tbuckley/cabot-search huggingface dataset:
Spi-B–Mediated Silencing of Claudin-2 Promotes Early Dissemination of Lung Cancer Cells from Primary Tumors
Authors: Wei Du, Xing Xu, Qing Niu, Xuexi Zhang, Yiliang Wei, Ziqiao Wang, Wei Zhang, Jun Yan, Yongxin Ru, Zheng Fu, Xiaobo Li, Yuan Jiang, Zhenyi Ma, Zhenfa Zhang, Zhi Yao, Zhe Liu
Journal: Cancer Research (2017)

Dissociation from epithelial sheets and invasion through the surrounding stroma are critical early events during epithelial cancer metastasis. Here we find that a lymphocyte lineage-restricted transcription factor, Spi-B, is frequently expressed in human lung cancer tissues. The Spi-B-expressing cancer cells coexpressed vimentin but repressed E-cadherin and exhibited invasive behavior. Increased Spi-B expression was associated with tumor grade, lymphatic metastasis, and short overall survival. Mechanistically, Spi-B disrupted intercellular junctions and enhanced invasiveness by reconfiguring the chromatin structure of the tight junction gene claudin-2 (CLDN2) and repressing its transcription. These data suggest that Spi-B participates in mesenchymal invasion, linking epithelial cancer metastasis with a lymphatic transcriptional program. Cancer Res; 77(18); 4809-22. ©2017 AACR.
Abstract 941: CXCL1-CXCR2 signaling might recruit the bone marrow-derived mesenchymal cells to the carcinoma-associated fibroblasts of gastric cancer
Authors: Masakazu Yashiro, Tomohisa Okuno, Hiroaki Kasashima, Yuichiro Miki, Hirohisa Nakamae, Kisyu Kitayama, Toshiyuki Kawashima, Takaharu Hatano, Heishiro Fujikawa, Tsuyoshi Hasegawa, Takahiko Nakane, Masayuki Hino, Kosei Hirakawa, Masaichi Ohira
Journal: Cancer Research (2017)

Abstract Background &amp; Aims: Activated fibroblasts in the tumor stroma, also termed carcinoma-associated fibroblasts (CAFs), play a critical role in the progression of cancer. In our previous studies, we identified CAFs as playing an important role in cancer progression in the development of gastric cancer. However, it remains unclear which factor recruit and promote CAFs. The aim of this study is to clarify from where CAFs originate and which factor recruits them into the gastric cancer microenvironment. Methods: In vitro study analyzed the chemotaxis-stimulating factor from gastric cancer cells using bone marrow-derived mesenchymal cells (BM-MCs). The nude mice with bone marrow transplantation from CAG-EGFP mice were used for the in vivo gastric cancer experiments. The influences of chemokine (C-X-C motif) receptor 2 (CXCR2) inhibitor on the migration of BM-MCs were examined in vitro and in vivo. Results: BM-MCs migrated into tumor stroma of in vivo gastric cancer. The number of BM-MCs was much greater in the gastric tumor than in normal tissue from three days after inoculation of cancer cells. C-X-C motif ligand 1 (CXCL1) from gastric cancer cells significantly (p&amp;lt;0.001) stimulated the chemoattractant ability of BM-MCs in vitro. Anti-CXCL1 antibody and CXCR2 inhibitor significantly (p&amp;lt;0.05) decreased the migration-stimulating activity of gastric cancer cells. A CXCR2 inhibitor, SB225002, decreased tumor size and lymph node metastasis of gastric tumor, and significantly (p=0.039) prolonged survival of gastric-tumor bearing mice. The histologic findings indicated that SB225002 decreased the recruitment of BM-MCs into the tumor stroma, resulting in the reduction of CAFs. Conclusions: BM-MSCs recruit into gastric tumor and differentiate into CAFs. CXCL1 from gastric cancer cells stimulates the recruitment of BM-MCs into gastric cancer locus via CXCR2 signalling. Inhibition of BM-MCs’ recruitment appears a promising therapy for gastric cancer. Citation Format: Masakazu Yashiro, Tomohisa Okuno, Hiroaki Kasashima, Yuichiro Miki, Hirohisa Nakamae, Kisyu Kitayama, Toshiyuki Kawashima, Takaharu Hatano, Heishiro Fujikawa, Tsuyoshi Hasegawa, Takahiko Nakane, Masayuki Hino, Kosei Hirakawa, Masaichi Ohira. CXCL1-CXCR2 signaling might recruit the bone marrow-derived mesenchymal cells to the carcinoma-associated fibroblasts of gastric 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 941. doi:10.1158/1538-7445.AM2017-941
Abstract 76: Synthetic lethal targeting of <i>BRCA</i> mutant tumors with antibody linked pyrrolobenzodiazepine dimers
Authors: Haihong Zhong, Ravinder Tammali, Cui Chen, Christine Fazenbaker, Kennedy Maureen, Noel Monks, Jay Harper, Ronald Herbst, Dave Tice
Journal: Cancer Research (2017)

