bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-305: Identification of p21 as a novel substrate of LATS2 in lung cancer
Authors: Yeung Benjamin 
Published: May 2015

Abstract
LATS2 is a serine/threonine kinase and tumor suppressor gene found to be downregulated and mutated in lung cancer. Although LATS2 has been shown to regulate many cancer-related functions such as maintenance of genomic stability, cell proliferation and apoptosis, its roles in lung tumorigenesis are largely unknown. In addition, the downstream cellular genes mediating LATS2 tumor suppressing function in lung cancer remains elusive. Since LATS2 kinase activity is essential for its function, therefore, identification and characterization of LATS2 substrates is critical in understanding the role it plays in lung tumorigenesis and is the focus of this study. To elucidate LATS2 function in lung cancer, we stably overexpressed LATS2 in a variety of lung cancer cell lines using a doxycycline-inducible lentivirus system. We have found that LATS2 strongly suppresses cell proliferation in all of cell lines tested. Further functional screening for LATS2 kinase substrates identified p21CIP1 to be a potential LATS2 substrate mediating LATS2 tumor suppressing function. p21 and LATS2 were found to bind each other as revealed by GST-pulldown and co-immunoprecipitation assays. Importantly, we found that LATS2 specifically phosphorylates p21 at S146, and that this site is critical for suppressing cell proliferation in lung cancer cells. These findings describe a novel LATS2 signalling pathway and improve our understanding of the role of LATS2 in lung tumorigenesis.
Citation Format: Benjamin Yeung. Identification of p21 as a novel substrate of LATS2 in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-305. doi:10.1158/1538-7445.AM2014-LB-305
Abstract LB-310: Single cell genome sequencing reveals clonal stability and diversity in breast cancer
Authors: Wang Yong , Navin Nicholas , Waters Jill , Leung Marco , Unruh Anna , Shi Xiuqing , Roh Whijae , Chen Ken , Scheet Paul , Vattathil Selina , Liang Han , Multani Asha , Zhang Hong , Meric-Bernstam Funda , Michor Franziska , Zhao Rui 
Published: May 2015

Abstract
Human breast cancers often display intratumor genomic heterogeneity. This clonal diversity confounds the clinical diagnosis and basic research of cancer, because single samples may not represent that tumor as a whole. Sequencing breast tumor cohorts en masse has identified many prevalent mutations, but has limited ability for resolving subclonal diversity. Here, we developed a whole-genome and exome single-cell sequencing approach (Nuc-Seq) using G2/M cells. To validate our method, we applied Nuc-Seq to sequence the whole genomes of two single cells from a genetically monoclonal breast cancer cell line (SK-BR-3) at high coverage depth (61X ± 5 sem, n=2) and breadth (83.70% ± 3.40 sem, n=2) to detect somatic mutations. Our analysis suggests that Nuc-Seq generates low allelic dropout rates (9.73% ± 2.19%) and low false positive error rates for point mutations (FPR = 1.24e-6). We then applied this method to sequence single normal and tumor cells from an estrogen-receptor positive breast cancer and a triple-negative ductal carcinoma at base-pair resolution. In parallel, we performed single cell copy number profiling. In both tumors, we observed a large number of rare variants that were not detected by sequencing the bulk tumor en masse. In contrast, we find that single cell copy number profiles are highly similar. Our data suggest that aneuploid rearrangements occurred early in tumor evolution and remained highly stable as the tumor mass expanded. In contrast we find that point mutations evolved gradually, generating extensive clonal diversity. Many of the diverse mutations were shown to occur at low frequencies (0.03 -10%) in the tumor mass by targeted duplex sequencing. Mathematical modeling suggests that the triple-negative tumor cells have an increased mutation rate (13.3X), while the ER+ tumor cells do not. These findings have important implications for the diagnosis, therapeutic treatment and evolution of chemoresistance in breast cancer.
Citation Format: Yong Wang, Nicholas Navin, Jill Waters, Marco Leung, Anna Unruh, Xiuqing Shi, Whijae Roh, Ken Chen, Paul Scheet, Selina Vattathil, Han Liang, Asha Multani, Hong Zhang, Funda Meric-Bernstam, Franziska Michor, Rui Zhao. Single cell genome sequencing reveals clonal stability and diversity in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-310. doi:10.1158/1538-7445.AM2014-LB-310
Abstract LB-311: Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T cells and granulocytes
Authors: Wheeler David A. , Wang Linghua , Swierczek Sabina , Hickman Kimberly , Drummond Jennifer A. , Muzny Donna , Gibbs Richard A. , Prchal Joseph 
Published: May 2015

