bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2120: Inhibition of multiple myeloma exosomes prevents bone loss and reduces tumor growth
Authors: Faict Sylvia T. , Veirman Kim De , Maes Ken , Bruyne Elke De , Heusschen Roy , Caers Jo , Vanderkerken Karin , Schots Rik , Menu Eline 
Published: August 2018

Abstract
Multiple myeloma, one of the most common hematological malignancies, will often manifest osteolytic lesions during disease development, throughout the whole body. MM is still considered an incurable malignancy, with a supportive micro-environment in the bone marrow. Extracellular vesicles such as exosomes are known to play an important tumor-promoting role in this micro-environment, by inducing angiogenesis and immune suppression. The aim of our study was to examine the effects of MM exosomes on osteolysis in vitro and in vivo, and to determine whether inhibition of exosome secretion can lead to a delay in tumor growth and prevent bone loss. We used the 5TGM1 model which is a syngeneic murine MM model, presenting typical MM characteristics such as osteolysis, angiogenesis and a serum M-spike. We examined the effects of conditioned medium from these MM cells and MM-derived exosomes on cell viability and proliferation of the MC3T3 pre-osteoblast cell line and on their ability to produce alkaline phosphatase (ALP). We saw a decrease in viability and ALP activity when adding exosomes or conditioned medium of the 5TGM1 myeloma cells to the osteoblasts. Moreover, RT-PCR analysis showed a decrease of various osteogenic differentiation genes when osteoblasts were exposed to 5TGM1 exosomes, demonstrating a diminished capacity of osteoblastic differentiation. We next added the exosome secretion inhibitor GW4869 to the 5TGM1 cells, thereby reducing the number of exosomes in the conditioned medium. This was confirmed through western blot of the typical exosome markers. The negative effects of the 5TGM1 conditioned medium on osteoblasts could be overturned by reducing the exosome content therein. In vivo, we injected 5TGM1 exosomes intravenously in healthy mice for three weeks and examined the effects on osteolysis by microCT and TRAP staining. We saw an increase in osteolysis, comparable to the typical osteolytic lesions in tumor-bearing mice. Furthermore, when inhibiting the exosome secretion in vivo in 5TGM1 mice, we observed a significant reduction in tumor load. Through this study we can conclude that exosomes from multiple myeloma cells can induce osteolytic lesions by inhibiting osteoblast proliferation and differentiation. These effects can be reversed by inhibiting the secretion of exosomes.
Citation Format: Sylvia T. Faict, Kim De Veirman, Ken Maes, Elke De Bruyne, Roy Heusschen, Jo Caers, Karin Vanderkerken, Rik Schots, Eline Menu. Inhibition of multiple myeloma exosomes prevents bone loss and reduces tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2120.
Abstract 2125: Cancer-associated fibroblasts-stimulated IL-11 promotes metastasis of gastric cancer cells mediated by upregulation of MUC1
Authors: Wang Xiaoxun , Che Xiaofang , Bai Ming , Fan Yibo , Liu Yunpeng , qu xiujuan 
Published: August 2018

