bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1124: Wnt-producing niche cells support cancer stem-like cells in pancreatic ductal adenocarcinoma
Authors: Wu Katherine , Grbovic-Huezo Olivera , Hartmann Griffin , Jacks Tyler , Tammela Tuomas 
Published: August 2018

Abstract
Despite modern advances in cancer therapy, the prognosis for pancreatic ductal adenocarcinoma (PDAC) remains dismal, highlighting the need for better understanding of the biologic underpinnings of the disease. Well established as a pathway for growth and regeneration, Wnt signaling maintains subpopulations of cancer cells in a stem-like state, contributing to the heterogeneous composition of tumors. Our previous work demonstrated that Porcupine, an essential enzyme for secretion of paracrine Wnt signals, can be used to mark Wnt-producing cells in normal and tumor tissues. We detected the presence of nuclear beta-catenin, a biomarker of active Wnt-signaling, in a subpopulation of cancer cells adjacent to Porcupine+ niche cells in murine PDAC tissue. Furthermore, genetic inactivation of Porcupine translated to a 25% increase in survival in PDAC-bearing mice. In vitro, we see a marked increase in spheroid formation and proliferation of the stem-like subpopulation over the rest of the primary tumor cells. Ongoing lineage-tracing experiments in an autochthonous murine model of PDAC will determine whether these cancer stem cells are able to produce their Wnt-secreting niche in vivo. Our current efforts are focused on the preclinical evaluation of Wnt inhibitors in the treatment of mouse and human PDAC as single agents or in combination with chemotherapy. Such findings open the door for interrogation of the Wnt pathway as a possible target for improving the clinical outcome of pancreatic cancer.
Citation Format: Katherine Wu, Olivera Grbovic-Huezo, Griffin Hartmann, Tyler Jacks, Tuomas Tammela. Wnt-producing niche cells support cancer stem-like cells in pancreatic ductal adenocarcinoma [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 1124.
Abstract 113: Gemcitabine treatment induces immunosuppressive microenvironment in pancreatic cancer by promoting the infiltration, growth, and polarization of macrophages
Authors: Deshmukh Sachin Kumar , Bhardwaj Arun , Tyagi Nikhil , Khan Mohammad Aslam , Srivastava Sanjeev K. , AL-Ghadhban Ahmed , Dugger Kari , Carter James E. , Singh Ajay P. , Singh Seema 
Published: August 2018

Abstract
Resistance to chemotherapeutic drugs remains a major cause of therapeutic failure in pancreatic cancer (PC) patients. Efficacy of chemotherapy is further limited by its debilitating effects on immune system. Apart from genetic abnormalities in tumor cells, the tumor immune- microenvironment plays a crucial role in PC chemoresistance. However, it is unclear how chemotherapy affects the cancer immunity or how it affects the tumor microenvironment (TME). In the present study, we demonstrate gemcitabine induces an increased infiltration of CD68+ M2 macrophages in pancreatic tumors isolated from an orthotopic xenograft murine model. Moreover, the conditioned media from PC cell lines cultured with gemcitabine (Gem-CM) promotes migration, invasion, and growth of RAW264.7 macrophage. Interestingly, Gem-CM induces an upregulation of tumor-associated or M2-polarized macrophage markers, arginase-1 and TGF-β1. Additionally, gemcitabine treatment of PC cell lines induces the expression of M2-polarization associated cytokines, growth factors and chemokines, including IL-8. IL-8 exhibits the greatest upregulation after culture with Gemcitabine. Further, IL-8 neutralization in Gem-CM diminished its ability to induce growth, migration, and invasion of RAW264.7 macrophages. Together, these findings suggest an indirect effect of gemcitabine on increasing macrophage trafficking and M2-polarization that potentially supports a pro-tumor microenvironment. These actions may contribute to the chemoresistance of PC. Prevention of gemcitabine-induced macrophage infiltration, growth and M2-polarization will offer a better strategy to counter chemotherapy-induced immunosuppression in PC.
Citation Format: Sachin Kumar Deshmukh, Arun Bhardwaj, Nikhil Tyagi, Mohammad Aslam Khan, Sanjeev K. Srivastava, Ahmed AL-Ghadhban, Kari Dugger, James E. Carter, Ajay P. Singh, Seema Singh. Gemcitabine treatment induces immunosuppressive microenvironment in pancreatic cancer by promoting the infiltration, growth, and polarization of macrophages [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 113.
Abstract 1132: PAX6 drives cancer cells toward a stem like state via GLI-SOX2 signaling axis in lung adenocarcinoma
Authors: Oki Akira , Hoque Mohammad O. 
Published: August 2018

