bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1995: PTHrP drives tumor initiation signaling pathways in the PyMT model of breast cancer progression
Authors: Zhang Rui , Li Jiarong , Badescu Dunarel , Karaplis Andrew , Ragoussis Jiannis , Kremer Richard 
Published: August 2018

Abstract
Parathyroid hormone-related peptide (PTHrP) was first discovered in cancer patients as the primary cause of malignancy associated hypercalcemia (MAH) & is overexpressed in most human breast tumors. We previously showed that PTHrP ablation, in the MMTV-PyMT murine model of breast cancer progression can dramatically prolong tumor latency, slows tumor growth & metastases. Here we examined the signaling pathways under the control of PTHrP in the pre-neoplastic stage of tumor development (hyperplasia) by generating MMTV-PyMT model in which the mammary epithelium, expressing membrane-targeted GFP, is distinguished from the membrane-targeted red fluorescent backlight of stromal & nonepithelial-derived mammary tissues. We constructed Pthrpflox/flox; Cre+ mT/mG tumor mice (PTHrP conditional KO) & Pthrpwt/wt; Cre+ mT/mG tumor mice (WT control). Next, we applied FACS to enrich the GFP+ mammary epithelial cells isolated from PTHrP KO & control tissues for subsequent RNAseq analyses. We then examined differentially expressed genes (DEGs) by comparing purified cell populations from PTHrP KO & control tissues. We identified 939 DEGs (p value &lt;0.01) & used DAVID bioinformatics resources to systematically analyze the KEGG pathways. Among the most significant pathways, extracellular matrix (ECM), focal adhesion,PI3K-Akt, RAS and WNT pathways were up-regulated in WT control cells compared to KO cells. In summary, PTHrP controls critical signaling pathways involved in breast cancer initiation at the pre-neoplastic stage & suggests that PTHrP ablation is a promising therapeutic strategy in breast cancer.
Citation Format: Rui Zhang, Jiarong Li, Dunarel Badescu, Andrew Karaplis, Jiannis Ragoussis, Richard Kremer. PTHrP drives tumor initiation signaling pathways in the PyMT model of breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1995.
Abstract 1998: Novel interplay between TANK-binding kinase (TBK1) and Yes-associated protein (YAP1) in KRAS mutant NSCLC
Authors: Saha Biswarup , Jaiswal Neha , Bora-Singhal Namrata , Chellappan Srikumar 
Published: August 2018

Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the United States. Lung adenocarcinomas are highly correlated with smoking and are characterized by mutations in KRAS, EGFR, BRAF and other oncogenes. Among them, KRAS mutations are widespread in adenocarcinomas in smokers and known to be a key player in various downstream signaling pathways contributing to genesis and progression of these tumors. More recently, the non-canonical IκB kinase, Tank Binding Kinase 1 (TBK1), has been found to facilitate tumorigenesis in KRAS mutant cancers. TBK1 has well documented functions in immune response, cell survival as well as in mitosis. While it has been suggested that TBK1-mediated regulation of Akt signaling might facilitate oncogenesis, the molecular mechanisms underlying TBK1 function downstream of KRAS is not fully elucidated. In a similar vein, Yes associated protein 1 (YAP1), the oncogenic component of the Hippo signaling cascade has been found to promote KRAS mediated oncogenesis and could substitute for the loss of Kras in mouse models of pancreatic cancer. In the present study, we have demonstrated a unique and novel molecular interplay between TBK1 and the oncogenic components of Hippo effector molecules, YAP1/TAZ. YAP1 and its ortholog, TAZ are known to be transcriptional co-activators, function to maintain organ size but often get activated in various types of cancer.
We find that TBK1 physically interacts with YAP1, and knock-down (KD) or knocking-out (KO) of TBK1 resulted in a significant elevation of YAP1/TAZ expressions at protein level. We have tested four different KRAS and EGFR mutant NSCLC cell-lines; interestingly, the upregulation of YAP1 upon depletion of TBK1 was only restricted to the KRAS mutant cell-lines. Further, depletion of TBK1 led to the enrichment of YAP1 in the nucleus; notably, there were only minimal changes in the levels of MST1/2 and LATS, raising the possibility that these changes occur independent of the classic hippo signaling pathway. Depletion of TBK1 also resulted in the induction of EMT-like features in these cells, and increased the proportion of stem-like side-population. Mechanistically, TBK1 physically interacts with YAP1 in the cultured cells, and could phosphorylate it in vitro, on T110, T114, S128 and S131 residues. The underlying molecular mechanism(s) by which TBK1 regulates YAP1 expression are under investigation, and we hypothesize that this regulatory event is exclusive to KRAS mediated oncogenesis, especially in the context of NSCLC.
Citation Format: Biswarup Saha, Neha Jaiswal, Namrata Bora-Singhal, Srikumar Chellappan. Novel interplay between TANK-binding kinase (TBK1) and Yes-associated protein (YAP1) in KRAS mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1998.
Abstract 200: FOXD1 promotes stromal investment in clear cell renal cell carcinoma
Authors: Bond Kyle H. , Fetting Jennifer , Gupta Ashwani , Duarte Christine W. , Karolak Michele , Congdon Clare B. , Emery Ivette , hAinmhire Eoghainín Ó , Humphreys Benjamin D. , Oxburgh Leif 
Published: August 2018