Abstract
Background: Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma and regulators of tumor progression. However, the molecular mechanism by which CAFs promote gastric cancer progression should be further explored.
Methods: Mouse model was used to certify that CAFs could promote peritoneal metastasis of gastric cancer cells. The expression of interleukin-11 (IL-11) was analyzed in two gastric cancer cell lines by real-time RT-PCR and ELISA. The role of IL-11 in gastric cancer cell migration and invasion explored by Transwell. Western blotting was conducted to detect the activation of STAT3 and ERK signaling pathway.
Results: In our study, we reveal that when CAFs co-cultured with gastric cancer cells secreted significant amounts of IL-11. CAFs promote the ability of migration and invasion through the production of IL-11 by stimulating JAK/STAT3 and MAPK/ERK pathways to upregulate MUC1 in gastric cancer cells. On the other hand, when IL-11 was deprived using a neutralizing antibody or inhibition of JAK/STAT3 and MAPK/ERK pathways with specific inhibitors, Stattic and PD-98059, markedly attenuated these CAFs-induced phenotypes in gastric cancer cells.
Conclusions: Taken together, these results revealed that CAFs play a significant role in the gastric cancer progression in the tumor microenvironment through IL-11-STAT3/ERK signaling by upregulating MUC1. Also, IL-11 targeted therapy can achieve an effective treatment against gastric cancer indirectly by exerting their action on stromal fibroblasts.
Citation Format: Xiaoxun Wang, Xiaofang Che, Ming Bai, Yibo Fan, Yunpeng Liu, xiujuan qu. Cancer-associated fibroblasts-stimulated IL-11 promotes metastasis of gastric cancer cells mediated by upregulation of MUC1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2125.
Abstract 2130: Novel ADAM9 variant induces prostate cancer metastasis
Authors: Hsieh Chia-Ling , Sung Shian-Ying 
Published: August 2018

Abstract
Prostate cancer often progresses from an androgen to castration-refractory prostate cancer and metastasizes to the bone and lymph nodes. However, there is no biomarker to predict the initiation of cancer metastasis. Therefore, it is an unmet need to understand molecules which induce metastasis to replace the prediction by PSA. Previous studies by us demonstrate the elevation of ADAM9 in PCa malignant progression. However, the role of ADAM9 in the tumor microenvironment is still not fully understood. Using laser capture microdissection of prostate tumor and stromal cells, indicating the increased of ADAM9 and reactive oxygen species in tumor-associated stromal cells. These inductions correlated with the increased expression of SOD-2 in tumor-associated stromal cells. Both electron microscope analysis and conditioned medium of stromal cells demonstrated the increased of soluble ADAM9 level in the medium. ELISA analysis of patient serum confirmed the increased of ADAM9 serum levels in prostate cancer patients. PCR and sequencing analysis confirmed a novel soluble ADAM9 (sADAM9v2) with deletion of membrane domain that induces cell migration through the activation of FAK and AKT phosphorylation. Our studies demonstrated the release of sADAM9 in tumor microenvironment correlated with reactive oxygen stress and regulate prostate cancer migration and metastasis. In conclusion, our studies showed that sADAM9 release by cancer-associated stromal cells could be a potential biomarker for prostate cancer progression.
Citation Format: Chia-Ling Hsieh, Shian-Ying Sung. Novel ADAM9 variant induces prostate cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2130.
Abstract 2134: IL6 and CXCL8 mediate redundant, targetable tumor-host interactions that drive osteosarcoma lung metastasis
Authors: Roberts Ryan D. , Cam Hakan , Brandolini Laura , Hinckley John M. , Gross Amy C. 
Published: August 2018

