tbuckley/cabot-search huggingface dataset:
Abstract 257: Clonal Analysis Of Multipotent Cardiovascular Progenitors That Generate Cardiomyocytes During Development
Authors: Konstantina Ioanna Sereti, Paniz Kamran Rashani, Peng Zhao, Reza Ardehali
Journal: Circulation Research (2014)

It has been proposed that cardiac development in lower vertebrates is driven by the proliferation of cardiomyocytes. Similarly, cycling myocytes have been suggested to direct cardiac regeneration in neonatal mice after injury. Although, the role of cardiomyocyte proliferation in cardiac tissue generation during development has been well documented, the extent of this contribution as well as the role of other cell types, such as progenitor cells, still remains controversial. Here we used a novel stochastic four-color Cre-dependent reporter system (Rainbow) that allows labeling at a single cell level and retrospective analysis of the progeny. Cardiac progenitors expressing Mesp1 or Nkx2.5 were shown to be a source of cardiomyocytes during embryonic development while the onset of αMHC expression marked the developmental stage where the capacity of cardiac cells to proliferate diminishes significantly. Through direct clonal analysis we provide strong evidence supporting that cardiac progenitors, as opposed to mature cardiomyocytes, are the main source of cardiomyocytes during cardiac development. Moreover, we have identified quadri-, tri-, bi, and uni-potent progenitors that at a single cell level can generate cardiomyocytes, fibroblasts, endothelial and smooth muscle cells. Although existing cardiomyocytes undergo limited proliferation, our data indicates that it is mainly the progenitors that contribute to heart development. Furthermore, we show that the limited proliferation capacity of cardiomyocytes observed during normal development was enhanced following neonatal cardiac injury allowing almost complete regeneration of the scared tissue. However, this ability was largely absent in adult injured hearts. Detailed characterization of dividing cardiomyocytes and proliferating progenitors would greatly benefit the development of novel therapeutic options for cardiovascular diseases.
Abstract 1094: Combining the pan-FGFR inhibitor AZD4547 with radiation in lung and head and neck squamous cell carcinoma
Authors: Andrew M. Baschnagel, Chunrong Li, Alecia M. Morgan, Sean R. Brennan, Kalley A. Russo, Paul M. Harari
Journal: Cancer Research (2017)

Abstract The fibroblast growth factor receptors (FGFR1, FGR2, FRG3, FGR4) are frequently altered or overexpressed in both lung and head and neck squamous cell carcinomas (SCC). Amplification of FGFR1 has been reported to be as high as 22% in lung SCC and 17% in head and neck SCC (HNSCC). FGFRs have been identified as a potential therapeutic target in lung and head and neck cancers. In addition, FGFRs activate multiple pathways involved in the radiation response including RAS/RAF/MAPK, PI3K/AKT and STAT. AZD4547 is a potent and selective tyrosine kinase inhibitor of the FGFR family and is currently being investigated in clinical trials. Since a substantial portion of lung cancer and HNSCC patients are treated with radiotherapy, we examined the anti-tumor effects of AZD4547 in combination with radiation in both lung and head and neck cancer model systems. FGFR protein and RNA expression and cell proliferation with AZD4547 were evaluated in 8 lung and 8 head and neck cancer cell lines. Clonogenic survival assays were performed on 4 lung and 4 head and neck cancer cell lines and xenograft experiments were performed on one HNSCC cell line. These cell lines demonstrated varying levels of FGFR1, 2 and 3 protein and RNA expression. The half maximal inhibitory concentration (IC50) of AZD4547 in these cell lines ranged from 0.05 to 128 uM. Sensitivity to AZD4547 did not correlate directly with protein or RNA expression. In vitro clonogenic survival assays showed limited effects of combining AZD4547 with radiation. However, significant tumor growth delay was observed with the combination of radiation and AZD4547 compared to radiation or drug alone in the SCC1483 FGFR2 expressing HNSCC xenograft model. These findings suggest that AZD4547 can augment the response of radiation in an in vivo model system. Further studies are underway to test these findings in additional cell lines including FGFR dependent amplified cancer cell lines. Citation Format: Andrew M. Baschnagel, Chunrong Li, Alecia M. Morgan, Sean R. Brennan, Kalley A. Russo, Paul M. Harari. Combining the pan-FGFR inhibitor AZD4547 with radiation in lung and head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1094. doi:10.1158/1538-7445.AM2017-1094
Abstract 3547: B cell receptor signaling regulates cellular metabolism in Chronic Lymphocytic Leukemia
Authors: Hima V. Vangapandu, Ondrej Havranek, William G. Wierda, Michael J. Keating, Richard Eric Davis, Christine M. Stellrecht, Varsha Gandhi
Journal: Cancer Research (2017)

