bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA22: Modeling recurrent metastatic melanoma in the mouse
Authors: Merlino Glenn T. , Day Chi-Ping , Mishra Pravin , Guo Theresa , Zaida Raza , Davis Sean , Meltzer Paul , Noonan Frances , Fabo Edward De , Ohler-Weaver Zoe , Dyke Terry Van 
Published: May 2015

Abstract
Recurrence and metastasis following resection and therapy are the most critical problems in progressive cancers and the main causes of cancer-related death. This problem is magnified in cutaneous malignant melanoma, which is highly metastatic in advanced stages and generally resistant to chemotherapy. Although new drugs such as Vemurafenib successfully target BRAFV600E and typically demonstrate a significant clinical response, progressive melanomas recur resulting in near uniform patient mortality. Dissection of processes underpinning recurrent and metastatic melanoma is certain to identify new therapeutic targets for more efficacious treatment. However, current preclinical studies do not model progressive recurrent disease, but rather rely on the growth response of human melanoma cell lines subcutaneously xenografted into immunocompromised mice as the efficacy endpoint; these studies have shown poor predictive power for clinical activity. Therefore we have designed new and improved genetically engineered mouse (GEM) models of progressive melanoma. These are being used to test targeted and immune-based therapies singly and in combination, and to study mechanisms associated with the resistance of recurrent/metastatic melanoma to promising clinical drugs.
To identify novel targets for advanced disease we hypothesized that metastatic melanomas can exploit hard-wired pathways employed by migratory embryonic melanocytes, but not mature melanocytes, to achieve a more aggressive malignant phenotype. We had previously generated a GEM model (iDCT-GFP) that expresses Green Fluorescent Protein specifically in all melanocytic cells in a doxycycline-regulatable manner. The iDCT-GFP mouse was used in concert with FACS to isolate melanoblasts from key developmental stages, sequence their transcriptomes using RNA-Seq, and identify genes/pathways common to metastatic melanoma cells. We have thus generated a full library of the genes expressed during embryonic development of the melanocyte. A detailed comparative analysis of mouse melanoblast gene expression profiles with human metastatic melanoma cells was then performed, identifying what we believe to be a small number of critical genes common to both. We anticipate that this approach will enhance our understanding of this fatal disease at both mechanistic and prognostic levels, and facilitate the identification of novel therapeutic targets for the treatment of metastatic melanoma.
Citation Format: Glenn T. Merlino, Chi-Ping Day, Pravin Mishra, Theresa Guo, Raza Zaida, Sean Davis, Paul Meltzer, Frances Noonan, Edward De Fabo, Zoe Ohler-Weaver, Terry Van Dyke. Modeling recurrent metastatic melanoma in the mouse. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA22.
Abstract IA9: Studying therapy response and resistance in mouse models of human breast cancer
Authors: Jonkers Jos 
Published: May 2015

Abstract
Mouse models of human cancer not only permit us to gain a detailed insight into the specific genetic changes that drive tumor development and metastasis but also provide powerful tools to study the mechanisms underlying drug response and acquired resistance. Once these processes are understood in sufficient detail it may be possible to design combination therapies that not only cause complete remissions but also eliminate remnant cells that might elicit recurrent disease.
We have developed genetically engineered mouse models (GEMMs) of E-cadherin mutated lobular breast cancer. These mice develop mammary tumors that closely resemble the lobular morphology and the metastatic spectrum of the cognate tumors in humans. We have used Sleeping Beauty (SB) based insertional mutagenesis (IM) screens in conditional E-cadherin mutant mice to identify cancer genes that collaborate with E-cadherin loss in mammary tumorigenesis. Approximately 50% of all tumors carry activating SB insertions in Fgfr2. These tumors are highly sensitive to FGFR inhibitors but eventually become resistant. We are currently analyzing SB insertions in FGFRi-resistant tumors to identify genes that are causal to the resistance phenotype.
We have also established GEMMs and patient-derived xenograft (PDX) models for BRCA1-deficient triple-negative breast cancer. These mice develop mammary tumors that are characterized by genomic instability and hypersensitivity to DNA-damaging agents, including platinum drugs and PARP inhibitors. Nevertheless, none of these drugs are curative: tumors grow back after drug treatment and eventually become resistant. We have used DNA methylation analysis and focused or whole-exome sequencing to identify resistance mechanisms in matched pairs of therapy-sensitive and –resistant BRCA1-deficient mammary tumors from our GEMMs and PDX models. We found that resistance of BRCA1-deficient GEMM tumors to the PARP inhibitor olaparib can be induced by several mechanisms, including activation of P-glycoprotein drug efflux transporters, type of BRCA1 founder mutation and 53BP1 loss. Therapy resistance of BRCA1-mutated PDX tumors is caused by additional intragenic deletions that lead to restoration of the open reading frame. Therapy resistance of BRCA1-methylated PDX tumors is driven by loss of BRCA1 promoter methylation or by a novel resistance mechanism involving de novo BRCA1 gene fusions created by intrachromosomal genomic rearrangements.
Citation Format: Jos Jonkers. Studying therapy response and resistance in mouse models of human breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA9.
Abstract PR08: Man's best friend for cancer driver-passenger discrimination
Authors: Zhao Shaying 
Published: May 2015

