tbuckley/cabot-search huggingface dataset:
Tumor-derived exosomes modulate PD-L1 expression in monocytes
Authors: Franziska Haderk, Ralph Schulz, Murat Iskar, Laura Llaó Cid, Thomas Worst, Karolin V. Willmund, Angela Schulz, Uwe Warnken, Jana Seiler, Axel Benner, Michelle Nessling, Thorsten Zenz, Maria Göbel, Jan Dürig, Sven Diederichs, Jérôme Paggetti, Etienne Moussay, Stephan Stilgenbauer, Marc Zapatka, Peter Lichter, Martina Seiffert
Journal: Science Immunology (2017)

In chronic lymphocytic leukemia (CLL), monocytes and macrophages are skewed toward protumorigenic phenotypes, including the release of tumor-supportive cytokines and the expression of immunosuppressive molecules such as programmed cell death 1 ligand 1 (PD-L1). To understand the mechanism driving protumorigenic skewing in CLL, we evaluated the role of tumor cell-derived exosomes in the cross-talk with monocytes. We carried out RNA sequencing and proteome analyses of CLL-derived exosomes and identified noncoding Y RNA hY4 as a highly abundant RNA species that is enriched in exosomes from plasma of CLL patients compared with healthy donor samples. Transfer of CLL-derived exosomes or hY4 alone to monocytes resulted in key CLL-associated phenotypes, including the release of cytokines, such as C-C motif chemokine ligand 2 (CCL2), CCL4, and interleukin-6, and the expression of PD-L1. These responses were abolished in Toll-like receptor 7 (TLR7)-deficient monocytes, suggesting exosomal hY4 as a driver of TLR7 signaling. Pharmacologic inhibition of endosomal TLR signaling resulted in a substantially reduced activation of monocytes in vitro and attenuated CLL development in vivo. Our results indicate that exosome-mediated transfer of noncoding RNAs to monocytes contributes to cancer-related inflammation and concurrent immune escape via PD-L1 expression.
Abstract 3177: KITENIN leads to resistance against temozolomide through enhancement of cancer stemness factors in mouse glioma model
Authors: Kyung-Hwa Lee, Eun-Jung Ahn, Shin Jung, Jae-Hyuk Lee, Kyung-Keun Kim, Kyung-Sub Moon
Journal: Cancer Research (2017)

Abstract Background: Recently, a new research spotlighted the role of KITENIN (KAI1 COOH-terminal interacting tetraspanin) on glioma invasiveness and progression, associated with the up-regulation of EMT (epithelial-mesenchymal transition) and cancer stemness markers. In this study, furthermore, it is investigated whether KITENIN leads to resistance against TMZ through enhancement of cancer stemness factors using mouse glioma model. Materials and Methods: TMZ-resistant T98G cell line (T98G/TR) was developed. EMT and cancer stemness markers and KITENIN expression were assessed by Western blotting and qRT-PCR. With KITENIN modulated U251 (knockdown) and GL261 (overexpression) cells, cell viability and apoptotic cell death factors after TMZ treatment were evaluated. Biological role of KITENIN on TMZ-resistance was investigated using magnetic resonance imaging (MRI) and immunofluorescence analysis for tumor sections of orthotopic glioma model. Using human glioma samples and primary cells, the mechanistic link between KITENIN and cancer stemness factors was confirmed. Results: T98G/TR cells showed increased expression of the KITENIN and EMT and cancer stemness factors. Also, In vitro assays revealed that KITENIN knockdown inhibited cell viability against TMZ treatment, whereas KITENIN overexpression promoted their viability, via apoptotic cell death pathway. In orthotopic glioma models, mice implanted with KITENIN-overexpressed cells showed resistance to TMZ on MRI and histopathological examination. The expression of KITENIN/ALDH1 or KITENIN/CD44 were co-localized and significantly higher in tumor sections of mouse transplanted with KITENIN-overexpressed cells than in tumor sections of mouse transplanted with control cells. Genetic down-regulation of KITENIN for KITENIN-overexpressed cell line and primary glioma cells led decreased expression of ALDH1 and CD44. In human glioma samples, high expression of KITENIN was closely related with high expression of ALDH1. Conclusion: KITENIN affects TMZ-resistance in malignant gliomas through induction of ALDH1 and CD44. Therefore, it could be suggested that KITENIN is therapeutic target to overcome TMZ-resistance of malignant gliomas. Citation Format: Kyung-Hwa Lee, Eun-Jung Ahn, Shin Jung, Jae-Hyuk Lee, Kyung-Keun Kim, Kyung-Sub Moon. KITENIN leads to resistance against temozolomide through enhancement of cancer stemness factors in mouse glioma model [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 3177. doi:10.1158/1538-7445.AM2017-3177
Abstract 5449: Nanoparticle delivery of miRNAs to inhibit GBM stem cells
Authors: Hernando Lopez-Bertoni
Journal: Cancer Research (2017)