Abstract Peripheral blood B cells in chronic lymphocytic leukemia (CLL) are quiescent, yet have an active RNA transcription and protein translation processes, suggesting that these malignant lymphocytes may be metabolically active. However, CLL metabolism and its relationship to disease biology has not been well-explored. In our previous investigation, we reported that compared with proliferative B-cell lines, metabolic fluxes of oxygen and lactate were low in quiescent peripheral blood B lymphocytes from CLL patients (Vangapandu, H.V. et al, AACR 2014). In 45 patient samples tested, glycolysis (extracellular acidification rate, ECAR) was consistently low (1 to 15 mpH/min/5 x 105 lymphocytes), whereas, oxygen consumption rate (OCR) varied considerably (5 to 190 pMoles/min/5 x 105 lymphocytes). Among the prognostic factors, high OCR correlated strongly with ZAP 70 positivity, unmutated IGHV status, greater β2M levels and higher Rai stage. In contrast, glycolytic flux (ECAR) from same patient samples did not associate with prognostic factors. Further, OCR did not vary on the basis of frequently occurring cytogenetic abnormalities, 13q14, 17p, and 11q deletions or trisomy 12. Since, ZAP 70 and IGHV unmutated status are associated with augmented B-cell receptor (BCR) pathway signaling, we tested the impact on OCR after genetic ablation of B-cell receptor (CH2 region of IgM). A CRISPR-Cas9-mediated BCR knockout mitigated OCR in a malignant B cell line without impacting the rate of proliferation. A critical node in the BCR pathway is PI3 Kinase and PI3K isoforms, δ and γ are involved in B-cell malignancies. Consistent with BCR ablation results, knocking out PIK3CD (codes for catalytic subunit δ), dramatically reduced OCR and ECAR. Pharmacological inhibitors of the PI3K pathway, duvelisib (a PI3K δ/γ inhibitor in phase III clinical trials) or idelalisib (FDA approved PI3K δ inhibitor) also decreased OCR. Direct inhibition of AKT with MK-2206 showed similar results. Collectively, these data suggest that CLL cellular metabolism is associated with prognostic factors and linked to BCR signaling pathway. Since, the PI3K inhibitors used in our study are being tested clinically for patients with CLL, investigations on the impact on metabolomics during therapy and translation of results to combination strategies need to be explored. Note: This abstract was not presented at the meeting. Citation Format: Hima V. Vangapandu, Ondrej Havranek, William G. Wierda, Michael J. Keating, Richard Eric Davis, Christine M. Stellrecht, Varsha Gandhi. B cell receptor signaling regulates cellular metabolism in Chronic Lymphocytic Leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3547. doi:10.1158/1538-7445.AM2017-3547
Abstract LB-010: Modeling the impact of mutations in ubiquitin pathway genes across human cancers
Authors: Hatice U. Osmanbeyoglu, Christina Leslie
Journal: Cancer Research (2017)

Abstract A number of ubiquitin pathway genes show a strikingly high frequency of somatic alterations across diverse human cancers. While several ubiquitin ligase genes with recurrent mutations or copy number alterations been studied in individual cancers, their role in many malignancies remains poorly understood. To better model the impact of ubiquitin pathway alterations, we developed a computational strategy for exploiting parallel phosphoproteomics and mRNA sequencing data for large tumor sets to link dysregulation of upstream signaling pathways with altered transcriptional response through the transcriptional circuitry. Our modeling allows us to interpret the impact of mutations and copy number events in terms of altered signaling and transcription factor (TF) activity. We used a multi-task learning strategy to jointly train phosphoprotein-TF interaction models across 10 human cancers for which large reverse-phase protein array and RNA-seq data sets are available through TCGA. We then applied a novel algorithmic approach to extract networks of signaling proteins and TFs whose inferred activities are correlated across tumors and whose dysregulation is associated with specific somatically altered ubiquitin pathway genes. Our analysis revealed both known and novel interactions of ubiquitin ligase genes with signaling pathways and transcriptional programs in a pan-cancer context. Citation Format: Hatice U. Osmanbeyoglu, Christina Leslie. Modeling the impact of mutations in ubiquitin pathway genes across human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-010. doi:10.1158/1538-7445.AM2017-LB-010
Abstract 429: Integrated genomic DNA and RNA profiling to predict cancer immunotherapy response
Authors: Pan Du, Xiaohong Wang, Zhixin Zhao, Huiquang Wang, Shidong Jia
Journal: Cancer Research (2017)