Abstract
Spontaneously occurring canine cancer represents one of the best cancer models. Herein we report a novel dog human comparison strategy that utilizes inter-species genomic arrangements occurring during the past &gt;75 million years to tackle a central aim of cancer research, namely cancer driver passenger discrimination. After showing that spontaneous canine colorectal cancers share similar molecular pathogenesis mechanisms as their human counterparts (Tang et al., 2010; Youmans et al., 2012), we compared copy number abnormalities between the two species (Tang et al., 2013). This led to the identification of 73 driver candidate genes (DCGs) and 38 passenger candidate genes (PCGs). Importantly, DCGs differ from PCGs in every analysis conducted to assess their cancer relevance. Moreover, while PCGs' functions appear random, DCGs' are significantly associated with cell proliferation and epithelial cell polarities. We are conducting 3D culture to validate these functions, leading to the discovery of several new tumor suppressors and cell polarity genes.
Besides colorectal cancer, we have also successfully applied this dog-human comparison strategy on triple negative breast cancers, of which copy number abnormalities are extensive. In summary, we have developed a novel approach to efficiently analyze the massive cancer genomic data generated by TCGA and others for cancer driver discovery.
Tang, J., Le, S., Sun, L., Yan, X., Zhang, M., Macleod, J., Leroy, B., Northrup, N., Ellis, A., Yeatman, T. J., et al. (2010). Copy number abnormalities in sporadic canine colorectal cancers. Genome research 20, 341-350.
Tang, J., Li, Y., Lyon, K., Camps, J., Dalton, S., Ried, T., and Zhao, S. (2013). Cancer driver-passenger distinction via sporadic human and dog cancer comparison: a proof-of-principle study with colorectal cancer. Oncogene.
Youmans, L., Taylor, C., Shin, E., Harrell, A., Ellis, A. E., Seguin, B., Ji, X., and Zhao, S. (2012). Frequent alteration of the tumor suppressor gene APC in sporadic canine colorectal tumors. PloS one 7, e50813.
This abstract is also presented as Poster B51.
Citation Format: Shaying Zhao. Man's best friend for cancer driver-passenger discrimination. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr PR08.
Abstract A02: Pak1 kinase inhibition sensitizes 11q13 amplified breast cancer cells to platinum based chemotherapy via downregulation of Fanconi anemia genes
Authors: Arias-Romero Luis E. , Villamar-Cruz Olga , Chernoff Jonathan 
Published: May 2015