Abstract Cancer cells arise from multiple complementary genomic and epigenomic abnormalities that deregulate pathways that control cell proliferation and tissue homeostasis. Epigenetic modifications, involving deregulation of non-coding RNAs, are emerging as critical determinants of gene expression and essential drivers of neoplastic phenotypes. Our knowledge of how these complex epigenetic mechanisms operate in the context of cancer cell phenotype regulation remains limited. Non-coding RNAs, in particular miRNAs, are emerging as critical epigenetic regulators of cell fate and oncogenesis. MiRNAs act by selectively inhibiting gene expression primarily by targeting mRNA for degradation usually via complementary 3’-UTR seed sequences. Numerous miRNAs have been found to regulate tumorigenesis and cancer cell stemness by virtue of their capacity to target tumor-suppressing or tumor promoting transcripts. We recently showed that the coordinated actions of Oct4 and Sox2 induce a tumor-propagating stem-like state in GBM cells through a mechanism that involves the induction of DNMTs and down-regulation of a network of miRNAs through promoter DNA methylation. Two of the miRNAs repressed by Oct4/Sox2, miR-148a and miR-296-5p, efficiently inhibit the tumor propagating capacity of GBM stem-like, making them excellent candidates for therapeutic intervention. Options for treating high-grade brain tumors remain limited. Recent developments in nanomedicine provide new and exciting opportunities to treat and manage brain tumors. Cationic polymers are a class of biomaterials with great promise for targeted molecular therapeutics. We combined this cutting-edge technology with our newly discovered stem cell inhibiting miRNAs to develop nano/miR conjugates to treat gliomas. We show these nano/miR conjugates distribute throughout an established tumor in vivo, and more importantly, delivering these tumor-suppressing miRNAs using PBAE polymers inhibits the growth of established GBM tumor in mouse models. Our findings demonstrate that identifying and validating stem cell-inhibitory in combination with current advances in nanomedicine will undoubtedly impact the development of novel therapies for targeting the CSC population and treating GBM. Citation Format: Hernando Lopez-Bertoni. Nanoparticle delivery of miRNAs to inhibit GBM stem cells [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 5449. doi:10.1158/1538-7445.AM2017-5449
Abstract 1652: Optogenetic immunoengineering to develop improved anti-cancer immunotherapy
Authors: Lian He, Nhung Nguyen, Gang Han, Yun Huang, Yubin Zhou
Journal: Cancer Research (2017)