Abstract
Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by augmented myelopoiesis leading to increased red cell mass with frequent excessive proliferation of other myeloid lineages. Over 95% of PV patients harbor JAK2V617F mutation, which confers proliferative advantage to affected myeloid progenitors. JAK2V617F, which is thought to be necessary but not sufficient for the disease, is often associated with acquired uniparental disomy on chromosome 9p (9pUPD). To better understand the underlying molecular basis of PV, we performed whole-exome sequencing and DNA copy-number analysis of 31 JAK2V617F-positive patients and further investigated the evolution of somatic mutations using longitudinal samples. In addition to JAK2 V617F and 9pUPD, we identified recurrent somatic mutation in an additional 5 genes including ASXL1, TET2, DNMT3A, and SF3B1 and recurrent DNA copy-number alterations at 1q and 18p. Forty-two percent of patients had at least one somatic mutation in an epigenetic modifier gene, and 23% of patients harbored mutation in RTK/RAS, RNA processing pathways, tumor suppressors and protein kinases. In 4 of 31 cases, variant allele abundance suggested somatic mutations of ASXL1, DNMT3A and SF3B1 may have preceded JAK2V617F. Interestingly, in 7 PV patients mutations also present in COSMIC were shared between the patients’ T-cell controls and granulocytes: 4 NF1, 2 ASXL1, and one each in TET2, IDH2, and DNMT3A, suggesting these genes mutated early in hematopoietic development. Absence of JAK2V617F in these T-cells ruled out cross-contamination of cell lineages. In an additional 4 cases, a minor JAK2V617F subclone acquired new mutations in DNMT3A, SF3B1, SMARCA2, and TET2 during PV progression. In summary, seventy percent of patients had mutation of at least one gene important to development of myeloid neoplasms, other than JAK2V617F. Our data reveal that these mutations, in particular NF1, may have arisen in some cases early in hematopoiesis but also in some patients during progression after diagnosis. These results suggest that the order of mutation is not as important as the total mutational burden in the development of PV.
Citation Format: David A. Wheeler, Linghua Wang, Sabina Swierczek, Kimberly Hickman, Jennifer A. Drummond, Donna Muzny, Richard A. Gibbs, Joseph Prchal. Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T cells and granulocytes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-311. doi:10.1158/1538-7445.AM2014-LB-311
Abstract LB-316: The landscape of actionable genomic lesions in small cell bladder cancer
Authors: Chang Matthew T. , Asthana Saurabh , Iyer Gopakumar , Desai Neil , Al-Ahmadie Hikmat , Chapman Jocelyn , Bochner Bernard H. , Rosenberg Jonathan E. , Bajorin Dean F. , Solit David B. , Taylor Barry S. 
Published: May 2015