Abstract
Activating mutations in Ras GTPases frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the Ras/Raf/MEK/ERK pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. Several studies have shown that signaling through the Ras/Raf/MEK/ERK pathway can be influenced by Pak1 kinase, a downstream effector of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase. In addition, it has been shown that Pak1 is amplified in several human cancer types, including 25-30% of breast tumor samples and cancer cell lines, and that its kinase activity is necessary for Ras mediated transformation.
In this work, we performed a comparative gene profiling study in order to identify differentially regulated genes between wild-type and Pak1 deficient mouse and human breast cancer cells. Several genes involved in the Fanconi Anemia/BRCA pathway - a DNA-damage response signaling pathway that is essential for repairing DNA interstrand cross-links induced by DNA-damaging agents like cisplatin and doxorubicin - were down-regulated in Pak1 deficient cells. The reduced expression of FANCD2 and FANCI was confirmed by qPCR and western blot in Pak1-depleted human breast cancer cells with or without 11q13 amplification. Interestingly, the depletion or chemical inhibition of Pak1 in 11q13 amplified breast cancer cells treated with cisplatin, compromised the ability of these cells to repair DNA by homologous recombination, induced cell cycle arrest, promoted apoptosis and resulted in reduced colony formation. In contrast, the inhibition or depletion of Pak1 had little effect on these cellular processes in Pak1-non-amplified breast cancer cells.
Because reduced Pak1 activity impaired Fanconi Anemia/BRCA signaling and consequently, repair by homologous recombination, inhibition of Pak1 represents a plausible strategy for expanding the utility of DNA-damaging treatments to Fanconi Anemia/BRCA-proficient 11q13 amplified breast cancers.
Citation Format: Luis E. Arias-Romero, Olga Villamar-Cruz, Jonathan Chernoff. Pak1 kinase inhibition sensitizes 11q13 amplified breast cancer cells to platinum based chemotherapy via downregulation of Fanconi anemia genes. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A02. doi: 10.1158/1557-3125.RASONC14-A02
Abstract A12: Erk2 phosphorylates Drp1 to promote mitochondrial fission and Ras-driven tumor growth.
Authors: Kashatus David 
Published: May 2015

Abstract
Oncogenic Ras mutations lead to activation of several downstream effector pathways that promote a tumorigenic phenotype. As targeting Ras directly has proven difficult, a great deal of effort has been expended trying to understand these downstream effector pathways and the biological processes that underlie their pro-tumorigenic activity. Several of the processes affected by aberrant Ras signaling, including apoptosis, metabolic reprogramming and proliferation, are tightly linked to mitochondrial function. Furthermore, each of these processes can be affected by changes in mitochondrial dynamics. As such, we hypothesized that altering the balance of mitochondrial fusion and fission might be a mechanism through which Ras promotes the phenotypes associated with tumor progression and thus might represent an attractive new target for the treatment of Ras-driven cancers. Here, we show that expression of oncogenic Ras leads to an increase in mitochondrial fragmentation and that blocking this phenotype, through knockdown of the mitochondrial fission-mediating GTPase Drp1, inhibits Ras-driven tumor growth. Mechanistically, this Ras-driven mitochondrial fission occurs through activation of the MAP Kinase pathway, which promotes fission through Erk2-mediated phosphorylation of Drp1 on Serine 616. Furthermore, Drp1 phospho-S616 levels are increased in pancreatic cancer tissues and cell lines and inhibition of this phosphorylation is sufficient to block Ras-mediated mitochondrial fission and Ras-induced tumor growth. Collectively, these data suggest that the mitochondrial fission machinery may be a novel target for treating Ras-driven malignancies.
Citation Format: David Kashatus. Erk2 phosphorylates Drp1 to promote mitochondrial fission and Ras-driven tumor growth.. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A12. doi: 10.1158/1557-3125.RASONC14-A12
Abstract A13: Constitutively-active HRAS suppresses stochastic Erk activity pulses in Madin-Darby canine kidney cells
Authors: Kawabata Noriyuki , Matsuda Michiyuki 
Published: May 2015

Abstract
The EGFR-Ras-ERK pathway is a major growth signaling cascade in many human cancers. Consequently, constitutive activation of Ras, which is found in 30% of human cancers, is believed to lead to constitutive ERK activation and, thereby, uncontrolled cell growth. Recently, we have reported that the cell growth is controlled not only by the basal ERK activity but also by the frequency of stochastic ERK activity pulses. In the present study, we have evaluated the effect of Ras on the temporal dynamics of Erk activity by using fluorescent resonance energy transfer (FRET) biosensors. We found that, in Madin-Darby Canine kidney (MDCK) cells expressing constitutively active HRAS (HRASV12), ERK activity stimulated by epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA), was markedly attenuated in comparison with the parent MDCK cells. Furthermore, the stochastic ERK activity pulses observed in the parent MDCK cells were almost completely abolished in the HRASV12-expressing MDCK cells. These observations have revealed that the temporal regulation of ERK activity is significantly different between normal and HRASV12-expressing cells.
Citation Format: Noriyuki Kawabata, Michiyuki Matsuda. Constitutively-active HRAS suppresses stochastic Erk activity pulses in Madin-Darby canine kidney cells. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A13. doi: 10.1158/1557-3125.RASONC14-A13
Abstract A16: Overexpression and ubiquitination of kinase suppressor of Ras 1 (KSR1) in human colon tumor cells
Authors: McCall Jamie L. , Kono Ken , Fisher Kurt W. , Furukawa Manabu , Lewis Robert E. 
Published: May 2015