Abstract
Forkhead transcription factors (FOX) play a role in the development of many cancers, including clear cell renal cell carcinoma (ccRCC). FOXD1, essential for angiogenesis in the developing kidney, has not previously been implicated in ccRCC. Tumor microarrays (TMAs) containing 41 patient-derived ccRCC tumors and 26 healthy cortex samples were stained for FOXD1, with 65% of tumor samples staining positively. Due to the effect of FOXD1 on angiogenesis, staining for stromal markers PECAM, αSMA, PDGFRβ and NG2 was also performed. A direct correlation was found only between FOXD1 and PDGFRβ (p&lt;4.5x10-6), suggesting interstitial fibroblast recruitment by FOXD1+ cancer cells. Increased expression of FOXD1 was found to correlate with increased stage (p=9.1x10-5) and reduced survival (FOXD1 low= 2830 days; FOXD1 high= 1913 days) from a Kaplan-Meier analysis of RNA-seq data from The Cancer Genome Atlas (TCGA). Potential FOXD1 target binding sites were determined using the TRANSFAC FOXD1 binding site matrix. SLIT2, a factor known to inhibit migration of pericytes, was uncovered from the analysis and was further found to be downregulated in response to FOXD1 overexpression in renal proximal tubule cells (RPTECs). To test the influence of SLIT2 on interstitialfibroblast migration, scratch assays on NRK-49F (rat kidney fibroblast) and Gli-1 (cardiac fibroblast) cells were performed and showed that SLIT2 reduced PDGFBB-induced cell migration (p&lt;0.027). A multiplex proximity ligation assay for multiple signaling pathways showed that SLIT2 treatment reduced the STAT signaling response to PGDFBB. To model the influence of SLIT2 on ccRCC stromal invasion in vitro, we devised a novel 3D invasion assay. In summary, 786-O ccRCC cancer cells were seeded into a 200um thick silk scaffold and cultured for 3 days to allow deposition of ECM. Scaffolds were then placed on top of a monolayer of interstitial fibroblasts and invasion into the cancer cell-filled scaffold was measured using confocal microscopy. The results showed a significant reduction of cell invasion into the cancer-filled matrix with the addition of recombinant SLIT2 to media (5µm p=1.34x10-4; 50µm p=1.64x10-2). In conclusion, we show that FOXD1 expression has prognostic relevance to patient survival in ccRCC, and that this may be due to modulation of SLIT2 expression.
Citation Format: Kyle H. Bond, Jennifer Fetting, Ashwani Gupta, Christine W. Duarte, Michele Karolak, Clare B. Congdon, Ivette Emery, Eoghainín Ó hAinmhire, Benjamin D. Humphreys, Leif Oxburgh. FOXD1 promotes stromal investment in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 200.
Abstract 2000: The regulatory role of endothelial nitric oxide synthase signaling in the growth of prostate cancer stem-like cells
Authors: Gao Weijie , Wu Dinglan , Wang Yuliang , Wang Zhu , Ma Taiyang , Chan Franky Leung 
Published: August 2018