Abstract Immunotherapy response varies widely, making it difficult for physicians to know whether immunotherapy will be effective for a given patient. Recent studies have reported that patients with high PD-L1 gene expression are likely to respond to checkpoint blocking drugs, but there are still many patients whose tumor test for the PD-L1 protein are negative and can respond to the drugs. In addition to the potential link between mismatch repair (MMR) gene mutations and clinical response to anti-PD1 immunotherapy drug, recent findings show that tumor mutation burden and microsatellite instable (MSI) are good indicators of the cancer immunotherapy responses. Using Predicine’s proprietary Gene RADAR (RNA and DNA single molecular digital Readings) technology, here we report the development of PrediSeq-CI (Cancer Immunotherapy) panel for comprehensive genomic profiling of DNA and RNA that are associated with cancer immunotherapy response. The panel has been tested using both tissue biopsy and plasma samples. The development of PrediSeq-CI test has potential to enable precision medicine in cancer immunotherapy. Finally, we also developed a liquid biopsy droplet digital PCR test to measure PD-L1 expression in blood. Citation Format: Pan Du, Xiaohong Wang, Zhixin Zhao, Huiquang Wang, Shidong Jia. Integrated genomic DNA and RNA profiling to predict cancer immunotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 429. doi:10.1158/1538-7445.AM2017-429
Abstract LB-264: Preclinical evaluation of DNA-PK as a therapeutic target in prostate cancer
Authors: Emanuela Dylgjeri, Jonathan F. Goodwin, Christopher M. McNair, Ayesha A. Shafi, Vishal Kothari, Felix Feng, Dana Rathkop, Karen Knudsen
Journal: Cancer Research (2017)

Abstract Prostatic adenocarcinoma (PCa) is dependent on androgen receptor (AR) signaling at all stages of disease, as AR activation induces both cell proliferation and survival. Though organ–confined disease can be treated, the response is transient. Reactivation of AR leads to castration resistant prostate cancer (CRPC), which remains fatal. Previously published studies demonstrate that AR activation promotes tumor cell survival and proliferation through a feed-forward loop involving the DNA repair factor DNA-dependent protein kinase (DNA-PK). Recent data from our lab has highlighted the role of DNA-PK in DNA damage repair as well as transcriptional regulation of pro-metastatic signaling. Strikingly, DNA-PK is the most deregulated kinase in metastatic CRPC. DNAPK is highly elevated and hyperactivated, and is an independent predictor of metastasis and overall survival in patients with high-risk disease. Concordantly, DNAPK suppression attenuated DNA-PK functions in NHEJ and transcriptional regulation. DNA-PK inhibition is sufficient to prevent proliferation in vitro and ex vivo, as well as tumor metastasis in vivo. Combined these findings highlight importance of DNA-PK functions as a transcriptional regulator and a mediator of NHEJ DNA repair and nominate it as a therapeutic target in PCa. Data presented here will interrogate the translational capacity of a specific DNA-PK inhibitor, a dual DNA-PK/TOR kinase inhibitor and a specific TOR kinase inhibitor in CRPC models. Currently, CC-115, a dual kinase inhibitor, is the only DNA-PK inhibitor in Phase1/2 trial in combination with Enzalutamide in PCa. Unbiased transcriptomic analyses were performed and will be used to identify mechanisms of action that lead to suppression of PCa growth in vitro and ex vivo. These findings will provide insight in the effectiveness of DNA-PK inhibitors as a single agent or combinatorial treatments and provide rational for its placement in the correct clinical space. Citation Format: Emanuela Dylgjeri, Jonathan F. Goodwin, Christopher M. McNair, Ayesha A. Shafi, Vishal Kothari, Felix Feng, Dana Rathkop, Karen Knudsen. Preclinical evaluation of DNA-PK as a therapeutic target in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-264. doi:10.1158/1538-7445.AM2017-LB-264
Abstract 872: Noninvasive monitoring of endogenous Pdl1 expression by using a dual reporter system
Authors: Min Zhou, Xinjian Liu, Fang Li, Chuan-Yuan Li
Journal: Cancer Research (2017)

