bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1544: Overexpression of Rab11 and E-cadherin promotes collective cell migration and indicates a poor prognosis in colorectal carcinoma
Authors: Chung Yuan-Chiang , Wei Wan-Chen , Hung Chia-Nung , Hsu Chih-Ping , Chiu Hsiang-Ling , Chang King-Jen , Chao Wei-Ting 
Published: July 2016

Abstract
Collective cell migration, whereby the cell-cell contacts such as E-cadherin are maintained during migration, has recently emerged, and the detailed mechanisms of this process are still unclear. The present study identified the role of Rab11 which functions in recycling endosome and the relation to E-cadherin in colorectal carcinoma and clarified the mechanism of Rab11 in the collective cell migration of cancer cells. The relationships between the overexpression of Rab11 and E-cadherin and survival were evaluated from colorectal carcinoma patients. A total of 107 patients with surgically resected colorectal carcinoma were enrolled in immunohistochemical study. The relationships between the overexpression of Rab11 and E-cadherin and survival were evaluated. GFP tagged Rab11 or Rab11 shRNA was introduced into HT-29 colon cancer cells for overexpression or knockdown. The interaction between E-cadherin and Rab11 was determined by immunoprecipitation. Rac1 and matrix metalloproteinase (MMP) activities were evaluated as functional effectors of collective cell migration. In the results, the expression of Rab11 and E-cadherin was not correlated with the stages of cancer or lymph node metastasis. However, the overall survival was poor in the group of 60 patients with duo-positive Rab11 and E-cadherin expression compared to the group (47 patients) without duo-positive expression (p = 0.038). In the cell biology assay, Rab11 was demonstrated through its physical interaction with E-cadherin, and overexpression of Rab11 was found to promote collective cell migration through the increased distribution of E-cadherin, which enhanced cell-cell connections. In addition, Rac1 activation and MMP2 expression were up-regulated upon Rab11 expression. This study demonstrated that Rab11and E-cadherin expression are poor indicators of survival time in colorectal carcinoma, but that Rab11 overexpression may contribute to increased collective cell invasion in colorectal carcinoma.
Citation Format: Yuan-Chiang Chung, Wan-Chen Wei, Chia-Nung Hung, Chih-Ping Hsu, Hsiang-Ling Chiu, King-Jen Chang, Wei-Ting Chao. Overexpression of Rab11 and E-cadherin promotes collective cell migration and indicates a poor prognosis in colorectal 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 1544.
Abstract 1573: The progesterone analogue, Norgestrel, impairs tumor immunity and promotes metastatic breast cancer progression
Authors: Dalotto Moreno Tomas , Rabinovich Gabriel Adrian , Salatino Mariana 
Published: July 2016

Abstract
The immune system is responsible for recognition and elimination of cancer cells. Tumors, however, can elicit different evasive mechanisms that contribute to immune escape Thus, understanding the immunosuppressive pathways that hamper tumor immunity is critical for the identification of novel therapeutic targets. Progestin-containing hormonal supplementation (as hormone replacement therapy or contraceptive) has been associated with an increase in the risk of breast cancer incidence and recurrence. Moreover, progesterone, as a natural hormone, generally impairs cellular immune responses responsible of preventingfetal rejection during pregnancy. We postulated that progestins and in particular the widely used contraceptive Norgestrel may impair tumor immunity and foster immunosuppressive tumor microenvironments. We injected Balb/c mice with the triple-negative 4T1breast tumor,, and treated them with a Norgestrel releasing depot for 30 days. Norgestrel-treated mice displayed a higher frequency of suppressive regulatory T cells (Tregs) in draining lymph nodes and tumors which displayed a CD4+CD25+Foxp3+CD44+ phenotype. Accordingly, norgestrel-treated mice showed greater number of exhausted PD1+ Tim-3+ CD8 T cells in the tumor microenvironment. Furthermore, in vitro exposure to Norgestrel also promoted differentiation and expansion of Tregs which activated the mTOR pathway assessed by phosphorylation of S6 ribonucleoprotein. These effects could not be prevented by the progesterone nuclear receptor antagonist, Zk 230211, suggesting that Norgestrel acts preferentially through membrane progesterone receptors. Although no significant difference regarding tumor growth could be observed, Norgestrel-treated mice showed greater number of lung metastasis. Mechanistically, Norgestrel-driven Treg cells showed increased expression of RANKL, a protein involved in breast cancer development and progression. Our results identify a novel progestin-mediated tumor-promoting mechanism and indicate caution onthe use of Norgestrel-supplementation therapies. Our findings suggest that Norgestrel may impair tumor immunity, thereby promoting metastatic dissemination of breast cancer cells.
Citation Format: Tomas Dalotto Moreno, Gabriel Adrian Rabinovich, Mariana Salatino. The progesterone analogue, Norgestrel, impairs tumor immunity and promotes metastatic breast cancer progression. [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 1573.
Abstract 1585: Molecular subtypes of breast cancers and normal mammary epithelial cells show hierarchical heterogeneity and complexity at single-cell resolution
Authors: Azizi Ebrahim , Colacino Justin , Fouladdel Shamileh , Wicha Max S. 
Published: July 2016