Abstract Pyrrolbenzodiazepine dimers (PBDs) are amongst the most potent DNA alkylating agents, with activity against a broad spectrum of tumors. PBDs form cross-links within the minor groove of DNA causing double strand breaks (DSB). DNA repair genes such as BRCA1 and BRCA2 play important roles in homologous recombination repair (HRR) of DSB. Cells defective in BRCA1 or BRCA2 are known to be sensitive to DNA interstrand crosslinks. Accordingly, it is possible that PBD-based ADCs will have enhanced killing of cells (synthetic lethality) in which HR processes are defective by inactivation of BRCA1 or BRCA2 genes in breast, ovarian and other cancers. To determine anti-tumor activity of PBD dimers, we have used MEDI0641, PBD-dimer conjugated to anti-5T4 antibody, against BRCA wild type and mutant xenograft tumor models. MEDI0641 was &amp;gt;3-fold more potent in BRCA1 or BRCA2 mutant models than in wild-type xenografts. Similar observations were seen in 25 patient-derived xenograft (PDX) models (19 breast and 6 ovarian) bearing mutations in BRCA1 or BRCA2 (blinded to 5T4 expression) treated with MEDI0641. Out of a total of 25 PDX models, 17 models had tumor regression with a single administration of MEDI0641 at 0.3 mg/kg (response rate = 68%), and 14 models showed response to 0.1 mg/kg of MEDI0641 (response rate = 56%). In BRCA wild-type PDX models, a higher dose of 1 mg/kg was required to achieve full anti-tumor efficacy. Retrospective analysis of 5T4 expression in PDX tumors demonstrated no correlation between efficacy and target expression in BRCA mutant PDX models. To further delineate the role of BRCA1/2 mutations in determining sensitivity to PBD, we used siRNA knock-down of both BRCA1 and BRCA2 in the DNA repair wild type HeLa cells. Knockdown of BRCA genes sensitized Hela cells to PBD payload and MEDI0641 in vitro. Anti-tumor activity of MEDI0641 was further examined in isogenic BRCA2 knockout xenograft models. Genetic deletion of BRCA2 markedly increased anti-tumor activity of MEDI0641. In conclusion, PBD based ADCs may have improved therapeutic window in cancer patients with somatic BRCA mutations. Citation Format: Haihong Zhong, Ravinder Tammali, Cui Chen, Christine Fazenbaker, Kennedy Maureen, Noel Monks, Jay Harper, Ronald Herbst, Dave Tice. Synthetic lethal targeting of BRCA mutant tumors with antibody linked pyrrolobenzodiazepine dimers [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 76. doi:10.1158/1538-7445.AM2017-76
Abstract 2829: Identification of transcriptomic signatures of organotropism in pancreatic cancer metastasis
Authors: Yi Zhong, Jun Fan, Jinlong Huang, Christine A. Iacobuzio-Donahue
Journal: Cancer Research (2017)