Abstract Programmed death-ligand 1 (Pdl1) is a key immune checkpoint protein facilitating tumor escape from host immune system. Clinical approval of anti-PD1 and anti-PDL1 antibodies for the treatment of a variety of malignancies underscores the promise of immune checkpoint therapy. Further progress in this promising area of research is likely to come from better understanding of the mechanisms for regulation of immune checkpoint proteins such as PDL1. In the present study, we designed a dual reporter imaging system to monitor Pdl1 expression by use of the CRSPR-Cas9 technology. A fusion reporter that consists of eGFP and Luc2 was introduced into downstream of the endogenous Pdl1 gene, right before the stop codon, through CRISPR-Cas9 mediated homologous recombination. A P2A self-cleaving motif is inserted between the fusion reporter gene (eGFP-Luc2) and Pdl1. The reporter system was introduced into two murine tumor cell lines, 4T1 and B16F10. In vitro, an increase in eGFP intensity and bioluminescence of the reporter cells was observed after exposure to ionizing radiation or IFN-gamma, which has been reported to upregulate the expression of Pdl1. In vivo, we were able to observe radiation induced increase in bioluminescence signals from tumor established by use of the reporter cells. Our study therefore provided proof of principle for the use of our endogenous Pdl1 reporter imaging system to monitor the expression levels of Pdl1 in vitro and in vivo noninvasively and serially. Citation Format: Min Zhou, Xinjian Liu, Fang Li, Chuan-Yuan Li. Noninvasive monitoring of endogenous Pdl1 expression by using a dual reporter system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 872. doi:10.1158/1538-7445.AM2017-872
Abstract 2502: Liquid diet introduction of tracers into mice for stable isotope-resolved metabolomics (SIRM) investigations
Authors: Ramon C. Sun, Marc O. Warmoes, Ye Yang, Pan Deng, Qiushi Sun, Andrew N. Lane, Richard M. Higashi, Teresa W-M Fan
Journal: Cancer Research (2017)

Abstract Tracer-based mapping of metabolic networks in vivo is a powerful approach for revealing metabolic reprogramming in human cancer. However, current in vivo labeling techniques for model animals face important challenges including insufficient depth of pathway coverage (e.g. inability to detect labeled nucleotides, proteins, and lipids) and stress-related artifacts. Here, we report stress-free administration of 13C6-glucose via liquid diet into mice. 13C enrichment was observed in metabolites of glycolysis, the Krebs cycle, the pentose phosphate pathway, nucleobases, UDP-sugars, as well as macromolecules glycogen, lipids, and proteins from major organs in NSG mice. We have applied the liquid diet method to map the glucose metabolic networks in NSCLC tumors in a patient-derived xenograft (PDX) model. We observed a high enrichment in the metabolites of glycolysis, Krebs cycle, and PPP as well as de novo synthesized nucleotides and amino acids by IC-UHR-FTMS analysis. Lung PDX displayed unexpected metabolic complexity, such as the use of pyruvate to fuel anaplerosis as well as gluconeogenesis. We also found high 13C enrichment in both tumor and plasma glutamine, which implies that glutamine in the PDX tumors largely came from other organs via the blood rather than being synthesized in situ. Our data showed that liquid diet is an effective and noninvasive means for comprehensive analysis of glucose-associated metabolic networks in human tumor xenografts, which can also be extended to SIRM studies with other fuel sources. Acknowledgements: This work was supported in part by grants: 1R01ES022191-01 (to TWMF and RMH), 1P01CA163223-01A1 (to ANL and TWMF), and 1U24DK097215-01A1 (to RMH, TWMF, and ANL) R.C. Sun was supported by a T32 training grant to M. Vore (5T32ES007266-25) Citation Format: Ramon C. Sun, Marc O. Warmoes, Ye Yang, Pan Deng, Qiushi Sun, Andrew N. Lane, Richard M. Higashi, Teresa W-M Fan. Liquid diet introduction of tracers into mice for stable isotope-resolved metabolomics (SIRM) investigations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2502. doi:10.1158/1538-7445.AM2017-2502
Abstract 794: Potential role of DLL4 in uveal melanoma vascular mimicry
Authors: Julia Escandon, Matthew G. Field, Stefan Kurtenbach, Jeffim Kuznetzov, Christina L. Decatur, J William Harbour
Journal: Cancer Research (2017)