Abstract
PAX6 is an essential transcription factor for embryonic stem cell maintenance, but its contribution to lung cancer stem cells (CSCs) remains unexplored. We demonstrate that PAX6 acts as an oncogene responsible for induction of cancer stemness properties and plays a biological role in tumor initiation and CSC expansion in lung adenocarcinoma (LUAD). Mechanistically, PAX6 activates Hedgehog-GLI signaling in a SMO-independent noncanonical manner, resulting in SOX2 upregulation directly by the binding of GLI to the proximal promoter region of the SOX2 gene. The overexpressed SOX2 enhances the expression of key pluripotent factors (OCT4 and NANOG) and suppresses differentiation lineage factors (HOPX and NKX2-1). Thus, PAX6 drives cancer cells toward a stem-like state via the GLI-SOX2 signaling axis in LUAD. In contrast, in the differentiated non-CSCs that represent most of the tumor cell population, PAX6 is transcriptionally silenced by its promoter methylation. In human lung cancer tissues, the positive linear correlations of PAX6 expression with GLI and SOX2 expression and its negative correlations with HOPX and NKX2-1 expression were observed. Therapeutically, the blockade of the PAX6-GLI-SOX2 signaling axis elicits a long-lasting therapeutic efficacy by limiting CSC expansion following chemotherapy. Our findings provide a rationale for targeting the PAX6-GLI-SOX2 signaling axis with chemotherapy as an effective therapeutic strategy.
Citation Format: Akira Oki, Mohammad O. Hoque. PAX6 drives cancer cells toward a stem like state via GLI-SOX2 signaling axis in lung adenocarcinoma [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 1132.
Abstract 1135: SOX9 regulates cancer stem-like cells and chemotherapy response in non-small cell lung cancer
Authors: Voronkova Maria , Luanpitpong Sudjit , Rojanasakul Yon 
Published: August 2018

Abstract
Lung cancer is the leading cause of cancer-related death worldwide in both men and women. A major limitation of the lung cancer chemotherapy effectiveness is drug resistance and tumor relapse, which both have been attributed to the acquisition of cancer stem-like cells (CSCs). Thus, it is crucial to identify specific markers and drug targets for this cell population. Our work is focused on the embryonic transcription factor SOX9, which has been implicated in CSC regulation in a number of cancer types, but little is known about its role in non-small cell lung cancer (NSCLC), the predominant type of lung cancer. In addition, the regulatory mechanisms and downstream targets of SOX9 as well as its role in chemoresistance are largely unknown. We hypothesized that SOX9 plays a key role in lung cancer progression and chemoresistance by stimulating cancer stem-like properties. To test this hypothesis, we genetically manipulated SOX9 expression in various NSCLC cell lines and evaluated its effects on CSC formation, biomarkers expression, and drug resistance. Our results showed that SOX9 depletion decreases the number of tumor spheres formed by NSCLC cells, thus supporting its role in CSC regulation in lung cancer. We also showed that SOX9 depletion dramatically downregulates the expression of a functional CSC regulator ALDH1A1. Consistent with this finding, SOX9 overexpression in non-cancer lung epithelial cells promotes tumor sphere formation. Moreover, we noticed that SOX9 expression goes up in response to chemotherapy exposure. Notably, SOX9 knockdown increases cell sensitivity to the chemotherapeutic cisplatin, whereas SOX9 overexpression decreases it. Depletion of SOX9 also increases CSC sensitivity to cisplatin, as demonstrated by the tumor sphere formation assay. Analysis of the Cancer Genome Atlas (TCGA) data showed that high SOX9 expression correlates with poor survival in NSCLC patients. Taken together, our results indicate the essential role of SOX9 in the regulation of CSCs in NSCLC. Since CSCs are a key driver of chemoresistance and relapse, our findings may have important implications in the development of novel therapeutic strategies for chemoresistant and recurrent lung cancer.
Citation Format: Maria Voronkova, Sudjit Luanpitpong, Yon Rojanasakul. SOX9 regulates cancer stem-like cells and chemotherapy response in non-small cell lung cancer [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 1135.
Abstract 1137: ANO1 confers the maintenance of stemness and radioresistance in glioma stem cells by stabilizing EGFRvIII
Authors: Lee Dae-Hee , Kim Hee-Jin , Kim Jeong-Yub , Park Jea-Yong , Park Myung-Jin 
Published: August 2018