Abstract Metastatic disease is the most common cause of death in pancreatic ductal adenocarcinoma (PDA) patients. The most common sites of metastatic spread of PDA are to the liver, lung, and peritoneum. The acquisition of advanced stage PDA tissue samples has greatly improved our descriptive understanding of pancreatic cancer metastasis; however, important aspects of PDA metastatic cell biology remain poorly understood. We have previously shown that distant metastases arise from genetically evolved subclones within the primary site of PDA. To understand the biologic basis of PDA metastatic subclone formation we established a transgenic mouse model of PDA based on heterozygous inactivation of Tgfbr2 in association with p48-Cre mediated activation of mutant Kras and Trp53 alleles (KPTC mice). This model revealed that metastatic efficiency and organotropism are related but independently controlled phenomena by mutant Trp53 gain of function in association with TGFb signaling. Pertubation of TGFb signaling reduced liver but not lung metastasis due to a profound extravasation deficiency characterized by sinusoidal growth and lack of desmoplastic stroma compared to KPC mice. Analogous findings were confirmed in liver samples from patients indicating their clinical relevance. Portal vein colonization as a direct mode of access to the liver was observed in both mice and humans. To better understand the cell- autonomous features that promote organ specific metastasis, we have established cell lines from primary and metastatic PDAs of KPC mice representing five different target organ sites (liver, lung, peritoneum, omentum, lymph node). RNAseq and WGCNA performed on extracted RNA from these established cell lines indicate gene expression modules that are unique to metastases. Among metastases, gene expression modules have also been identified that are unique to local versus distant metastases. Analyses are ongoing to functionally validate these modules in additional samples of mouse and human PDA. These findings establish a novel paradigm for understanding pancreatic cancer metastasis and the observed clinical latencies of liver versus lung metastases specifically. Identification of cell-autonomous and micro-environmental mechanisms that support PDA organotropism have the potential to reveal novel targets for therapeutic intervention and modulation of the lethal metastatic phenotype. Citation Format: Yi Zhong, Jun Fan, Jinlong Huang, Christine A. Iacobuzio-Donahue. Identification of transcriptomic signatures of organotropism in pancreatic cancer metastasis [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 2829. doi:10.1158/1538-7445.AM2017-2829
Abstract 1739: Analysis of EML4-ALK fusion transcripts in plasma and platelets to monitor response to crizotinib in EML4-ALK positive non-small cell lung cancer patients (NSCLC)
Authors: Cristina Aguado, Cristina Teixido, Ana Gimenez-Capitan, Maria de los Llanos Gil, Sonia Rodriguez, Santiago Viteri, Niki Karachaliou, Erika Aldeguer, Vicente Peg, Lidia Alonso, Miguel Angel Molina-Vila, Rafael Rosell
Journal: Cancer Research (2017)

Abstract Background: Rearrangements in anaplastic lymphoma kinase (ALK) gene can be detected in 5-7% of EGFR and KRAS wild-type advanced NSCLC patients (p). Fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) are currently used for screening but are unable to identify the specific fusion partner and are unpractical to monitor clinical responses due to difficulty of obtaining rebiopsies. The RT-PCR technique has the potential to overcome this pitfall and allow patient monitorization in blood. Methods: A total of 405 formalin-fixed paraffin-embedded (FFPE) samples from advanced NSCLC were analyzed by ALK IHC (Ventana D5F3) and FISH (Vysis). Positive patients were confirmed by RT-PCR and submitted to Sanger in order to identify the variant. In a subset of 36 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, fusion transcripts were analyzed by RT-PCR in mRNA purified from plasma and platelets and correlated with clinical response. Results: ALK IHC was analyzed in 405 NSCLC patients and 37 tested positive (9.1%) whereas 25 (7.7%) were identify as translocated by FISH (n=323). ALK fusion transcripts were analyzed by RT-PCR and a new fusion variant of ALK was identified. A total of 36 p benefited from crizotinib treatment, including the p with the new variant. Monitoring of EML4-ALK fusion transcripts in the plasma ad platelets of 35 ALK positive patients revealed a good correlation with clinical outcome to crizotinib treatment, with the fusion transcripts becoming undetectable in p with good clinical responses. Conclusions: Analysis of ALK fusion transcripts in mRNA purified from plasma and platelets can have a value in patients with no biopsy available and to monitor the course of the disease. Citation Format: Cristina Aguado, Cristina Teixido, Ana Gimenez-Capitan, Maria de los Llanos Gil, Sonia Rodriguez, Santiago Viteri, Niki Karachaliou, Erika Aldeguer, Vicente Peg, Lidia Alonso, Miguel Angel Molina-Vila, Rafael Rosell. Analysis of EML4-ALK fusion transcripts in plasma and platelets to monitor response to crizotinib in EML4-ALK positive non-small cell lung cancer patients (NSCLC) [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 1739. doi:10.1158/1538-7445.AM2017-1739
Abstract 533: XIAP BIR domain suppresses miR-200a expression and subsequently promotes EGFR protein translation and anchorage-independent growth of bladder cancer cell
Authors: Xin Liao, Chao Huang, Jingxia Li, Chuanshu Huang
Journal: Cancer Research (2017)