Abstract
The analysis of average gene expression in cell populations may obscure the heterogeneity of rare cells such as cancer stem cells (CSCs). The use of CSC markers to enrich for these cell populations has proven valuable in their molecular characterization. However, conventional gene expression analysis of these CSC enriched populations is still not conducive to elucidating their heterogeneity. We exploited single-cell resolution methods using C1 and BioMark HD platform and TaqMan assays in the analysis of CSCs and non-CSCs/differentiated tumor cells. The expression of 96 target genes was studied at single cell level in a multiplex RT-qPCR setting. Breast cancer cell lines including MCF7 (luminal), BT474 (HER2+), SUM149 (Basal), and MDA-MB-231 (Basal-Claudin low) that represent major different subtypes of breast cancers and normal mammary epithelial cells (NM) were studied at single cell resolution. Despite similarities, expression profiles of 96 target genes were distinctly different between subtypes of breast cancers and also with that of NM cells. Interestingly, results of single cell studies revealed significant levels of hierarchical heterogeneities within and between each analyzed population of cells. The observed heterogeneous signatures were due to both different expression levels as well as presence/absence of certain genes. We could identify CSCs with EMT (i.e. CD44+/CD24-/ALDH-/CDH2+/Vimentin+), MET (i.e. ALDH+/CD44-/CD24+/CDH1+/Vimentin-), and dual EMT-MET (CD44+/CD24-/ALDH+/CDH1+ or CDH2+/Vimentin+) characteristics. This methodology enabled us to also identify a range of several different non-CSCs/differentiated single cells with heterogeneous expression patterns for CD44, CD24, ALDH, ESR, PGR, HER2, Vimentin, CDH1, CDH2, EpCAM, and Cytokeratins that were similar to luminal, HER2 overexpressed, basal, and basal-Claudin low breast cancer cells. Additionally, NM single cells also showed significant heterogeneity that was similar to the wide spectrum patterns of some single breast cancer cells described above. This study highlights the use of single cell technologies to redefine tumor cell characterization, revealing heterogeneity of single tumor cells with respect to stem cell properties, metastatic and drug resistance characteristics. This will further improve the identification of new markers/pathways that can be used to develop new target therapies for better therapeutic responses in cancer patients.
Citation Format: Ebrahim Azizi, Justin Colacino, Shamileh Fouladdel, Max S. Wicha. Molecular subtypes of breast cancers and normal mammary epithelial cells show hierarchical heterogeneity and complexity at single-cell resolution. [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 1585.
Abstract 162: Genomic analysis of uterine aspirates improves diagnosis and captures the intratumor heterogeneity in endometrial cancer
Authors: Mota Alba , Colas Eva , Garcia-Sanz Pablo , Campoy Irene , Rojo-Sebastian Alejandro , Chiva Luis , Alonso Sonsoles , Gatius Sonia , Gil-Moreno Antonio , González-Tallada Xavier , Díaz-Feijoo Berta , Ziober Malinwska Patrycja , Bobiński Marcin , Reventos Jaume , Matias-Guiu Xavier , Moreno-Bueno Gema 
Published: July 2016