Abstract
Small cell cancers are aggressive tumors with unfavorable prognosis. Small cell bladder carcinomas are a particularly troublesome and poorly differentiated tumor where little is known and in which few targeted therapeutic options exist for molecularly defined patients. We therefore sought to characterize both common and actionable aberrant pathways in small cell bladder tumors to serve as a guide for therapeutic development. Utilizing a combination of deep targeted capture and whole-genome sequencing approaches, we characterized the mutational and DNA copy number alteration spectrum of twenty patients with small-cell bladder cancer including multi-region profiling of a subset of cases with mixed small cell and urothelial histologies. Integrating molecular, clinical, and pathway data along with comparative genomic analyses of 371 urothelial bladder and small cell lung cancers, we identified histology- and lineage-specific lesions and significant differences in the prevalence of specific pathway aberrations. Whole-genome sequencing revealed structurally complex tumors and, in some cases, somatic hypermutation, including one sample harboring more than 150,000 clonal mutations. Aberrations in G1/S cell cycle progression appear to be pathognomonic in small cell tumors. Furthermore, additional lesions affecting both pro/anti apoptotic as well as metabolic pathways occurred in patterns that are distinct from other small-cell and bladder cancers. In total, 85% of small cell bladder cancer samples contain at least one potentially clinically actionable lesion. These results indicate that integrative genomic analyses of small-cell bladder cancer facilitates therapeutic development and pathway targeting in a complex mutational landscape.
Citation Format: Matthew T. Chang, Saurabh Asthana, Gopakumar Iyer, Neil Desai, Hikmat Al-Ahmadie, Jocelyn Chapman, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, David B. Solit, Barry S. Taylor. The landscape of actionable genomic lesions in small cell bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-316. doi:10.1158/1538-7445.AM2014-LB-316
Abstract LB-322: The senescence-associated Sin3B protein promotes inflammation and pancreatic cancer progression
Authors: Rielland Maite , Cantor David , Graveline Richard , Hadju Cristina , Mara Lisa , Miller George , David Gregory 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is strikingly resistant to conventional therapeutic approaches. We have previously demonstrated that the histone deacetylase associated SIN3B protein is essential for oncogene-induced senescence in cultured cells. Here we report that SIN3B is required for activated KRAS-induced senescence in vivo using a mouse model of pancreatic cancer. Surprisingly, impaired senescence caused by genetic inactivation of Sin3B is associated with delayed PDAC progression, correlating with an impaired inflammatory response. At the molecular level, SIN3B mediates KRAS-induced Il-1a production in a cell autonomous and senescence dependent manner. These results indicate for the first time that senescence-associated inflammation positively correlates with PDAC progression and identify SIN3B as a therapeutic target to inhibit inflammation-driven tumorigenesis.
Citation Format: Maite Rielland, David Cantor, Richard Graveline, Cristina Hadju, Lisa Mara, George Miller, Gregory David. The senescence-associated Sin3B protein promotes inflammation and pancreatic cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-322. doi:10.1158/1538-7445.AM2014-LB-322
Abstract LB-326: Structural basis of lipid-binding and regulation in PI3Kα
Authors: Miller Michelle S. , Schmidt-Kittler Oleg , Bolduc David M. , Brower Evan T. , Chaves-Moreira Daniele , Allaire Marc , Kinzler Kenneth W. , Jennings Ian G. , Thompson Philip E. , Cole Philip A. , Amzel L. Mario , Vogelstein Bert , Gabelli Sandra B. 
Published: May 2015

Abstract
PI3Kα is a well-established target for the development of novel cancer therapeutics. Currently, all inhibitors in clinical trials target the highly conserved ATP-binding site, which has made the development of PI3K selective inhibitors difficult, with many inhibitors displaying cross-reactivity against protein kinases.
We have used X-ray crystallography and fluorescence quenching studies to characterize the lipid-binding site of PI3Kα and the structural basis of regulation by nSH2. A newly determined p110α/niSH2 crystal structure is the first to reveal the nSH2 domain in complex with wild-type p110α, allowing investigation of the mechanisms of nSH2 regulation. Key interactions between the nSH2 domain and the activation loop suggest a mechanism by which the kinase domain is kept in an inactive conformation until activation by phosphopeptide binding. Key differences in nSH2 domain binding to p110α were identified between the wild-type and oncogenic mutant, p110αH1047R. Increased buried surface area and two unique salt-bridges are suggestive of tighter regulatory control in the wild-type PI3Kα compared with the oncogenic mutant. A second structure reveals the details of PI3K binding to a lipid substrate mimetic, diC4-PIP2. Unexpectedly, we found an additional lipid-binding site, and this striking observation was confirmed by fluorescence quenching experiments. The identification of multiple lipid binding sites provides additional targets that may enable more selective inhibition among the various isoforms, or even between mutant and wild-type forms of PI3Kα.
Citation Format: Michelle S. Miller, Oleg Schmidt-Kittler, David M. Bolduc, Evan T. Brower, Daniele Chaves-Moreira, Marc Allaire, Kenneth W. Kinzler, Ian G. Jennings, Philip E. Thompson, Philip A. Cole, L. Mario Amzel, Bert Vogelstein, Sandra B. Gabelli. Structural basis of lipid-binding and regulation in PI3Kα. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-326. doi:10.1158/1538-7445.AM2014-LB-326
Abstract LB-330: Four individually druggable Met hotspots mediate HGF-driven tumor progression
Authors: Hultberg Anna , Basilico Cristina , Blanchetot Cristophe , Jonge Natalie D. , Hanssens Valérie , Boeck Gitte D. , Mira Alessia , Cazzanti Manuela , Morello Virginia , Dreier Torsten , Saunders Michael , Haard Hans D. , Michieli Paolo 
Published: May 2015