Abstract The X-linked inhibitor of apoptosis protein (XIAP) is a well-known potent apoptosis suppressor, and also participates in cancer cell biological behaviors, therefore attracting great attentions as a potential antineoplastic therapeutic target for past years. We found here that lacking of XIAP expression resulted in a remarkable suppression of EGFR expression, consequently leading to the deficient of anchorage-independent cell growth. Further study demonstrated that BIR domain of XIAP was crucial for regulating the EGFR translation by suppressing the transcription and expression of miR-200a. Mechanistic studies indicated that BIR domain activated the PP2A activity by decreasing the phosphorylation of PP2A at Tyr307 in its catalytic subunit, PP2A-C. Such activated PP2A prevented the deviant phosphorylation and activation of MAPK kinases/MAPKs, their downstream effector c-Jun, and in turn inhibiting transcription of c-Jun-regulated the miR-200a. Collectively, our study uncovered a novel function of BIR domain of XIAP in regulating the EGFR translation, providing significant insight into the understanding of the XIAP overexpression in the cancer development and progression, further offering a new theoretical support for using XIAP BIR domain and EGFR as targets for cancer therapy. Citation Format: Xin Liao, Chao Huang, Jingxia Li, Chuanshu Huang. XIAP BIR domain suppresses miR-200a expression and subsequently promotes EGFR protein translation and anchorage-independent growth of bladder cancer cell [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 533. doi:10.1158/1538-7445.AM2017-533
Abstract 4928: Impact of <i>E. hirae</i> on the tumoricidal activity of cyclophosphamide
Authors: Romain Daillere, Marie Vetizou, Laurence Zitvogel
Journal: Cancer Research (2017)

Abstract The tumor microenvironment is influenced by anticancer therapies, and even more so by those affecting the gut homeostasis. We previously reported that a deviated repertoire of the intestinal microbiome called « dysbiosis », caused by broad spectrum antibiotics compromised the efficacy of cyclophosphamide (CTX), an immunomodulatory alkylating agent exerting cytotoxic effects against cancer, highlighting the importance of the gut microbiota in this mechanism (Viaud, Science, 2013). CTX is responsible for disrupting the gut barrier integrity as well as intestinal homeostasis, allowing a NOD2-dependent translocation of several Gram-positive bacteria into secondary lymphoid organs. CTX breaks the intestinal tolerance towards the intestinal microbiota and leads to immunization of the host against some bacterial strains. Here, we identified a Gram positive bacteria, Enterococcus hirae, which markedly modulates the intestinal and systemic immunity through the elicitation of bacterial-specific Th1 and pathogenic Th17 cells. Moreover, we have shown that E. hirae is capable of enhancing tumor-specific CD4+ and CD8+ T cell responses against candidate tumor antigens. In parallel, we have demonstrated that intestinal epithelial cells NOD2 receptors represent ‘‘gut immune checkpoints’’ restricting the immunogenicity of E. hirae. Finally, E. hirae specific-memory Th1 immune responses selectively predicted longer progression-free survival in advanced lung or ovarian cancer patients treated with immunotherapy and chemotherapy (platinum salts- or CTX-based chemotherapy) (Daillère, Immunity, 2016). Altogether, E. hirae represents a valuable probiotic against cancer, an oncomicrobiotic ameliorating the efficacy of the most common alkylating immunomodulatory compound. Citation Format: Romain Daillere, Marie Vetizou, Laurence Zitvogel. Impact of E. hirae on the tumoricidal activity of cyclophosphamide [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 4928. doi:10.1158/1538-7445.AM2017-4928
Abstract 1655: Organotypic 3D models to characterize the molecular requirements for NK and T-cell infiltration
Authors: Wolfgang Sommergruber, Annika Osswald, Viola Hedrich, Marta Majewska, Helmut Dolznig
Journal: Cancer Research (2017)