Abstract
Background: Endometrial cancer (EC) is the most common cancer in female genital tract in developed countries. Although the majority of ECs are diagnosed in early stages, with a 5-year overall survival of around 80%, an early detection of these tumors is crucial to increase survival of patients given that advanced tumors are associated with poorer outcome. Furthermore, the correct assessment of pre-clinical diagnosis is also decisive to guide the surgical management and treatment of the patient.
Results: Genetic analysis of uterine aspirates identifies the mutational profile of endometrial cancers and represents the intra-tumor heterogeneity found in the analysis of multiple tumor regions from hysterectomy.
Conclusions: The current study reveals the potential of the genetic analysis of uterine aspirates as a pre-operative tool to diagnosis, even in biopsies with insufficient material, with a sensitivity of 93.7% and a specificity of 91.7%. Additionally, genetic analysis of uterine aspirates allows to capture the intra-tumor heterogeneity identified in ECs.
Citation Format: Alba Mota, Eva Colas, Pablo Garcia-Sanz, Irene Campoy, Alejandro Rojo-Sebastian, Luis Chiva, Sonsoles Alonso, Sonia Gatius, Antonio Gil-Moreno, Xavier González-Tallada, Berta Díaz-Feijoo, Patrycja Ziober Malinwska, Marcin Bobiński, Jaume Reventos, Xavier Matias-Guiu, Gema Moreno-Bueno. Genomic analysis of uterine aspirates improves diagnosis and captures the intratumor heterogeneity in endometrial cancer. [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 162.
Abstract 1620: Elucidating metastatic signaling networks in TNBC by investigating RKIP-regulated kinome
Authors: Yesilkanal Ali E. , Frankenberger Casey , Rabe Daniel C. , Johnson Gary L. , Rosner Marsha 
Published: July 2016

Abstract
Metastatic progression of tumors is the major cause of death in patients with triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer. However, since metastasis is a multi-step process, unraveling its complexity is a major challenge. One effective way of tackling this question is to study natural blockers of the metastatic process, metastasis suppressors, and identify the mechanisms by which they regulate metastasis. Raf kinase inhibitory protein (RKIP), a protein that regulates kinase activity, is a suppressor of TNBC metastasis. Although RKIP inhibits the activity of key kinases such as Raf-1, GRK2, NIK/IKK in cultured cells, the kinase targets of RKIP in tumors are not known. To address this question, we used a mass spectrometry approach involving inhibitor-conjugated beads to identify kinases that are down-regulated by RKIP in human TNBC xenograft tumors. Our results identified novel targets of RKIP whose kinase activity is either down-regulated or up-regulated by RKIP. We used bioinformatics analysis to build RKIP-regulated signaling networks based upon RKIP-induced changes in kinase activity and related gene expression. Elucidating RKIP function at a systems level reveals the interplay between key metastatic signaling cascades, particularly in relation to cell migration and invasion, and can potentially identify novel anti-metastatic target combinations in TNBCs.
Citation Format: Ali E. Yesilkanal, Casey Frankenberger, Daniel C. Rabe, Gary L. Johnson, Marsha Rosner. Elucidating metastatic signaling networks in TNBC by investigating RKIP-regulated kinome. [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 1620.
Abstract 1650: Whole-genome RNAi screen identified BCAS1 as a novel modifier of non-small cell lung carcinoma radioresistance
Authors: O’Leary Colin , Deraska Peter , D’Andrea Alan , Kozono David 
Published: July 2016