Abstract The application of current channelrhodopsin-based optogenetic tools is limited by the lack of strict ion selectivity and the inability to extend the spectra sensitivity into the near-infrared (NIR) tissue transmissible range. Here we present an NIR-stimulable optogenetic platform (termed “Opto-CRAC”) that selectively and remotely controls Ca2+ oscillations and Ca2+-responsive gene expression to regulate the function of model cellular systems, as well as cells of the immune system. When coupled to upconversion nanoparticles, the optogenetic operation window is shifted from the visible range to NIR wavelengths to enable wireless and remote photoactivation of Ca2+-dependent signaling and optogenetic modulation of immunoinflammatory responses. In a mouse model of melanoma by using ovalbumin as surrogate tumor antigen, Opto-CRAC has been shown to act as a genetically-encoded “photoactivatable adjuvant” to improve antigen-specific immune responses to specifically destruct tumor cells. In addition, we have extended similar engineering approaches to photomanipulate membrane contact sites that play critical roles in controlling lipid metabolism and calcium signaling in cancer cells. Our study represents a solid step forward towards the goal of improving spatial and temporal control of anti-cancer therapy through optogenetic immunoengineering. Note: This abstract was not presented at the meeting. Citation Format: Lian He, Nhung Nguyen, Gang Han, Yun Huang, Yubin Zhou. Optogenetic immunoengineering to develop improved anti-cancer immunotherapy [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 1652. doi:10.1158/1538-7445.AM2017-1652
Abstract 5488: APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL
Authors: Zhaodong Li, Brian Abraham, Alla Berezovskaya, Nadine Farah, Yu Liu, Theresa Leon, Adele Fielding, Shi Hao Tan, Takaomi Sanda, Abraham Weintraub, Benshang Li, Shuhong Shen, Jinghui Zhang, Marc Mansour, Richard Young, Thomas Look
Journal: Cancer Research (2017)

Abstract Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells resulting in clonal selection. Although most cancer causing mutations have been detected in the protein-coding regions of the cancer genome, driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention. Here we report a C-to-T single nucleotide transition that occurs as a somatic mutation in noncoding sequences 4 kb upstream of the transcriptional start site of the LMO1 oncogene in primary samples from patients with T-cell acute lymphoblastic leukaemia. This single nucleotide alteration conforms to an APOBEC-like cytidine deaminase mutational signature, and generates a new binding site for the MYB transcription factor, leading to the formation of an aberrant transcriptional enhancer complex that drives high levels of expression of the LMO1 oncogene. Since APOBEC-signature mutations are common in a broad spectrum of human cancers, we suggest that noncoding nucleotide transitions such as the one described here may activate potent oncogenic enhancers not only in T-lymphoid cells but in other cell lineages as well. Citation Format: Zhaodong Li, Brian Abraham, Alla Berezovskaya, Nadine Farah, Yu Liu, Theresa Leon, Adele Fielding, Shi Hao Tan, Takaomi Sanda, Abraham Weintraub, Benshang Li, Shuhong Shen, Jinghui Zhang, Marc Mansour, Richard Young, Thomas Look. APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL [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 5488. doi:10.1158/1538-7445.AM2017-5488
Abstract 2708: A custom gene expression panel for consensus molecular subtype classification of archival primary and metastatic colorectal cancers
Authors: Ling-Yuh Huw, Robert Piskol, Felipe de Sosa e Melo, Doris Kim, Xueping Qu, Hartmut Koeppen, Mark Lackner, Garret Hampton, Omar Kabbarah, Rachel Tam
Journal: Cancer Research (2017)

