason I. Herschkowitz. LncRNA AK001796 as a therapeutic target in aggressive breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1598.
Abstract 1600: Polo-like kinase 1 induces epithelial-to-mesenchymal transition and promotes epithelial cell motility by activating CRAF/ERK signaling
Authors: Wu Jianguo , Ivanov Andrei I. , Fu Zheng 
Published: July 2016

Abstract
Polo-like kinase 1 (PLK1) is a key cell cycle regulator that has been implicated in the development of various cancers, including prostate cancer. However, the functions of PLK1 beyond cell cycle regulation remain poorly characterized. Here, we report that PLK1 overexpression in prostate epithelial cells triggers oncogenic transformation. It also results in dramatic transcriptional reprogramming of the cells, leading to epithelial-to-mesenchymal transition (EMT) and stimulation of cell migration and invasion. Consistently, PLK1 downregulation in metastatic prostate cancer cells enhances epithelial characteristics and inhibits cell motility. The signaling mechanisms underlying the observed cellular effects of PLK1 involve direct PLK1-dependent regulation of CRAF with subsequent stimulation of the MEK1/2-ERK1/2-Fra1-ZEB1/2 signaling pathway. Our findings highlight novel non-canonical functions of PLK1 as a key regulator of EMT and cell motility in normal prostate epithelium and prostate cancer. This study also uncovers a previously unanticipated role of PLK1 as a potent activator of MAPK signaling.
Citation Format: Jianguo Wu, Andrei I. Ivanov, Zheng Fu. Polo-like kinase 1 induces epithelial-to-mesenchymal transition and promotes epithelial cell motility by activating CRAF/ERK signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1600.
Abstract 1610: Inhibiting HuR, a RNA-binding protein, for inhibition of pancreatic cancer EMT and CSCs
Authors: Dong Ruochen , Polireddy Kishore , Zhang Ying , Chen Qi 
Published: July 2016

Abstract
Purpose
Epithelial- mesenchymal transition (EMT) contributes importantly to cancer cell metastasis, and formation of cancer stem cells (CSCs). An RNA-binding protein, HuR, plays an important role in many solid tumors for promoting cell proliferation, metastasis, anti-apoptosis and drug resistance. However, the role of HuR in cancer cell EMT and CSC has not been elucidated. Here we aim to investigate the role of HuR in pancreatic cancer EMT and CSC, and developing a new HuR inhibitor ST-3 as an inhibitor for pancreatic cancer EMT and CSCs.
Methods
Fluorescence Polarization assay and surface plasmon resonance assay was utilized for St-3, HuR and target mRNA binding. Scratching assay and matrigel invasion assay were used for cell migration and invasion, whereas MTT assay for viability. Tumor spheroid formation assay was used as an indication of CSCs. Western blot and RT-qPCR was used for protein and mRNA expression.
Results
Knockdown of HuR with siRNA inhibited migration of pancreatic cancer cells MIAPaCa-2, and suppressed the expression of Vimentin, Snail, and increased E-cadherin expression, showing inhibition in EMT. The suppression of Snail is due to accelerated mRNA decay. Overexpression of HuR protected mRNA of Snail from degradation, suggesting that Snail is a direct target of HuR. Knockdown of HuR also decreased pancreatic cancer spheroids formation.
St-3 inhibited the proliferation of pancreatic cancer cell lines more potently in HuR-high cells MIAPaCa-2 (IC50 ∼2 μM), than in HuR-low cells BxPc-3 and PANC-1 (IC50 6-20 μM). St-3 directly bound to HuR, and inhibited binding of HuR with its target mRNAs. St-3 treatment mimicked the HuR knockdown effects in inhibiting cell migration, EMT, and spheroids formation.
Conclusion
HuR is an important regulator in pancreatic cancer EMT and CSCs. ST-3 as a novel HuR inhibitor inhibited pancreatic cancer EMT and CSCs. Further investigation is under way.
Citation Format: Ruochen Dong, Kishore Polireddy, Ying Zhang, Qi Chen. Inhibiting HuR, a RNA-binding protein, for inhibition of pancreatic cancer EMT and CSCs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1610.
Abstract 1616: Galectin-4 interferes with the integrin β4/Src/FAK cascade and attenuates metastasis in urothelial carcinoma
Authors: Lin Li-Fang , Wu Meei-Maan , Lee Te-Chang 
Published: July 2016

Abstract
Galectin-4 (Gal-4), a multifunctional lectin, is presented at both intracellular and extracellular sites. Recent studies have shown that Gal-4 plays certain role in attenuating cancer progression and metastasis. We have also observed that patients with urothelial carcinoma (UC) with the lower Gal-4 expression were at higher grade and stage. In addition, the Gal-4 expression is inversely associated with lymph node invasion and prognosis. Since how Gal-4 attenuates the cancer metastasis in UC has not been well investigated, the goal of the present study is to understand the role of Gal-4 in UC progression. We ectopically expressed Gal-4 in UC cells and found that increased Gal-4 significantly inhibits cell proliferation, colony formation, migration, and invasion. We also demonstrated that Gal-4 overexpression leads to a significant decrease the adhesion of UC cells to the basement membrane substrate laminin. Mechanistically, we found that Gal-4 overexpression significantly reduces the expression of the laminin receptor integrin α6β4. Besides to downregulation of integrin β4, Gal-4 overexpression also reduces phosphorylation of Src and focal adhesion kinase (FAK) and promotes anoikis. Together, the present results revealed that Gal-4 reduces the metastasis activity of UC cells by interfering integrin β4/Src/FAK cascade, which are of essential to prevent the suspended cells from anoikis. These results suggest that Gal-4 could be considered as a pivotal factor in the migration and invasion of UC cells.
Key words: Galectin-4, integrin β4, migration, invasion, metastasis, anoikis, urothelial cancer
Citation Format: Li-Fang Lin, Meei-Maan Wu, Te-Chang Lee. Galectin-4 interferes with the integrin β4/Src/FAK cascade and attenuates metastasis in urothelial carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1616.