Abstract
Cumulative studies indicate that there is a small subpopulation of cancer cells present in cancers or solid tumors referred as cancer stem-like cells (CSCs) as they share some common characteristics with stem cells, particularly self-renewal and multipotency, and these CSCs may contribute to the tumor initiation, treatment resistance and relapse. Recent advances also indicate that prostate cancer stem-like cells (PCSCs) may play a critical role in the development of castration-resistant prostate cancer (CRPC) and also its metastasis. Here, we demonstrated using an established CRPC xenograft model (VCaP-CRPC) that both the xenograft tumors and a xenograft-derived cell line contained more PCSC population, which showed higher expression levels of endothelial nitric oxide synthase (eNOS) and elevated intracellular NO production. PCSCs, isolated from prostaspheres derived from prostate cancer cell lines (DU145, LNCaP and VCaP) using a newly developed agar-based non-attachment 3D-culture method, exhibited up-regulation of eNOS and increased intracellular NO levels. Interruption of eNOS signaling by NOS inhibitors and shRNA-knockdown could significantly suppress the sphere formation capability of prostate cancer cells. Exogenous overexpression of eNOS could promote the tumor growth capacity of prostate cancer cells and their metastasis in vivo, while knockdown of eNOS could prevent the tumor growth and metastasis. Combined transcriptome-sequencing analysis and qPCR validation of prostaspheres upon eNOS-knockdown identified some potential targets of eNOS/NO signaling in the PCSC-enriched prostaspheres. In summary, our results suggest that eNOS/NO signaling may play a positive role in the growth regulation of PCSCs and eNOS might be a potential target for advanced prostate cancer. This study is supported by a General Research Fund from the Research Grants Council of Hong Kong (project code 14107617) and an Innovation and Technology Fund (GHP/003/16GD) from the Innovation and Technology Commission of Hong Kong.
Citation Format: Weijie Gao, Dinglan Wu, Yuliang Wang, Zhu Wang, Taiyang Ma, Franky Leung Chan. The regulatory role of endothelial nitric oxide synthase signaling in the growth of prostate cancer stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2000.
Abstract 201: Multiregion joint somatic genotyping in ovarian cancer proves optimal tumor sampling for clinical sequencing
Authors: Pongor Lorinc , Munkacsy Gyongyi , Vereczkey Ildiko , Pete Imre , Gyorffy Balazs 
Published: August 2018

Abstract
Introduction. Genetic heterogeneity of ovarian tumors is caused by the accumulation of novel mutations through time. A result of this process is a spatially heterogeneous tumor with a fractal-like architecture, comprising of a mixture of spatially separated clones, sub-clones, and single cells. Spatial heterogeneity renders clinical sequencing a challenging task because clinically relevant mutations can go undetected. Here, we compare the genetic composition of single tumors with multiple DNA samples extracted from different regions of the tumor in diverse combinations to examine the effects of spatial separation on tumor heterogeneity.
Methods. We derived tumor samples from five patients with ovarian cancer. Three tumor tissue samples were collected from each patient, in each of these, DNA was extracted from a total of eight segments of different sizes (5x3x8 total segments). Exome sequencing was performed and we examined DNA mutations identified from a biopsy sample, from three merged tissue segments with immediate vicinity to the biopsy, and from segments from spatially distant tissue samples merged into one. We compared identified mutations and copy-number variations called from the exome-seq data.
Results. Three patients had heterozygous germline alterations affecting the BRCA pathway, paired with somatic TP53 mutations, one patient had multiple somatic mutations affecting the PI3K pathway, the last patient had the most common activating mutations in the PIK3CA and KRAS genes. When comparing the different sequencing runs, increasing the size of the tumor sample did not affect the overall quantity of mutations identified. Clonal mutations were identifiable in all samples, while sub-clonal mutations shifted. In case of a hypermutating phenotype, increasing the sequenced sample size strongly decreased the number of identified somatic mutations, most probably due to dilution of sub-clones. These observations are confirmed by an in silico model, in which we shuffled regions from publicly available multi-region sequencing data into known compositions.
Conclusion. In hypermutating tumors the number of detected mutations increases as the size of the sequenced sample decreases. Generally, increasing the tumor sample size did not affect the number of identifiable mutations. Our findings suggest that clinical sequencing using small biopsy samples can generate adequate mutation calling results.
Citation Format: Lorinc Pongor, Gyongyi Munkacsy, Ildiko Vereczkey, Imre Pete, Balazs Gyorffy. Multiregion joint somatic genotyping in ovarian cancer proves optimal tumor sampling for clinical sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 201.
Abstract 2014: CAMSAP3, a tubulin minus-end binding protein, attenuates epithelial-to-mesenchymal transition and alters microtubule dynamic in non-small cell lung cancer
Authors: Pongrakhananon Varisa , Wattanathamsan Onsurang , Takeichi Masatoshi 
Published: August 2018