Abstract Stratification of Colorectal Cancer (CRC) into actionable molecular subtypes has tremendous clinical value. Recently, a consolidated classifier identified four molecularly distinct CRC subtypes (CMS1-4) that were associated with unique biology and clinical outcomes based on global transcriptional analysis of frozen tissues. Here, we developed and applied a novel CRC panel that is ideally suited for transcriptional classification of archival clinical samples. Findings from in silico analysis demonstrated that the 800 genes on our panel could accurately classify CRC samples from external public datasets into the correct CMS subtypes. We applied our panel in the analysis of a novel cohort of 312 formalin-fixed paraffin-embedded (FFPE) tissues from 205 patients, and were able to detect all 4 CMS subtypes in primary CRCs and in metastases. When we examined the CMS subtypes of primary tumors and matched metastases from 50 patients we found 70% of cases to be concordant, as were key biologies, such as WNT/MYC pathway activation in CMS2 and EMT features in tumors of the CMS4 subtypes. This was confirmed by in situ hybridization (ISH) using the markers ASCL2 for CMS2 and SPARC for CMS4, respectively. Discordance in the CMS subtypes between primary tumors and matched metastases were observed in 30% of cases and may reflect tumor heterogeneity. Our findings suggest that our CRC-focused panel many have clinical utility for CMS classification of FFPE samples, and point to potential risks of using CMS subtypes of primary tumors to inform clinical decision-making at the metastatic stage in a subset of patients. Citation Format: Ling-Yuh Huw, Robert Piskol, Felipe de Sosa e Melo, Doris Kim, Xueping Qu, Hartmut Koeppen, Mark Lackner, Garret Hampton, Omar Kabbarah, Rachel Tam. A custom gene expression panel for consensus molecular subtype classification of archival primary and metastatic colorectal 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 2708. doi:10.1158/1538-7445.AM2017-2708
Abstract 3051: Mechanism of early dissemination and metastasis in Her2+ mammary cancer
Authors: Kathryn Harper, Maria Soledad Sosa, David Entenberg, Hedayatollah Hosseini, Julie Cheung, Rita Nobre, Alvaro Avivar-Valderas, Chandandaneep Nagi, Nomeda Girnius, Roger Davis, Eduardo Farias, John Condeelis, Christoph A. Klein, Julio A. Aguirre-Ghiso
Journal: Cancer Research (2017)

Abstract Metastasis is the leading cause of cancer related deaths and these lesions develop from disseminated cancer cells (DCC) that can remain dormant. Metastasis initiating cells are thought to originate from a subpopulation present in progressed invasive tumors. However, DCCs detected in patients before the manifestation of breast cancer metastasis contain fewer genetic abnormalities than primary tumors or than DCCs from patients with metastases. These findings and those in pancreatic cancer and melanoma models argued that dissemination might occur during early stages of tumor evolution. Yet, the mechanisms that might allow early-disseminated cancer cells (eDCC) to complete all steps of metastasis were unknown. Here we show that in early lesions (EL), before any overt primary tumor (PT) masses are detected, there is a sub-population of Her2+/P-p38lo/P-ATF2lo/TWISThi/E-cadherinlo early cancer cells that are invasive and disseminate to target organs. Intra-vital imaging and organoid studies of early lesions revealed that Her2+ eDCC precursors locally invaded, intravasated and lodged in target organs. Her2+ eDCCs activated a Wnt-dependent EMT-like dissemination program but without complete loss of epithelial phenotype that was reversed by Her2 or Wnt inhibition. Surprisingly, while the majority of eDCCs are TWISThi/E-cadherinlo and dormant, they eventually initiate metastasis. Our work identifies a mechanism for early dissemination whereby Her2 aberrantly activates a program similar to mammary ductal branching that spawns eDCCs capable of forming metastasis after a dormancy phase. Citation Format: Kathryn Harper, Maria Soledad Sosa, David Entenberg, Hedayatollah Hosseini, Julie Cheung, Rita Nobre, Alvaro Avivar-Valderas, Chandandaneep Nagi, Nomeda Girnius, Roger Davis, Eduardo Farias, John Condeelis, Christoph A. Klein, Julio A. Aguirre-Ghiso. Mechanism of early dissemination and metastasis in Her2+ mammary 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 3051. doi:10.1158/1538-7445.AM2017-3051
Abstract LB-007: Leveraging spatial heterogeneity in tumor purity for improved somatic variant calling of archival tumor-only samples
Authors: Rebecca F. Halperin, Winnie S. Liang, Erica Tassone, Jonathan Adkins, Megan Russell, Nhan Tran, Nicole Hank, James Newell, Sandeep Gupta, Michael Berens, Ronald Korn, David W. Craig, Sara A. Byron
Journal: Cancer Research (2017)