Abstract
Introduction: Despite optimal chemotherapy, radiotherapy and/or surgery, non-small cell lung carcinoma (NSCLC) remains the leading cause of cancer-related death in the United States. Therefore, there is a need for agents, such as radiosensitizers, that can improve the efficacy of current therapies. Using a whole-genome shRNA screen, we sought to identify and characterize novel gene products that may be involved in NSCLC radioresistance. We hypothesize that these proteins may represent novel targets for NSCLC radiosensitization.
Materials and Methods: A whole-genome pooled retroviral shRNA screen was performed using the Hannon-Elledge library of 74,705 distinct shRNAs directed against over 18,000 genes, to identify gene knockdowns that showed cytotoxicity only in cells treated with fractionated radiation given daily Monday-Friday. To confirm targets identified in the whole-genome screen, we treated A549 and NCI-H460 NSCLC cells with siRNAs targeted against the genes of interest and assessed cell viability following irradiation using the CellTiter-Glo assay and clonogenic survival assays.
Results: We identified six novel genes (BCAS1, c7orf24, CDC45L, KIAA0101, TCN1 and TNC) whose knockdown sensitized NSCLC cells to radiation. Of the six genes, siRNA knockdown of BCAS1 showed the most consistent increases in sensitivity to ionizing radiation. Analysis of cell viability following radiation revealed that BCAS1 knockdown resulted in a 50% additional decrease in cell viability in A549 and NCI-H460 cells following 8 and 4 Gy of ionizing radiation, respectively. We confirmed these results by clonogenic survival assays. To assess for tumor-specific expression in NSCLC, we compared expression data between matched normal tissue and NSCLC biopsy samples and found that BCAS1 is substantially more highly expressed in tumor tissues. Examination of affinity capture-mass spectroscopy data suggested that BCAS1 interacts with RUVBL2, a RuvB-like AAA ATPase, which has known functions in DNA damage and repair.
Conclusions: BCAS1 emerged from a whole-genome RNAi screen as a potential target for improving the efficacy of radiotherapy in NSCLC. We demonstrated that BCAS1 is overexpressed in tumor tissues compared to normal lung, and that its knockdown consistently sensitizes NSCLC cell lines to radiation, validating the screen hit. Ongoing work suggests that BCAS1 may modulate DNA damage repair. Further studies to understand the mechanism by which BCAS1 is involved in radioresistance are necessary.
Citation Format: Colin O’Leary, Peter Deraska, Alan D’Andrea, David Kozono. Whole-genome RNAi screen identified BCAS1 as a novel modifier of non-small cell lung carcinoma radioresistance. [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 1650.
Abstract 1658: M3814, a novel investigational DNA-PK inhibitor: enhancing the effect of fractionated radiotherapy leading to complete regression of tumors in mice
Authors: Zenke Frank T. , Zimmermann Astrid , Sirrenberg Christian , Dahmen Heike , Vassilev Lubo , Pehl Ulrich , Fuchss Thomas , Blaukat Andree 
Published: July 2016

Abstract
Physical or chemical agents that damage DNA such as ionizing radiation are among the most widely used classes of cancer therapeutics today. Double strand breaks (DSB) generated in DNA by radiation induce multitude of cellular responses, including DNA repair, cell cycle arrest or cell death if the damage is left unrepaired. A complex set of molecular events are responsible for DNA repair via two major mechanisms - homologous recombination (HR) or non-homologous end joining (NHEJ). DNA-PKcs with its regulatory protein subunits, Ku70 and Ku80, is an integral component of NHEJ and considered an attractive intervention point to inhibit DNA repair.
We have developed an orally bioavailable, highly potent, and selective inhibitor of DNA-PK, M3814, for cancer therapy in combination with DNA damaging modalities such as radiation, and radio-chemotherapy. Here, we present the preclinical characterization of M3814 using biochemical, cellular and human tumor xenograft models. M3814 sensitized multiple tumor cell lines to radiation therapy in vitro and strongly enhanced the antitumor activity of ionizing radiation in vivo with complete tumor regression applying a clinically relevant fractionated radiation regimen. These effects are due to inhibition of DNA-PK protein kinase activity as demonstrated by the levels of DNA-PK autophosphorylation in human tumor cell lines, and xenograft tumors M3814 is currently investigated in PhI clinical trials.
Citation Format: Frank T. Zenke, Astrid Zimmermann, Christian Sirrenberg, Heike Dahmen, Lubo Vassilev, Ulrich Pehl, Thomas Fuchss, Andree Blaukat. M3814, a novel investigational DNA-PK inhibitor: enhancing the effect of fractionated radiotherapy leading to complete regression of tumors in mice. [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 1658.
Abstract 1723: Novel drug candidates CEP1430 and CEP1507 against cancer stem cells and circulating tumor cells in advanced stage pancreatic cancer
Authors: Sharma Cristian , Narayanan Padmini , Sharma Michael , Rodriguez Robert , Navel Miriam , Stanton Donna , Amezcua Natalee , Sharma Shaleekha , Amiri Mandana , Jani Jitesh , Sharma Sherven , Sharma Jay P. 
Published: July 2016