Abstract
Cancer metastasis become the major cause of mortality in cancer patients, which the cancer migration exerts this aggressiveness. Epithelial to mesenchymal transition (EMT) plays an important role on cell movement and survival of the cancer cells during metastasizes. The establishment of front-rare polarization is involved with the alteration of cytoskeleton and cell-cell interaction, contributing to the notable morphological transformation from cobble stone-like epithelial to fibroblast-like mesenchymal feature. Microtubule dynamic has gained attention as a modulator behind these phenotypic changes and the EMT-related signal trafficking. Tubulin behavior has been shown to be governed by microtubule-binding proteins including a family of Calmodulin-regulated spectrin-associated proteins (CAMSAPs), a tubulin minus-end binding proteins. To illustrate the role of CAMSAPs on mesenchymal transition, CAMSAP2 and 3 genes were knockout using CRISPR-Cas9 system. Wound scratching and transwell migration assays demonstrate that non-small cell lung cancer becomes more motile with an elevation of actin stress fiber and focal adhesion protein paxillin following CAMSAP3 knockout, whereas CAMSAP2 depletion shows no significant effect. The mesenchymal markers including Slug, N-Cadherin and ZEB1 were substantial up-regulated, in opposite to the epithelial marker E-cadherin. Furthermore, CAMSAP3 removal causes a decrease of tubulin dynamic and consequently sustains an active state of EMT-regulatory proteins. This study reveals the negative
regulatory effect of CAMSAP3, a non-centrosomal microtubule minus-end binding protein, on mesenchymal transition and cell motility.
Citation Format: Varisa Pongrakhananon, Onsurang Wattanathamsan, Masatoshi Takeichi. CAMSAP3, a tubulin minus-end binding protein, attenuates epithelial-to-mesenchymal transition and alters microtubule dynamic in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2014.
Abstract 2025: CD147/EMMPRIN mediates epithelial-mesenchymal transition of head and neck squamous cell carcinoma
Authors: Suzuki Shinsuke 
Published: August 2018

Abstract
Epithelial-mesenchymal transition (EMT) is a key mechanism in the progression of solid tumors. This process is characterized by the development of more migratory, invasive cell behavior. Transforming growth factor-β (TGF-β) has been well characterized as a potent inducer of EMT. CD147, also known as extracellular matrix metalloproteinase inducer (EMMPRIN), a member of the immunoglobulin superfamily, is highly expressed in cancer cells and induces malignant characteristics in various tumors, including head and neck squamous cell carcinoma (HNSCC). Accumulating evidence indicates a contribution of CD147/EMMPRIN to tumorigenesis of solid tumors. However, the function of CD147/EMMPRIN in EMT and TGF-β-induced tumorigenicity in HNSCC has not yet been explored. To determine the role of CD147/EMMPRIN in EMT and TGF-β-induced tumorigenic behavior, SAS, a tongue squamous cell carcinoma cell line, was stimulated with TGF-β. After stimulation with TGF-β, we found that SAS cells acquired a spindle-shaped morphology. Immunoblotting analysis showed that the expression of vimentin was upregulated and E-cadherin was downregulated after TGF-β treatment. This result suggests that EMT was induced by TGF-β in SAS cells. In addition, expression of CD147/EMMPRIN was upregulated in SAS cells using TGF-β treatment. TGF-β stimulation enhanced the migratory ability of the cells. Furthermore, the TGF-β-induced migratory ability, and the change in cellular morphology was diminished by CD147/EMMPRIN knockdown. These results suggest that CD147 is involved in TGF-β-induced EMT and the migratory capacity of HNSCC.
Citation Format: Shinsuke Suzuki. CD147/EMMPRIN mediates epithelial-mesenchymal transition of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2025.
Abstract 2028: ZEB2 promotes cancer cell survival and angiogenesis by cooperating with transcription factor Sp1
Authors: Ko Dongjoon 
Published: August 2018