Abstract
Osteosarcoma (OS) kills patients through aggressive metastatic spread, primarily to lung tissues. Our lab has sought to understand the tumor-host interactions that facilitate growth of OS cells specifically within the lung. We previously identified two intercellular signaling molecules, IL6 and CXCL8, which exhibit enhanced expression when primary tumors become lung metastases. Here, we show that epigenetic changes drive aberrant expression of ΔNp63, endowing OS cells with the capacity to colonize lung tissue. IL6 and CXCL8 serve as downstream mediators induced directly by ΔNp63 and necessary for survival and proliferation within the lung. Inhibition of IL6 and CXCL8 signaling has no direct effect on the proliferation of OS cells, but IL6 inhibition has a profound effect on their ability to form colonies in soft agar. In preclinical mouse models of OS, inhibitors of IL6 and CXCL8 signaling profoundly impair the ability of OS cells to colonize lung tissue, completely preventing metastasis in some models. Co-culture studies suggest that strong paracrine interactions with bronchial epithelial and smooth muscle cells, but not macrophages or lung fibroblasts, drive increased expression of IL6 and CXCL8. These data suggest a mechanism where aberrant ΔNp63 expression within developing OS tumors generates subsets of tumor cells endowed with increased IL6 and CXCL8 expression. This triggers feed-forward paracrine loops with bronchial epithelial and smooth muscle cells that facilitate growth and survival within the lung, leading to metastasis.
Citation Format: Ryan D. Roberts, Hakan Cam, Laura Brandolini, John M. Hinckley, Amy C. Gross. IL6 and CXCL8 mediate redundant, targetable tumor-host interactions that drive osteosarcoma lung metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2134.
Abstract 214: Genetic and transcriptional instability alters cell line drug response
Authors: Ben-David Uri , Siranosian Ben , Ha Gavin , Tang Helen , Lyons Nicholas J. , Burns Robert , Nag Anwesha , Cimini Beth , Tsvetkov Peter , Tubelli Andrew A. , Wong Bang , Thorner Aaron R. , Bittker Joshua , Meyerson Matthew , Beroukhim Rameen , Golub Todd R. 
Published: August 2018

Abstract
Inconsistencies in cell line-based studies jeopardize reproducibility of cancer research. Natural evolution leading to genetic and transcriptional heterogeneity within cancer cell lines may contribute to such inconsistencies. To systematically test this hypothesis, we performed comprehensive genetic and transcriptomic characterization of 27 strains of the common breast cancer cell line MCF7, and then assessed the response of those strains to 321 anti-cancer compounds. We found extensive variation in genomic profiles and responses to small molecules across strains. Genetic variation occurred at all levels – point mutations, rearrangements, and copy number changes – and affected multiple oncogenes and tumor suppressor genes. Similar findings were obtained across 23 strains of the lung cancer cell line A549, indicating that such variation is a general property of cancer cell lines. These changes resulted in substantial differences in gene expression programs, cell morphology and proliferation, and strikingly high variability in drug response. Over 75% of the compounds that exhibited strong activity in some of the strains, were completely inactive in other strains. These results indicate that genomic variation within commonly used cancer cell lines is extensive, resulting in disparate drug responses. Such variation may contribute to difficulties in conducting reproducible cell line-based studies.
Citation Format: Uri Ben-David, Ben Siranosian, Gavin Ha, Helen Tang, Nicholas J. Lyons, Robert Burns, Anwesha Nag, Beth Cimini, Peter Tsvetkov, Andrew A. Tubelli, Bang Wong, Aaron R. Thorner, Joshua Bittker, Matthew Meyerson, Rameen Beroukhim, Todd R. Golub. Genetic and transcriptional instability alters cell line drug response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 214.
Abstract 2143: IL-6 mediated signaling regulates cytotoxic effect of Burkitt lymphoma cells by combined treatment of Danusertib and BKM120
Authors: Liu Jun , Ahn Kwang-Sung , Hong Jun-Shik , Yoon Sung-Soo 
Published: August 2018

