bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1125: Developmental pluripotency associated 4 oncogene interacts with Wnt/β-catenin signaling and stem cells regulatory genes to control pituitary tumor cells invasiveness
Authors: Sarkar Dipak K. , Jabbar Shaima , Gangisetty Omkaram 
Published: August 2018

Abstract
The developmental pluripotency associated 4 (DPPA4) gene has an important role in self-renewal and pluripotency in embryonic stem cells. It is re-expressed in several malignant tumors and is identified as a new pluripotency-related oncogene. We have recently identified elevated expression of DPPA4 in aggressive pituitary tumors induced by estrogen in fetal alcohol exposed rats. In this study, we determined the role of DPPA4 in pituitary tumor growth and invasiveness by employing CRISPR/Cas9 knock-down of DPPA4 and conducting cell proliferation, in vitro soft agar anchorage-independent growth assays, and in vivo tumor formation assay using cell spheres from pituitary tumors of alcohol-fed and control-fed animals. Pituitary tumor cells of fetal alcohol-fed rats and control diet-fed rats were grown in ultra-low attachment plate to develop pituispheres. In vitro and in vivo studies showed pituispheres of alcohol-fed rats had higher cell proliferation rate, increased colony formation in soft agar, and higher tumor development in mice xenografts compared to those in pituispheres of alcohol-fed rats. Pituispheres of alcohol-fed rats also had increased mRNA levels of cell growth, cell stemness and EMT regulatory genes. CRISPR-Cas9 knockdown of DPPA4 in pituispheres reduced the tumor cell ability to proliferate, migrate and form colony in soft agar and grow in mice xenografts. Pituispheres of alcohol-fed rats also showed increased protein levels of Wnt/beta-catenin signaling molecules (Wnt 3, beta-catenin, LPR5, GSK3), stemness regulatory factors (KLF4, Sox2, Nanog) and EMT factors as compared to those in control-fed pituispheres. DPPA4 knockdown reduced the levels of Wnt signaling and stem cells regulatory proteins and EMT factors in alcohol-fed rat pituispheres. These data suggest that DPPA4 is expressed in aggressive pituitary tumors and regulates the growth and invasion of these tumors via activation of Wnt/beta-catenin signaling and stem cells regulatory genes. (This work is supported by a National Institute of Health grant R01 AA11591).
Citation Format: Dipak K. Sarkar, Shaima Jabbar, Omkaram Gangisetty. Developmental pluripotency associated 4 oncogene interacts with Wnt/β-catenin signaling and stem cells regulatory genes to control pituitary tumor cells invasiveness [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 1125.
Abstract 1128: Exosomal ID3 is pro-metastatic through guiding NRF1-induced breast cancer stem cells across the blood-brain-barrier
Authors: Das Jayanta K. , Doke Mayur , Deoraj Alok , Felty Quentin , Roy Deodutta 
Published: August 2018

Abstract
Nuclear respiratory factor 1 (NRF1) and inhibitor of differentiation protein 3 (ID3) are transcription regulating proteins. Recently we have uncovered a novel oncogenic function of NRF1 in breast cancer development and progression. In this study, we tested the postulate that exposure to PCB153 contributes in ID3 over-expressing endothelial stem cells (EndSCs) chaperoning and guiding of mesenchymal NRF1 breast cancer stem cells (BCSCs) across the blood-brain barrier. BCSCs/EndSCs were subjected to functional gain/loss of ID3 and/or NRF1 to test if PCB153 [1ng/ml] exposure produces NRF/ID3 signals regulating lineage specific BCSCs organ entry. First, we tested whether NRF1 promotes transmigration of breast cancer using a 3D blood-brain barrier (BBB) model consisting of breast tumor initiating cells (BTICs) or MDAMB231 cells, brain endothelial cell layer, and astrocytes. NRF1 overexpression increased the propensity for BTICs and mesenchymal enriched MDAMB231 BCSCs to adhere to brain endothelial cells and migrate across a human BBB model. Increased adhesion of NRF1+ BCSCs with ID3+ EndSCs was detected. ID3 EndSCs promoted the transmigration of BCSCs through the BBB. We found differential effects by endocrine disruptors, namely PCB153 and PCB77. The treatment with PCB153 showed increased growth of NRF1+ BCSCs tumor spheroids. PCB153 also induced the tumor cell adhesion to microvascular endothelium and transendothelial migration of BCSCs. The exosomal ID3 released from endothelial cells helped the mesenchymal NRF1+ BCSCs to cross through blood brain barriers. Xenograft experiments showed that ID3+ brain EndSCs not only supported the growth of estrogen treated NRF1+ BCSC tumorospheroids, but guided them to the brain in zebrafish. These findings show for the first time a key role for ID3 and NRF1 by which specific circulatory EndSCs accompany a particular sub-type of BCSCs to distant metastatic sites where they most likely facilitate the seeding, survival, and proliferation of BCSCs. This knowledge is important for pre-clinical testing of NRF1/ID3 modifying agents that prevent the spread of breast cancer to the brain. This work was, in part, supported by a VA MERIT Review (VA BX001463) grant to DR.