Abstract
The metastatic cascade essential for tumor progression consists of local invasion, intravasation, extravasation, micrometastasis, cancer cell survival in the circulation, and metastatic colonization. In particular, epithelial-mesenchymal transition (EMT) has been demonstrated a critical process whereby epithelial cells undergo molecular changes to acquire mesenchymal phenotypes through upregulation of EMT-inducing transcription factors. We previously showed that ZEB2, through cooperation with the transcription factor Sp1, plays an important role in the transcriptional upregulation of mesenchymal genes such as integrin α5 and vimentin during cancer cell invasion. Here, we show that ZEB2 cooperates with Sp1 for promoting not only EMT and invasion but also diverse cellular functions during metastasis. ZEB2 induces expression of Sp1-regulated genes such as VEGF, survivin, bcl-2 and cyclin D1 in an Sp1-dependent manner. Collaboration between ZEB2 and Sp1 induces cancer cell survival and proliferation, endothelial cell activation, and tumor angiogenesis. Furthermore, Sp1 stabilizes ZEB2 protein, supporting the presence of a positive feedback loop between ZEB2 and Sp1. Clinical data show that ZEB2 expression was correlated to Sp1 expression, and that those factors were a crucial for predicting survival in cancer patients. Our findings demonstrate cooperative roles of ZEB2 and Sp1 in regulating cancer cell survival and angiogenesis beyond invasion during cancer progression.
Citation Format: Dongjoon Ko. ZEB2 promotes cancer cell survival and angiogenesis by cooperating with transcription factor Sp1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2028.
Abstract 203: Regenerable altruism drives chemotolerance in clonal cancer cells
Authors: Lee Kee Wah , Masroni Muhammad Sufyan , Tan Karen Meiling , Li Mo-Huang , Zhou Lihan , Tucker Steven , Ngo Lynette Su Mien , Chang Chan Fong , Bay Boon Huat , Tan Soo Yong , Hartman Mikael , Chua Huiwen , Loh Tze Ping , Putti Thomas , Leong Sai Mun , Koay Evelyn Siew-Chuan 
Published: August 2018

Abstract
Introduction: Cancer is thought to represent a breakdown of multicellular cooperation and reversion to Darwinian dynamics characterized principally by self-interested competition. However, there is increasing evidence that cancer cells can behave as communities, manifesting social behaviors that influence cancer progression.
Methods: Circulating tumor cells enrichment, microRNA extraction, qRT-PCR, MTS assays, RNA in situ hybridization, immunohistochemical staining, SILAC-based mass spectrometry, flow cytometry, ChIP-sequencing, and western blotting.
Results: We report here evidences of altruistic cooperation in clonal breast cancer cells. Heterogeneity in expression of a microRNA, miR-125b, leads to sectoring of clonal breast cancer cell populations into minority miR-125b-high and majority miR-125b-low subpopulations. Enhanced population-wide tolerance to taxane-based chemotherapy is mediated by the miR-125b-high minority, in part through increased secretion of extracellular public goods such as insulin-like growth factor binding protein 2 (IGFBP2) and chemokine (C-C motif) ligand 28 (CCL28). Cost-benefit analysis established this helping behavior to be altruistic, as survival benefits conferred to the miR-125b-low cells, via public goods sharing, occurred at a fitness cost to the miR-125b-high cells. Notwithstanding this fitness cost, miR-125b-high altruists regenerate readily from isolated populations of miR-125b-low defectors, via Kruppel-like factor 2-mediated epigenetic mechanism of histone deacetylation. As therapeutic proof-of-principle, we demonstrated that targeting extracellular IGFBP2 and CCL28, through ligand neutralization, markedly blunted the tolerance response of cancer cells towards taxane chemotherapy.
Conclusions: Our results demonstrate how positive social engagement such as altruism may be employed by heterogeneous clonal cancer communities to drive chemotolerance, and understanding of such social behaviors could help formulate more effective treatment strategies.
Citation Format: Kee Wah Lee, Muhammad Sufyan Masroni, Karen Meiling Tan, Mo-Huang Li, Lihan Zhou, Steven Tucker, Lynette Su Mien Ngo, Chan Fong Chang, Boon Huat Bay, Soo Yong Tan, Mikael Hartman, Huiwen Chua, Tze Ping Loh, Thomas Putti, Sai Mun Leong, Evelyn Siew-Chuan Koay. Regenerable altruism drives chemotolerance in clonal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 203.