Abstract
Even though Burkitt Lymphoma is relative has a good response to combined treatment, some part of outcome of chemotherapy is very poor. One of the obstacles is the chemoresistance due to several cytokines which are released from stromal cells. The effects of either Danusertib or BKM120 on Namalwa and BJAB, respectively, were different. On Namalwa the IC 50 of Danusertib was 24.64 µM (72 h) and BKM120 was 12.44 µM (72h). On BJAB the IC 50 of Danusertib was 6.63 µM (72h) and BKM120 was 1.42 µM (72h). But in the combined treatment, we found that BJAB showed less sensitive than Namalwa, the IC 50 on Namalwa was Danusertib 8.33 µM+ BKM120 2.08 µM (72h) and on BJAB was Danusertib 20.36 µM+ BKM120 5.09 µM (72h). To figure out the resistant pattern of these two cell lines we performed 3 steps treatment with 16 µM Danusertib and 4 µM BKM120, every step we culture 1.5×105/mL cells in 24hours first, and then treated with combined inhibitors 48 hours. We found that although Namalwa was sensitive to combined treatment at the first step, it was more easily to become resistant to combined treatment. To confirm the resistant pattern, co-culture system was used to identify what kinds of cytokines are involving in the chemoresistance of Burkitt lymphoma. We found that IL-6 was induced with stromal cell including inflammatory cytokines when cells were co-cultured with stromal cells. Also, IL-6 mediated signaling pathway such as JAK/STATIL-6 and AKT pathway, was activated by IL-6 and sIL-6. We suggest that IL-6 mediated signaling could mediate signaling regulates cytotoxic effect of Burkitt lymphoma cells by combined treatment of Danusertib and BKM120 as well as inflammatory effects may regulate the response of chemotherapeutic treatment.
Citation Format: Jun Liu, Kwang-Sung Ahn, Jun-Shik Hong, Sung-Soo Yoon. IL-6 mediated signaling regulates cytotoxic effect of Burkitt lymphoma cells by combined treatment of Danusertib and BKM120 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2143.
Abstract 2155: Modeling therapeutic response in BRAF V600-mutant melanoma using patient-derived xenografts
Authors: Feng Tianshu , Golji Javad , Li Ailing , Zhang Xiamei , Ruddy David , Stuart Darrin , Meyer Matthew 
Published: August 2018

Abstract
Approximately 50% of metastatic melanoma harbor oncogenic mutations of BRAF, resulting in constitutive activation of the MAPK signaling pathway. Treatment using BRAF and MEK inhibitor combination significantly improved survival in patients with BRAF V600-mutant melanoma. However, the duration of response remains limited as most patients develop resistance. Previously, our group established a collection of patient derived xenografts (PDXs), and conducted a PDX clinical trial using a 1x1x1 experimental design. The PDX clinical trial showed that BRAF V600-mutant melanoma models varied in their response to BRAF and MEK inhibitors, similar to observations in the clinical setting. Therefore, we sought to elucidate the mechanisms governing differential responses to MAPK inhibition in vivo. The PDX models were classified into complete and partial responders based on their sensitivity to BRAF and MEK inhibitors. Using this classification, we characterized the downstream signaling associated with therapeutic response. Whereas complete responders showed almost full suppression of MAPK signaling, partial responders showed heterogeneous levels of MAPK signaling upon BRAF and MEK inhibition. Ongoing work seeks to identify determinants of therapeutic response using biased and unbiased approaches, in an effort to inform combination strategies that improve survival in patients with BRAF V600-mutant melanoma.
Citation Format: Tianshu Feng, Javad Golji, Ailing Li, Xiamei Zhang, David Ruddy, Darrin Stuart, Matthew Meyer. Modeling therapeutic response in BRAF V600-mutant melanoma using patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2155.
Abstract 2167: Efficacy assessment of BTK inhibitor ibrutinib in de novo and viral-induced B cell lymphoma
Authors: Wang Jessie Jingjing , Zheng Meiling , Huang Xuesong , Song Yanrui , Qian Wubin , Zhang Likun , Cai Jie , Guo Sheng , Li Henry Qixiang , Ouyang Davy Xuesong 
Published: August 2018