Abstract Multiple studies have demonstrated that the presence of tumor infiltrating lymphocytes is strongly correlated with increased survival. However, the level of infiltration within a specific tumor entity and between various tumor types varies widely. Increasing the degree of lymphocyte infiltration in a tumor represents an innovative drug concept. Organotypic 3D models consisting of tumor spheroids, stromal fibroblasts and Natural Killer (NK) or T-cells could represent valuable models to appropriately model infiltration and establish novel therapeutic concepts in the area of immune-oncology. As a first step in the development of a model for lymphocyte infiltration, the cytotoxicity and infiltration of human NK cells in 3D tumor spheroids were analyzed. Different NK cell lines and primary NK cells had a toxic effect on 3D tumor spheroids upon co-culture. Cryosections of co-cultured tumor spheroids showed infiltrated NK cells inside tumor spheroids. Infiltrated NK cells recovered from tumor spheroids were characterized by flow cytometry. Results showed that a higher infiltration correlates with cytotoxicity on tumor spheroids and transcriptomes of infiltrated vs. non infiltrated NK cells differ substantially. IL-12 stimulation increased the killing effect of NK cells on tumor spheroids, inducing higher expression of Perforin, IFNγ and GranzymeB levels. 3D tumor spheroids were embedded in a Matrigel/Collagen mixture with fibroblasts and the effect of compounds on NK cell infiltration was monitored. It was demonstrated that not only IL-12 increased NK cell infiltration, but also several compounds. Moreover, encapsulated 3D models with different cell types (tumor cells, fibroblasts, NK or T-cells) were established at a bioreactor scale to mimic the in vivo situation of complex tumor tissues. We could demonstrate NK and T-cell infiltration into these encapsulated 3D tumor spheroids. These encapsulated model systems permit long-term cultures to study the effect of compounds and/or NK or T-cells on later stages of tumorigenesis. In conclusion, this study demonstrates that organotypic 3D models are a valuable tool for the analysis of the molecular mechanisms that regulate lymphocyte infiltration into tumors. Citation Format: Wolfgang Sommergruber, Annika Osswald, Viola Hedrich, Marta Majewska, Helmut Dolznig. Organotypic 3D models to characterize the molecular requirements for NK and T-cell infiltration [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 1655. doi:10.1158/1538-7445.AM2017-1655
Implementation of WHO package of essential non-communicable disease interventions in the occupied Palestinian territory: assessment of patient perceptions to changes in quality of care with participatory ranking methods
Authors: Nadim Barghouthi, Ramez Dweakat, Yaser Bouziyeh, Reem Abu-Hijleh, Ilhama Shamasnah, Asad Ramlawi, Wendy Venter
Journal: The Lancet (2017)
Abstract 5650: Enhancement of CAR-T cell activity via PD-1 knockdown by self-deliverable RNAi
Authors: Alexey Wolfson, Alexey Eliseev, Taisia Shmushkovich, Monica Betancur-Boissel, Monica Betancur-Boissel, Nathalie Scholler
Journal: Cancer Research (2017)

Abstract Background: A growing body of evidence indicates that the blockade of PD-1 and other immunosuppressive receptors can increase the efficacy of adoptively transferred cells in immunotherapy for cancer. The expression of PD-1 can be suppressed by ex vivo treatment of transferred lymphocytes by self-deliverable RNAi (sd-rxRNA®) compounds. sd-rxRNAs are based on proprietary chemical modifications of siRNA compounds making them stable to nuclease degradation and capable of penetration into target cells without the use of transfection reagents or physical methods. Aim: To determine whether the reduction of PD-1 by ex vivo treatment of mesothelin-targeting CAR-T cells with sd-rxRNA will improve the efficacy of meso-CAR-T cells in a mouse model of ovarian cancer. Methods: Second-generation human CAR-T cells expressing P4 antibody fragments targeting mesothelin (meso-CAR-T) were treated ex vivo with PD-78, a self-deliverable siRNA silencing the PD-1 gene. The meso-CAR-T cells were then injected into tumors in a xenograft mouse model of human ovarian cancer (A1847 cell line expressing mesothelin and PD-L1) in NSG mice. The tumor volumes were monitored over the course of one month. After the animals were sacrificed, human CD45-containing cells extracted from the tumor were analyzed for PD-1 expression by flow cytometry. Results: We observed a statistically significant reduction in tumor growth in the group of mice injected with meso-CAR-T cells pretreated ex vivo with PD-78. The post-mortem tumor analysis by flow cytometry showed that the expression of PD-1 in meso-CAR-T cells was significantly suppressed for the full duration of the experiment (one month). Conclusion: Our results suggest that the silencing of immunosuppressive genes by ex vivo treatment with sd-rxRNA may improve efficacy of CAR-T cells in the treatment of solid tumors. A similar approach may be applied to other types of adoptive cell transfer. Citation Format: Alexey Wolfson, Alexey Eliseev, Taisia Shmushkovich, Monica Betancur-Boissel, Monica Betancur-Boissel, Nathalie Scholler. Enhancement of CAR-T cell activity via PD-1 knockdown by self-deliverable RNAi [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 5650. doi:10.1158/1538-7445.AM2017-5650