Abstract
Kinase Suppressor of Ras 1 (KSR1) is required for oncogenic Ras-induced transformation in mouse embryonic fibroblasts (MEFs) and human colon tumor cells, but is dispensable for normal cellular development. It is also overexpressed in a variety of human tumors, including human colon tumor cells. Seven human colon tumor cell lines with mutated and activated Ras (GEO, CBS, FET, SW480, HCT15, DLD1, and HCT116), one with wild type Ras (CaCo2), and non-transformed human colonic epithelial cells (HCECs) were assessed for KSR1 by western blot. Compared to HCECs, all eight tumor cell lines showed a marked decrease in electrophoretic motility. Seven of eight cell lines had a clear increase in KSR1 expression regardless of Ras mutation status. The purpose of the study is to examine the mechanism by which KSR1 is up-regulated in cancer cells.
Previous studies indicate that KSR proteins interact with multiple E3 ubiquitin ligase complexes including members homologous to the E6AP carboxyl terminus (HECT) domain family and the really interesting new gene (RING) family, including Cullin (Cul) 1, Cul4A, Cul4B, Cul7, damage-specific DNA binding protein 1 (DDB1), and DDB1-Cullin associating factor 1 (DCAF1), and ubiquitin protein ligase E3 component N-recognin 5 (UBR5/EDD1). Using tagged expression vectors and immunoprecipitation techniques, we investigated whether KSR1 is a substrate or a component of E3 ligase complexes. Both FLAG-tagged and endogenous KSR1 are ubiquitinated in the human colon tumor cell line, HCT-116. In HEK 293T cells, truncated KSR1 constructs were used to determine that KSR1 ubiquitination is dependent on the presence of the putative kinase domain in the C-terminal region. Furthermore, the kinase domain is sufficient for KSR1 ubiquitination by Cul4A/4B RING ligases (CRLs); however, silencing of Cul4A/4B by RNAi does not inhibit KSR1 ubiquitination. These data indicate that multiple Cullin family members may function to ubiquitinate KSR1. Additionally, KSR1 does not exclusively bind to Cullins, but also interacts with other components of the multi-subunit CRLs, including DDB1 and DCAF1. Therefore, KSR1 may not only be a direct substrate but also a member of the large complex helping to modulate activity of the CRL. Overall, these data suggest that Cul4A/4B-dependent ubiquitination of the KSR1 putative kinase may function to modulate KSR1-dependent signaling.
Citation Format: Jamie L. McCall, Ken Kono, Kurt W. Fisher, Manabu Furukawa, Robert E. Lewis. Overexpression and ubiquitination of kinase suppressor of Ras 1 (KSR1) in human colon tumor cells. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A16. doi: 10.1158/1557-3125.RASONC14-A16
Abstract A19: A Ras-Arf-Egr-C/EBPβ axis underlying oncogene-induced senescence and cancer
Authors: Salotti Jacqueline , Sakchaisri Krisada , Johnson Peter F. 
Published: May 2015