Abstract
Activation of Met by HGF plays a key role in tumor progression. Using a newly developed llama platform generating human-like immunoglobulins, we selected 68 different antibodies that competed with HGF for binding to Met. HGF-competing antibodies recognized four hotspots localized in different domains of Met. One hotspot coincides with the previously identified HGF β-chain binding site on blades 2-3 of the SEMA β-propeller. Two hotspots lie within SEMA blade 5 and IPT domains 2-3, respectively, where the HGF α-chain is thought to bind. The last hotspot identifies a new region across the PSI-IPT 1 domains. Individual or combined targeting of these hotspots effectively interrupted HGF-Met signaling in multiple biochemical and biological assays. Selected antibodies directed against SEMA blades 2-3 and the PSI-IPT 1 region inhibited brain invasion and prolonged survival in a glioblastoma multiforme model, prevented metastatic disease following neo-adjuvant therapy in a triple-negative mammary carcinoma model, and suppressed cancer cell dissemination to the liver in a KRAS-mutant metastatic colorectal cancer model. These results identify multiple regions of Met responsible for HGF-mediated tumor progression, unraveling the complexity of HGF-Met interaction and providing new molecular tools for targeting Met activity in cancer.
Citation Format: Anna Hultberg, Cristina Basilico, Cristophe Blanchetot, Natalie De Jonge, Valérie Hanssens, Gitte De Boeck, Alessia Mira, Manuela Cazzanti, Virginia Morello, Torsten Dreier, Michael Saunders, Hans De Haard, Paolo Michieli. Four individually druggable Met hotspots mediate HGF-driven tumor progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-330. doi:10.1158/1538-7445.AM2014-LB-330
Abstract LB-34: 3-Dimensional air-liquid interface organoid culture of primary human tumor biopsies
Authors: Neal James T. , Cantrell Michael , Rack Paul , Kuo Calvin J. 
Published: May 2015

Abstract
The application of primary organoid cultures to cancer modeling holds promise for combining the accurate multilineage differentiation and physiology of in vivo systems with the facile in vitro manipulation of transformed cell lines. We have previously described a single air-liquid interface culture method that can be used to engineer oncogenic mutations into primary epithelial/mesenchymal organoids from mouse colon, stomach, and pancreas (Ootani et al., Nature Medicine 15(6):701-6 (2009); Li et al., in press). We have recently modified this methodology to allow the robust long-term 3-dimensional culture of a wide variety of primary neoplasms from human biopsy samples. These primary tumor organoids accurately recapitulate the architecture and histopathology of the tumors from which they were derived, including epithelial and mesenchymal compartments. These tumor organoids can be further passaged into 96-well format to enable a variety of genetic and pharmacologic manipulations with the overall goal of enabling mechanistic studies of tumorigenesis and obtaining clinically actionable information regarding chemosensitivity and resistance to therapy.
Citation Format: James T. Neal, Michael Cantrell, Paul Rack, Calvin J. Kuo. 3-Dimensional air-liquid interface organoid culture of primary human tumor biopsies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-34. doi:10.1158/1538-7445.AM2014-LB-34
Abstract LB-40: Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition
Authors: Bolden Jessica , Tasdemir Nilgun , Dow Lukas , Es Johan H. van , Wilkinson John E. , Zhao Zhen , Clevers Hans , Lowe Scott W. 
Published: May 2015