Abstract
Despite improvements in treatment modalities, pancreatic cancer remains the fourth leading cause of cancer mortality in the US. The 5-year survival rate is less than 6% because of the extent of metastases at the time of diagnosis. The treatment of pancreatic cancer remains challenging however there is much optimism with targeted strategies and trial designs. The interrogation of pathway centric targets that regulate the regenerative and metastatic activities in the tumor, adequate molecular-hypothesis driven trial designs with robust prognostic and predictive markers of response are necessary for the development of effective therapeutic strategies for long term anti-tumor benefit.
Here, we examined the efficacy of CEP1430 and CEP1507 to target cancer stem cells (CSC) and circulating tumor cells (CTC) in human pancreatic cancer. The pancreatic CSCs expressed the following markers(CD133,CD44,CXCR4,SSEA3/4,Oct4,ALDH,Telomerase,& Nestin). In vitro CEP1430 inhibited the growth of CSCs whereas CEP1507 inhibited CTCs that expressed the following markers [CK19, CEA, CA19-9,CK8 /18,h-TERT,C-MET,CK20,EpCAM, Vimentin, E- Cadherin, MUC1, CEA CAM5,CD45 neg]. Gemcitabine on the other hand suppressed the viability of non-CSCs (differentiated tumor Cells) by 70%. In accord, in vivo studies showed that CEP1507 when combined with gemcitabine eliminated the engraftment of human pancreatic cancer CTCs by 85% (n = 20,p&lt;0.001). In contrast, CEP1430 in combination with gemcitabine selectively inhibited CSCs by 80% (n = 20,p&lt;0.001) and was more effective than the individual agents. This data demonstrates that CEP1430 and CEP1507 that target CSCs and CTCs respectively may change the treatment paradigm and enhance the efficacy of gemcitabine in advanced pancreatic cancer. Further studies will evaluate the full potential of this approach to target the CSCs - and metastasis-initiating cells (CTCs) as combination therapy against locally advanced and metastatic pancreatic cancer.
Citation Format: Cristian Sharma, Padmini Narayanan, Michael Sharma, Robert Rodriguez, Miriam Navel, Donna Stanton, Natalee Amezcua, Shaleekha Sharma, Mandana Amiri, Jitesh Jani, Sherven Sharma, Jay P. Sharma. Novel drug candidates CEP1430 and CEP1507 against cancer stem cells and circulating tumor cells in advanced stage pancreatic cancer. [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 1723.
Abstract 1724: Pancreatic cancer stem cell metastasis and mitochondrial respiration is dependent on the the ISG15-mediated ubiquitin-like modification process known as ISGylation
Authors: Sainz Bruno , Alcala Sanchez Sonia , Vallespinos Mireia 
Published: July 2016

Abstract
We recently discovered that CSCs of distinct solid tumors (e.g. pancreatic, colon, and liver) contain intracellular vesicles coated in the ATP-dependent transporter ABCG2, which act as a sink for the accumulation of riboflavin (vitamin B2). Using autofluorescence and other CSC markers, such as CD133, we have begun to dissect CSCs at the genetic and protein level. Using RNAseq to transcriptionally distinguish CSCs from non-CSCs, we observed that pancreatic CSCs of different primary PDAC tumors exhibit a transcriptional gene activation signature belonging to the Type I interferon (IFN) signaling pathway. In particular, CSCs up-regulate the interferon-stimulated gene 15, a 165 amino acid (17kDa) protein that is induced by Type I IFN treatment and functions to ISGylate proteins, a ubiquitin-like modification process whereby ISG15 can be covalently linked to cytoplasmic and nuclear proteins. We have discovered that CSCs not only upregulate the expression of monomeric ISG15, but numerous proteins within CSCs are ISGylated, the level of ISGylation correlates with their metastatic capacity and knockdown of ISG15 ablates pancreatic CSCs functions, such as self-renewal, migration and invasion in vivo and mitochondrial respiration. Thus, our data indicate that the ISGylayion pathway is active in CSCs and plays an important role in the “stem-like” properties of these cells. We have also elucidated the mechanism underlying the differential regulation of ISG15 in CSCs versus non-CSCs. Specifically, using over expression lentiviral vector systems and pharmacological inhibitors (i.e. BRD4 inhibitor JQ-1), we show that MYC controls the expression of miR22, a micro-RNA that targets, among others transcripts, a number of Interferon Regulatory Factors (IRFs) that are essential for intracellular IFN signaling, including ISG15 expression. CSCs express low levels of MYC and miR-22, relieving the inhibitory block on IRFs and subsequent ISG15 signaling. As expected, over expression of MYC increases miR-22 levels and blocks IRF-mediated ISG15 expression. While the intricacies of these complex and distinct pathways still need to be unraveled at the CSC level, our data suggest that MYC may be a key universal player in these pathways, and targeting ISG15 in CSCs may represent a unique approach to altering the biology of CSCs.
Citation Format: Bruno Sainz, Sonia Alcala Sanchez, Mireia Vallespinos. Pancreatic cancer stem cell metastasis and mitochondrial respiration is dependent on the the ISG15-mediated ubiquitin-like modification process known as ISGylation. [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 1724.