Citation Format: Jayanta K. Das, Mayur Doke, Alok Deoraj, Quentin Felty, Deodutta Roy. Exosomal ID3 is pro-metastatic through guiding NRF1-induced breast cancer stem cells across the blood-brain-barrier [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 1128.
Abstract 1136: Decrease in maturation of stem cells along the neuroendocrine lineage contributes to stem cell overpopulation that drives human CRC development
Authors: Boman Bruce M. , Zhang Tao , Modarai Shirin , Opdenacker Lynn , Jeremy Fields 
Published: August 2018

Abstract
Stem cell (SC) overpopulation is thought to drive tumor initiation and progression during colon cancer development, but it is unclear what causes the SC overpopulation. Because most neuroendocrine (NE) cells (NECs) in normal colonic crypts reside within the SC niche at the crypt bottom, we thought that aberrant NECs might be linked to the SC overpopulation. We hypothesized that (i) in normal crypts, SC and NEC populations are anatomically and functionally related, and (ii) during tumorigenesis, changes in these relationships quantitatively correlate with increased SC numbers. We tested this hypothesis - using quantitative immunohistochemical mapping - as a first step towards understanding how interactions between SC and NEC might become altered during colon tumorigenesis. In normal human colonic crypts, most (&gt;80%) cells staining for ALDH1, a colonic SC marker, co-stained for chromogranin-A (CGA) and several other NE markers. Neither ALDH1+ nor CGA+ cells co-stained for MCM2, a marker for proliferating cells. These findings indicate that, in normal colonic crypts, many ALDH1+ cells have NE characteristics. In contrast, the proportion of ALDH1+ cells that co-stained for NE markers progressively decreased (to &lt;20%) during the stepwise progression to cancer (from normal crypts to normal-appearing FAP crypts to adenomatous crypts to colon carcinomas). However, the absolute number of ALDH+ cells progressively increased during this progression, reflecting the extent of the SC overpopulation. These findings suggest that (i) NEC maturation is integral to regulation of SC population size and (ii) a decreased rate of NEC maturation contributes to SC overpopulation during colon tumorigenesis.
Citation Format: Bruce M. Boman, Tao Zhang, Shirin Modarai, Lynn Opdenacker, Fields Jeremy. Decrease in maturation of stem cells along the neuroendocrine lineage contributes to stem cell overpopulation that drives human CRC development [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 1136.