Abstract
BET family proteins are novel therapeutic targets for cancer and inflammation and represent the first epigenetic readers against which small-molecule inhibitors have been developed. First generation BET inhibitors have shown some therapeutic efficacy in pre-clinical models, however the consequences of disrupting BET protein function in normal tissues are largely unknown. Using an inducible and reversible transgenic RNAi mouse model targeting the BET family protein Brd4, we show that acute suppression of Brd4 in adult animals has immediate and dramatic effects in multiple tissues. Brd4-depleted mice displayed epidermal hyperplasia, alopecia, and decreased cellular diversity and stem cell depletion in the small intestine. To test whether the loss of intestinal stem cells induced by Brd4 suppression would have consequences in combination with agents that induce acute gut toxicity, we subjected mice to a sub-lethal irradiation. Whereas control mice showed intestinal recovery 4-5 days following irradiation, Brd4-depleted mice showed dramatic and continued crypt-villus atrophy, implying that potent BET protein inhibition in combination with cytotoxic chemotherapy may show significantly enhanced toxicity in the clinic. These findings provide important insight into Brd4 function in normal tissues and importantly, predict several potential outcomes associated with potent and sustained inhibition of BET protein function.
Citation Format: Jessica Bolden, Nilgun Tasdemir, Lukas Dow, Johan H. van Es, John E. Wilkinson, Zhen Zhao, Hans Clevers, Scott W. Lowe. Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-40. doi:10.1158/1538-7445.AM2014-LB-40
Abstract LB-44: Persistent androgen ablation promotes enhanced neuroendocrine features in Pten-deficient prostate cancer
Authors: Mulholland David J. 
Published: May 2015

Abstract
Background: The development of potent androgens has increased survival of CRPC patients. Clinical data also suggests that the number of neuroendocrine (NE) CaPs frequently found in soft tissue metastasis has steadily increased over recent years and may be correlated with the use of potent androgen receptor (AR) inhibitors such as Enzalutamide or Aberaterone Acetate. These data suggest that NE cells may escape hormonal castration and that active inhibition of the AR may promote aggressive disease. Approach. To investigate this hypothesis, we have taken both genetic and pharmacological approaches to oppose AR signaling in Pten deficient CaP. Surgical castration of Pten-null mutant mice (Pb-Cre+;PtenL/L) led to both an increased EMT signature but also enhanced content of NE cells that were Synaptophysin+ and Pten-low/null. Chronic Enzalutamide treatment (4 wks., 10 mg/kg/d) promoted an increased percentage Synaptophysin+ cells, an observation that was potentiated when coinciding with surgical castration. Interestingly, the highest potentiation of NE cells was in the proximal anterior region of Pten-null mice. Consistent with our previous results, epithelial deletion of AR signaling in Pten-null epithelium (Pb-Cre+;PtenL/L;ArL/Y) did not prevent CaP progression under surgical castrate conditions. Moreover, compared to Pten-null mutants, Pten-null;Ar-null mutants showed an enhanced stem cell signature (p63+ cells, LSChigh subpopulation) but also marked increase content of NE cells upon both surgical castration and chronic Enzalutamide treatment (4-8 wks., 10 mg/kg/d). To consider whether total systemic ablation of the AR signaling axis could impact progression, resected Pten-null explants (“chuncks”) were isolated from Pb-Cre+;PtenL/L mutants and transplanted to the kidney capsule of Tfm;Rag1-null mice, immune incompetent hosts that are genetically null for Ar. Consistent with our hypothesis, Tfm;Rag1-null mutants showed more NE cells in explants than those transplanted to control AR intact control (Rag1-null) mice. Conclusion: Chronic blockade of the AR signaling axis results in a poorly differentiated phenotype characterized by increased stemness and enhanced NE phenotype.
Citation Format: David J. Mulholland. Persistent androgen ablation promotes enhanced neuroendocrine features in Pten-deficient prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-44. doi:10.1158/1538-7445.AM2014-LB-44