Abstract Archival tumor samples present a rich resource of annotated specimens for genomics research. However, standard variant calling approaches require a matched normal sample from the same individual, which is often not available with archival tissue. Without a matched normal sample, it is very difficult to distinguish between true somatic variants and germline variants that are private to the individual. Archival FFPE sections often contain adjacent normal tissue, but this normal tissue is often contaminated with infiltrating tumor cells. Comparative somatic variant callers are designed to exclude variants present in the normal sample, so a novel approach is required to leverage sequencing of adjacent normal tissue. Here we present LumosVar 2.0, a software package designed to jointly analyze multiple samples from the same patient. The approach is based on the concept that the allelic fraction of somatic variants, but not germline variants, would be diluted by the presence of normal tissue. Given the allele specific copy number state and expected tumor fraction of each sample, one can model the expected allelic fractions of somatic and germline variants. LumosVar estimates allele specific copy number and tumor sample fractions from the data, and uses the model to call somatic and germline variants. LumosVar is also able to detect sub clonal events and spatial heterogeneity between samples. To evaluate this approach, we used a glioblastoma dataset, where enhancing (high tumor content) and non-enhancing (low tumor content) samples were available for each patient, as well as the matched normal sample to define the true somatic variants. We show that both sensitivity and positive predictive value are improved by analyzing the high tumor and low tumor jointly compared to analyzing the samples individually or in silico pooling of the two samples. Finally, we apply this approach to a set of breast and prostate archival FFPE tumor samples where normal samples were not available for germline sequencing. Citation Format: Rebecca F. Halperin, Winnie S. Liang, Erica Tassone, Jonathan Adkins, Megan Russell, Nhan Tran, Nicole Hank, James Newell, Sandeep Gupta, Michael Berens, Ronald Korn, David W. Craig, Sara A. Byron. Leveraging spatial heterogeneity in tumor purity for improved somatic variant calling of archival tumor-only samples [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-007. doi:10.1158/1538-7445.AM2017-LB-007
Abstract 3883: Transcriptome analysis reveals mitochondrial gene signature upregulation in gastric cancers expressing the stem cell marker CD133
Authors: Han Hong Lee, Yoon Ho Ko, Tae-Min Kim, Won-Sang Park
Journal: Cancer Research (2017)

Abstract Gastric cancers expressing the stem cell marker CD133 are more aggressive than those that do not express the marker, and are associated with more unfavorable clinical outcomes. The CD133-associated aggressive behavior of gastric cancer remains poorly understood at the molecular level. In the present study, we performed gene expression profiling of bead-sorted CD133+ and CD133- KATO III cell lines to derive in vitro molecular signatures of CD133 expression in gastric cancer. Three expression signatures associated with CD133 expression ('Mitochondria', 'Cell cycle', and 'Lipid metabolism') were inferred upon study of a module association map of the key molecular signatures associated with CD133 expression in gastric cancer. Using the public gene expression profiles, we show that the patients with overexpression of CD133 show unfavorable clinical outcomes compared to CD133- patients in the context of up-regulation of 'Mitochondria' expression signature. We further showed that CD133+ KATO III cells had a higher mitochondrial function and were more susceptible to the mitochondrial inhibitors rotenone, antimycin A, and NaN3, than were CD133- cells. Together, our findings suggest that transcriptional up-regulation of the 'Mitochondria' gene signature may identify CD133+ gastric cancers; such data are of clinical and pharmacological relevance. Note: This abstract was not presented at the meeting. Citation Format: Han Hong Lee, Yoon Ho Ko, Tae-Min Kim, Won-Sang Park. Transcriptome analysis reveals mitochondrial gene signature upregulation in gastric cancers expressing the stem cell marker CD133 [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 3883. doi:10.1158/1538-7445.AM2017-3883