Abstract 1140: Genes preserving stem cell state in group 3 medulloblastoma brain tumor initiating cells contribute to therapy evasion and relapse
Authors: Singh Sheila Kumari , Bakhshinyan David , Venugopal Chitra , Adile Ashley , Singh Mohini , Qazi Maleeha , Manoranjan Branavan , Kameda-Smith Michelle 
Published: August 2018

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Of current molecular subgroups, Group 3 patients face the highest incidence of metastatic spread and overall patient survival of less than 50%. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naïve tumors provide limited clinical benefit, since recurrent metastatic MBs are highly genetically divergent from their primary tumors. By adapting the existing COG (Children's Oncology Group) protocol for children with newly diagnosed high-risk MB to the treatment of immuno-deficient mice intracranially engrafted with human MB brain tumor initiating cells (BTICs), we have characterized the rare treatment-refractory cell population in Group 3 MBs. MB cell populations recovered separately from brains and spines during the course of tumor development and therapy were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy to relapse. One of the most intriguing observations from our gene expression data was consistent over-expression in the treatment-refractory cell population of proteins belonging to the Inhibitor of DNA-binding/differentiation (ID) family (transcription factors with a basic helix-loop-helix motif that act as suppressors cellular differentiation), and a longevity-associated protein known as bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4). This persistent upregulation of genes preserving undifferentiated state and cellular longevity further strengthens the hypothesis of stem-cell like cells driving tumor relapse in MB. Targeting ID1 and BPIFB4 using both knockdown (KD) and knockout (KO) strategies has resulted in decreased self-renewal and tumorigenicity of both primary and recurrent MB cells, further highlighting their potential as novel therapeutic targets in MB. Our differential genomic and gene expression profiles of the “treatment-responsive” tumors against those that fail therapy have successfully contributed to discovery and characterization of novel therapeutic targets for the most aggressive subgroup of MB.
Citation Format: Sheila Kumari Singh, David Bakhshinyan, Chitra Venugopal, Ashley Adile, Mohini Singh, Maleeha Qazi, Branavan Manoranjan, Michelle Kameda-Smith. Genes preserving stem cell state in group 3 medulloblastoma brain tumor initiating cells contribute to therapy evasion and relapse [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 1140.
Abstract 1165: A tissue-engineered bone mimetic in vitro model for monitoring metastatic PCa growth and therapy response
Authors: Paindelli Claudia , Hutmacher Dietmar , Friedl Peter , Dondossola Eleonora 
Published: August 2018

Abstract
Despite recent advances in prostate cancer (PCa) treatment, the outcome of metastatic disease remains frequently fatal and the underlying biology poorly understood. Thus, the development of clinically relevant in vitro models to monitor PCa biology in organotypic bone-like environment is critical to uncover mechanisms of therapy resistance and identify more effective treatments. To establish a bone-mimetic culture, we combined the following components: (i) bioactive osteoblasts depositing bone-like calcified extracellular matrix, (ii) complex 3D surface geometries, (iii) multicellular tumor application as spheroids/organoids, and (iv) applicability for live-cell microscopy to monitor the development of lesions over time. Calcified polycaprolactone (PCL) scaffolds were functionalized with bone-derived human mesenchymal stem cells (hMSCs) differentiated to osteoblasts, to generate a 3D niche-like calcified scaffold. PCa spheroids (PC3, C4-2B, patient-derived xenografts) were on-planted and their growth and invasion longitudinally monitored by advanced microscopy. PCa spheroids seeded on the organotypic bone model could be maintained and expanded over weeks, sufficient for monitoring therapy response to docetaxel, a first-line therapy for advanced PCa. The bone mimetic culture further revealed resistance to docetaxel mainly at the invasive edges, through a mechanism depending on the presence of osteoblasts. Thus, this 3D in vitro organotypic model will be suitable for dissecting the physical and molecular PCa cell-osteoblast interaction involved in PCa growth and therapy resistance.
Citation Format: Claudia Paindelli, Dietmar Hutmacher, Peter Friedl, Eleonora Dondossola. A tissue-engineered bone mimetic in vitro model for monitoring metastatic PCa growth and therapy response [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 1165.