Abstract Uveal melanoma is the most common malignancy of the eye. Thanks to gene array analysis it is possible to classify uveal melanoma in Class 1 (low metastasis risk) and Class 2 (high metastasis risk) tumor. This classification will ultimately determine the tumor treatment, risk of metastasis and patient surveillance. Progression to metastasis remains by far the greatest problem in uveal melanoma and is associated with loss of BAP1 tumor suppressor. Bioinformatic analyses of RNA-Seq indicated that pro-angiogenic genes such as DLL4, VEGFA, VEGFC and HIF1a are overexpressed in Class 2 compared to Class 1 uveal melanoma while angiogenic inhibitors such as ZFP36L1, HIF1AN, VEGFB, VHL and HIF3A are downregulated. Further, we found that DLL4 is among the 5 most highly overexpressed genes associated with BAP1 loss in clinical specimens and in uveal melanoma cell lines induced to deplete BAP1. DLL4 is a Notch ligand known to regulate endothelial cells, bone marrow endothelial cell progenitors and angiogenesis. We hypothesize that DLL4 contributes to vascular mimicry in uveal melanoma. To test this hypothesis, we will test uveal melanoma cell lines induced to deplete BAP1 using shRNA in cell culture-based and in vivo models. The results of this research have the potential to elucidate the mechanism by which vascular mimicry occurs in uveal melanoma. Citation Format: Julia Escandon, Matthew G. Field, Stefan Kurtenbach, Jeffim Kuznetzov, Christina L. Decatur, J William Harbour. Potential role of DLL4 in uveal melanoma vascular mimicry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 794. doi:10.1158/1538-7445.AM2017-794
Abstract 5426: LPA stimulates glycolytic shift in ovarian cancer
Authors: Ji Hee Ha, Rangasudhagar Radhakrishnan, Jeremy D. Ward, Muralidharan Jayaraman, Danny N. Dhanasekaran
Journal: Cancer Research (2017)

Abstract Cancer cells resort to aerobic glycolysis to meet the increased energy consumption and growth requirement during active proliferation. While it has been observed that the cancer cells preferentially shift to aerobic glycolysis, the extraneous growth factors involved in this process is largely unknown. Since our previous studies have shown that lysophosphatidic acid (LPA) plays a critical role in the pathophysiology of ovarian cancers, we investigated the role of LPA in the metabolic reprogramming of ovarian cancer cells. Our results using XFe96 analyzer indicate that LPA stimulates aerobic glycolysis in multiple ovarian cancer cell lines as well as in patient-derived ovarian cancer cells. Physiological role for LPA in this process is demonstrated by the observation that the inhibitors of LPA-receptors attenuate the glycolytic shift stimulated by the ascitic fluid derived cancer patients. We further demonstrate that the silencing Gαi2, a downstream signaling mediator for LPA, inhibits LPA-stimulated glycolytic shift in ovarian cancer cells. Further analyses indicated that LPA-stimulated metabolic reprogramming involves the generation of reactive oxygen species (ROS). Treatment of cells with N-Acetyl Cysteine (NAC), a ROS-scavenger, inhibited the glycolytic shift stimulated by LPA. In addition, our studies point to a role for LPA-stimulated HIF1α activation in this process. These results indicate that LPA-stimulated metabolic reprogramming in ovarian cancer cells involve ROS-generation via LPA-Gαi2-HIF1α-dependent signaling pathway. Together with the findings that the glycolytic shift is crucially involved in tumor cell survival our studies point to LPA-Gαi2-HIF1α signaling axis as a potential target for therapy in ovarian cancer. Citation Format: Ji Hee Ha, Rangasudhagar Radhakrishnan, Jeremy D. Ward, Muralidharan Jayaraman, Danny N. Dhanasekaran. LPA stimulates glycolytic shift in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5426. doi:10.1158/1538-7445.AM2017-5426