Abstract
In normal cells, persistent oncogenic Ras activation triggers senescence, an intrinsic tumor suppression mechanism that protects cells from malignant transformation. Oncogene-induced senescence (OIS) is dependent on tumor suppressors such as p19/p14Arf, and loss of those genes facilitates transformation by oncogenic Ras. We previously reported that C/EBPβ, a transcription factor that has both pro- and anti-oncogenic functions, contributes to OIS in primary fibroblasts. Notably, C/EBPβ is down-regulated in H- or K-RasV12-transformed NIH 3T3 cells in a manner that requires loss of p19Arf. The potential role of C/EBPβ down-regulation in RasV12-induced transformation prompted us to investigate the mechanisms of Cebpb gene transcription. Here we show that Cebpb is an early growth factor-induced gene whose induction is suppressed by H-RasV12 in NIH 3T3 cells and p19Arf-/- MEFs. The early growth response (Egr) transcription factors are also down-regulated by H-RasV12 in these cells. Over-expression of any of Egr proteins (Egr1-4) restored C/EBPβ levels in 3T3Ras cells. Interestingly, Egrs induce growth arrest and senescence in 3T3Ras cells in a manner that is only partially dependent on reactivation of C/EBPβ. Egr1-4 proteins stimulated transcription from a promoter-reporter construct containing ∼3 kb of the Cebpb 5' flanking region. The proximal Cebpb promoter contains several putative Egr binding motifs, and mutating three of these sites disrupted Egr-mediated transactivation of the Cebpb promoter. Chromatin immunoprecipitation assays showed that ectopically expressed and endogenous Egrs bind to the Cebpb proximal promoter. Furthermore, microarray data from Oncomine show a strong correlation between CEBPB and EGR expression in human tumor samples, regardless of whether C/EBPβ levels increase or decrease in tumors compared to normal tissue. Since CEBPB and EGRs are down-regulated in lung adenocarcinomas and their elevated expression is associated with a better prognosis in lung cancer patients (Prognoscan), we over-expressed Egrs in A549 lung adenocarcinoma cells, which carry a KRAS mutation. Ectopic Egr2-4 induced CEBPB mRNA expression and dramatically suppressed cell proliferation. Collectively, our data indicate that decreased Egr levels account for oncogenic Ras-induced down-regulation of C/EBPβ in certain transformed cells, and restoration of Egrs induces growth arrest and C/EBPβ expression. Our findings identify the Egr-C/EBPβ axis as an important pathway in determining the cellular response (transformation or senescence) to oncogenic Ras-Arf signaling.
Citation Format: Jacqueline Salotti, Krisada Sakchaisri, Peter F. Johnson. A Ras-Arf-Egr-C/EBPβ axis underlying oncogene-induced senescence and cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A19. doi: 10.1158/1557-3125.RASONC14-A19
Abstract A43: RUNX3 and pRB form a complex and regulate restriction-point commitment
Authors: Chi Xin-Zi , Lee You-Soub , Lee Jung-Won , Lee You-Mie , Ito Yoshiaki , Bae Suk-Chul 
Published: May 2015

Abstract
Throughout the cell cycle, a cell monitors cumulative exposure to specific signals over time and makes a critical decision to pass through the restriction (R) point. Although the R-point decision is fundamental to normal differentiation and G1-S transition, the mechanism for the decision has been poorly understood. RUNX3 functions as a tumor suppressor and is frequently inactivated by DNA hyper-methylation in the stomach, bladder, colon, and lung. Recently, we have shown that adenovirus-Cre infected LSL-K-RasG12D mice induced lung adenocarcinoma (ADC) in prolonged latency (median survival, 220 days) and Runx3f/f/LSL-K-RasG12D mice rapidly induced ADC (median survival, 79 days), indicating a strong tumor suppressor activity of Runx3 against oncogenic K-Ras (Lee et., 2013. Cancer Cell. 2013 Vol. 24, pp 603-616). In the present study, we found that targeted disruption of Runx3 results in a delay in pRB phosphorylation and cell cycle progression through the R-point in mouse embryonic fibroblast cells. During the R-point interval, RUNX3 transiently formed a complex with pRB and BRD2 and induced Cdkn1a (p21Waf1/Cip1/Sdi1; p21). The complex was dissociated when by Cyclin D1 which was induced 4 hours after serum stimulation and p21 expression was turned off. However, oncogenic K-Ras maintained the complex. These results identify the series of molecular events associated with R-point commitment and provide an insight into the relationship between R-point commitment and oncogene surveillance.
Note: This abstract was not presented at the conference.
Citation Format: Xin-Zi Chi, You-Soub Lee, Jung-Won Lee, You-Mie Lee, Yoshiaki Ito, Suk-Chul Bae. RUNX3 and pRB form a complex and regulate restriction-point commitment. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A43. doi: 10.1158/1557-3125.RASONC14-A43