Abstract 1168: The “humanized” chicken embryo chorioallantoic membrane (CAM) as a personalized platform for high-throughput (HTP) screening of cancer therapeutics
Authors: Shapira Shiran , Bogin Oren , Arber Nadir 
Published: August 2018

Abstract
Background
Every day, millions of people are taking medications that will not help them. “Personalized medicine,” is the tailoring of medical treatment to a single person, shape his response to a particular treatment and aims to better target intervention, maximize benefit and minimize harm. Several techniques are available to grow primary cell cultures from tumors; however, very few have been found to be promising. Novel, cost-effective model that similarly mimic tumor biology and provide faster information on the activity of anticancer therapies could therefore make an important contribution to the advancement of personalized medicine. Chick Chorioallantoic Membrane (CAM) assays have been used to study the process and therapeutics involving angiogenesis, tumor cell invasion and metastasis. The CAM is naturally immuno-deficient and rich in vascularity therefore an ideal system, allowing to generate 3D cancerous “organoids” in a very efficient, reproducible and cost-effective manner and translates basic research to the clinic.
Aim
1) Generate a “personalized medicine” HTP system for a quick and reliable evaluation of the effectiveness of different therapeutic options on of 3D "organoid" tumors; 2) Using the "humanized egg" as a low-cost and highly efficient mimetic of the mouse PDX model ".
Methods
Fertilized eggs were incubated until day 3 (37°C, 75-90% humidity). 2ml of albumin was pulled from the egg to separate the CAM membrane from the egg shell. Then, a small window in the egg shell has been made, and resealed with adhesive tape. On day 7, 3-5x106 tumor cells were transplanted onto the CAM membrane. The cancer cells become a visible tumor after 3 days. Different therapeutics (such as Erbitux, anti-CD24 mAb) were tested. Tumor growth was monitored by "live imaging" device.
Results
The efficiency and reproducibility of human cancer cell lines engraftment has been demonstrated. LV-GFP-Puro plasmid was constructed and used to generate GFP-encoded lentiviruses which then were used to generate a stable colorectal cancer cell line expressing GFP. The CAM tumors were evaluated histopathologicaly and IVIS fluorescent imaging.
Anti-CD24 mAb inhibited tumor growth by ~70%.The presence of the humanized mAb in the engrafted tissue was confirmed by western blot analysis and IHC.
Conclusions
The ability to evaluate ex-vivo cancer tissue response to potential therapeutics in “humanized” settings within days is a very powerful tool.
Citation Format: Shiran Shapira, Oren Bogin, Nadir Arber. The “humanized” chicken embryo chorioallantoic membrane (CAM) as a personalized platform for high-throughput (HTP) screening of cancer therapeutics [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 1168.
Abstract 1180: Quantifying melanoma drug resistance and tumor heterogeneity by live cell interferometry
Authors: Leslie Kevin A. , Huang Dian , Murray Graeme , Guest Daniel , Roy Irena J. , Piva Marco , Moriceau Gatien , Lo Roger S. , Teitell Michael A. , Reed Jason C. 
Published: August 2018

Abstract
Melanoma is the most aggressive type of skin cancer. Tumor heterogeneity and drug resistance are significant obstacles to survival benefits from mutation-targeted therapy. Over 50% of metastatic melanomas harbor V600BRAF mutations. Targeting of MUTBRAF melanoma with BRAF inhibitor monotherapy or the combination of BRAF and MEK inhibitors leads to a high rate of initial responses, but adaptive and acquired resistance frequently leads to clinical relapse. Although the presence of V600BRAF mutations guides the selection of therapy with MAPK inhibitors, methods to track preexisting and adaptive resistance and thereby predict response patterns, or to use this new information to modify therapy, are still lacking. Here, we aimed to develop a rapid, massively parallel tumor cell profiling method, based on Live Cell Interferometry (LCI), to quantify heterogeneous single tumor cell responses and emergent drug resistance. LCI is an ex vivo imaging approach that quantifies changes in total cell biomass, biomass motion, or cell stiffness over time. We report a novel high-throughput screening version of the LCI platform, HSLCI, which rapidly profiles changes in biomass in BRAF inhibitor (BRAFi)-sensitive, parental melanoma cell lines and their isogenic, BRAFi-resistant sub-lines. We show reproducible results from two different HSLCI platforms at two institutions and generate biomass kinetic signatures capable of discriminating between BRAFi-sensitive and -resistant melanoma cells within 24 hours. Our measurements require no fluorescence or dye labeling and are faster than field-standard growth inhibition assays. The accuracy and speed of HSLCI in profiling tumor cell heterogeneity and therapy resistance are promising features of potential tools to guide patient therapeutic selections.