Abstract
Bruton's tyrosine kinase (BTK) is crucial for B cell maturation. Its activation has also been considered as a major oncogenic driver for various B cell-derived lymphoid cancers. A BTK inhibitor, Ibrutinib, has been approved for mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia, a form of non-Hodgkin's lymphoma (NHL). Ibrutinib has also shown encouraging efficacies in defuse large B cell lymphoma (DLBCL), specifically in activated B cell-like (ABC) subtype, but not in germinal center B cell-like (GCB) subtype. We have established a series of patient derived xenograft (PDX) models, recapitulating diverse genotypes of de novo DLBCL patients, including two MYD88L265P/CD79BY197N double mutants (LY2298, LY2264), one MYD88L265P single mutant (LY0257), and a variety of wild-types (LY2214, LY3604, and LY6934, etc.). This cohort of PDX models serve as perfect preclinical tools to investigate Ibrutinib responses in different genotypes. Our studies demonstrated a moderate to robust efficacies of Ibrutinib in the MYD88/CD79B double mutants, suggesting that CD79B mutation is the predictive biomarker for chronic activation of B cell receptor (BCR) signaling, as well as generally good responses to BTK inhibitor. Interestingly, the MYD88 single mutant model LY0257, where the disease is likely driven by constitutive activation of MYD88 signaling, also showed response to Ibrutinib when dosed in drinking water. In the wild type PDXs, two of seven models tested so far are either partially responsive or sensitive to Ibrutinib, while the others are resistant to the treatment. It seems that Ibrutinib response does not always require CD79B mutation, and BCR pathway addiction may occur by other means in DLBCL, even when MYD88 signaling is constitutively active. Notably, all 5 wild type DLBCL PDXs that are non-responsive to Ibrutinib are EBV positive verified by RNAseq. These EBV-transformed B lymphoma PDX models, which share the similar histopathology as de novo DLBCL, but have distinct molecular pathology signatures and different pathogenesis. In efficacy studies, none of the transformed B lymphoma PDXs showed response to Ibrutinib. Taken together, our DLBCL and EBV-induced lymphoma PDX models provide a valuable preclinical platform for evaluating BTK inhibitors, as well as future drug discovery efforts on other targets in the BCR and MYD88 pathways, such as PI3K, SYK, and IRAK4.
Citation Format: Jessie Jingjing Wang, Meiling Zheng, Xuesong Huang, Yanrui Song, Wubin Qian, Likun Zhang, Jie Cai, Sheng Guo, Henry Qixiang Li, Davy Xuesong Ouyang. Efficacy assessment of BTK inhibitor ibrutinib in de novo and viral-induced B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2167.
Abstract 2170: Single mouse preclinical trial: A tool for translational research
Authors: Mignard C , boisferon M Hillairet de , Bichat F , France D , Duchamp O 
Published: August 2018

Abstract
Roughly, 85% of preclinical agents entering oncology clinical trials fail to demonstrate sufficient safety or efficacy to gain regulatory approval. Hence, there is a need for experimental systems which better mimic the inter-patient response heterogeneity observed in the clinic. Patient-derived tumor xenograft (PDX) mouse models have emerged as a relevant oncology research tool to study tumor evolution, drug response, biomarkers, resistance phenomenon and adjusting chemotherapeutic approaches for individual patients. We will here expose the effectiveness of the single mouse preclinical trial paradigm for evaluating drug response, as mono or combo therapy using our well-characterized PDX collection. Based on the “1 PDX tumor/1 mouse/1 treatment” experimental design, a cohort of colorectal, breast, pancreas, lungs PDX models (minimum 20 of each) was used to explore response to Standard Of Care (SOC) and combo therapy used in clinic. We compared single-animal response data with treatment group data taken from historical experiments. We demonstrated that about &gt;80% of the individual response matched the treatment group data, supporting the idea of using one single animal to predict the drug response. The response of each PDX to treatment was correlated to their histological and genetic profiles. This approach represents a new experimental design to address the tumor biology of cancer patients, and investigate targeted therapies in relevant mouse models, which could improve our ability to predict clinical trial responses, stratify patients for clinical trial, identify drug resistance mechanism, responsive sub-populations as well as biomarker. By combining genomic profiling data and drug screening data, and clinical data from patients, SMPT process is a helpful tool for precision cancer medicine and individualized drug selection.
Citation Format: C Mignard, M Hillairet de boisferon, F Bichat, D France, O Duchamp. Single mouse preclinical trial: A tool for translational research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2170.