Citation Format: Kevin A. Leslie, Dian Huang, Graeme Murray, Daniel Guest, Irena J. Roy, Marco Piva, Gatien Moriceau, Roger S. Lo, Michael A. Teitell, Jason C. Reed. Quantifying melanoma drug resistance and tumor heterogeneity by live cell interferometry [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 1180.
Abstract 1187: Comparison of intra-tumor heterogeneity and clonal evolution across lung cancer subtypes by multi-region whole genome sequencing
Authors: Zhang Tongwu , Sampson Joshua , Bertazzi Pier Alberto , Pesatori Angela , Consonni Dario , Zhu Bin , Hicks Belynda , Hua Xing , Shi Jianxin , Brown Kevin , Chanock Stephen , Landi Maria Teresa 
Published: August 2018

Abstract
Both lung squamous cell carcinoma (LUSC) and lung cancer with neuroendocrine features (LUNE; i.e., small cell carcinoma (SCLC), large cell carcinoma (LCNEC) and other subtypes) are associated with tobacco smoking and have a very poor prognosis. We sought to characterize their clonal architecture and illustrate how the evolutionary patterns differ across these lung cancer subtypes. We performed multi-region whole genome sequencing of 83 samples from 36 LUSC and 67 samples from 23 LUNE patients that had been resected before systemic therapy.
Among somatic copy number alterations, we observed genome doubling intra-tumor heterogeneity (ITH) and massive genomic instability in both subtypes. For somatic nucleotide variants (SNVs), the total mutation burden was higher in LUSC (16.7 average number of mutations/Mb) than LUNE (12.7/Mb), but for SNVs ITH was higher in LUNE. Among driver genes, TP53, CDKN2A, CR1, and NRK in LUSC and TP53, KRAS, KMT2D, and RB1 in LUNE were frequently mutated and were always clonal. Evidence of positive selection was found for TP53, PTEN, KMT2D and KEAP1 in LUSC, and for TP53 and KRAS in LUNE. As expected, the dominant mutation signatures in LUSC clones included signatures 4, 1, and 5, while APOBEC signatures (2 and 13) were predominantly found in sub-clones. In contrast, no evidence of APOBEC signatures were found in LUNE. Among structural variants, LUNE had more events (339.25 average number of events/tumor) than LUSC (206.7/tumor), with considerable ITH in both subtypes, particularly in LUNE. In LUNE, the dominant mechanism responsible for SVs included fork stalling and template switching within the microhomology-mediated break-induced repair (MMBIR). We found recurrent fusion events with hotspots including those previously identified near TTC28/CHEK2 (42% LUSC and 35% LUNE) and LRP1B (42% LUSC). Additional hotspots were found in chromosome bands 20p12.1 (22% LUSC), 1p31.1 (19% LUSC) and 12p11.22 (22% LUNE). We found &gt;10-fold higher transposon insertions (LINE1) in LUSC (71.9 average number of events/tumor) than LUNE (6.3/tumor). Our findings improve our evolutionary understanding of these lung cancer subtypes and warrant further investigations on the mechanisms involved in clonal genomic instability.
Citation Format: Tongwu Zhang, Joshua Sampson, Pier Alberto Bertazzi, Angela Pesatori, Dario Consonni, Bin Zhu, Belynda Hicks, Xing Hua, Jianxin Shi, Kevin Brown, Stephen Chanock, Maria Teresa Landi. Comparison of intra-tumor heterogeneity and clonal evolution across lung cancer subtypes by multi-region whole genome 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 1187.