Abstract
Anoctamin-1 (ANO1), also known as TMEM16A, is a Ca2+-activated chloride channel known to mediate a number of physiologic functions such as mediating acute and chronic pain and regulating blood vessels and airway smooth muscle. In particular, ANO1 expression is amplified in a variety of cancers, and overexpression of ANO1 is not favorable for clinical prognosis. Previous studies have reported that ANO1 is associated with tumorigenesis, proliferation, migration, and invasion of cancer cells, but the mechanism is not clear yet. In this study, we examined role of ANO1 in the maintenance of stemness and radio-resistance in glioma stem cells (GSCs). Knockdown of ANO1 with shRNA and treatment of ANO1 specific inhibitors (CaCCAo1 and TAO1) suppressed the expression of Notch intracellular domain, Nestin and EGFRvIII and decreased self-renewal activity and invasion in GSCs. Suppression of ANO1 increased radiation sensitivity by inducing ROS-mediated GSCs death. However, inhibition of chloride channel activity, the main function of ANO1, was found to be unaffected in this event. Interestingly, we found that ANO1 retained stemness by direct binding to EGFRvIII, which is specifically expressed in GSCs, and that the chaperone property of ANO1 function may affect the stability of EGFRvIII. In intracranial mouse model of GSCs, knockdown of ANO1 increased the survival rate of mice by suppressing tumor formation. Taken together, we suggest that ANO1 is a crucial molecule involved in the maintenance of stemness and radiation resistance in GSCs and may be a good therapeutic target for treating glioblastoma.
Citation Format: Dae-Hee Lee, Hee-Jin Kim, Jeong-Yub Kim, Jea-Yong Park, Myung-Jin Park. ANO1 confers the maintenance of stemness and radioresistance in glioma stem cells by stabilizing EGFRvIII [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 1137.
Abstract 1141: A novel regulatory gene subnetwork of glioma stem-like cells
Authors: Deng Changwang , Le Son B. , Tran David D. 
Published: August 2018

Abstract
Glioblastoma (GBM) is the most common and deadliest malignant brain tumor in adults. GBM is enriched in glioma stem-like cells (GSCs) that contribute to tumor initiation and treatment resistance and thus a natural focus for therapeutic development. However, targeting GSCs has been a challenge because of a lack of master regulators specific to GSCs and not to normal brain cells. Therefore, systematic identification of the GSC-specific common regulatory program will improve our understanding of GSCs and provide an opportunity to develop GSC-specific therapeutics that are efficacious and safe. To accomplish these objectives, we have recently developed two innovative tandem computational platforms, GeneRep and nSCORE, which were subsequently experimentally validated. The tandem platforms complement each other and allow us to 1) interrogate large-scale gene expression profiles of GSCs, GBM-differentiated cells, normal neuronal precursor cells (NPCs) and astrocytes (NAs) to extract candidate GSC-specific gene regulatory networks; and 2) functionally rank GSC-specific core master regulators, respectively. A cluster of 8 interrelated master subnetworks emerged, which were functionally grouped into the stemness and cancer pathways, some of which belonged to the Sox, Olig and Myc families. By enforcing the expression of this cluster in NAs, we were able to reprogram these normal cells into GSCs as measured by the neurosphere formation and in vivo tumorigenesis assays, confirming the critical requirement of this cluster for the GSC identity. Furthermore, this network cluster was present and functioned cooperatively to maintain GSCs in several patient-derived GSC lines examined to date. Survival and neurosphere formation rates of GSCs were profoundly suppressed when at least two nodes in this cluster were depleted by siRNA compared to depletion of the individual nodes. Our data establish a novel gene regulatory cluster controlling GSCs and provide a compelling rationale for its therapeutic targeting to reduce tumor recurrence.
Citation Format: Changwang Deng, Son B. Le, David D. Tran. A novel regulatory gene subnetwork of glioma stem-like cells [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 1141.
Abstract 1142: STK31 contributes to lung carcinogenesis through induction of stemness and resistance to EGFR-TKI therapy
Authors: Lau Eunice Yuen-Ting , Chin Isabella Kit-Nam , Fong Alvin Hong-Wai , Ma Victor Wan-San , Cho William Chi-Shing 
Published: August 2018

Abstract
Lung adenocarcinoma (LUAD), the most common histological subtype of lung cancer, remains one of the leading causes of cancer-related deaths worldwide. With improving knowledge in the molecular aberrations underlying lung carcinogenesis, a large number of targeted therapies are being developed to better patient's survival. EGFR-activating mutations are one of the most frequent genetic alterations in advanced lung adenocarcinoma, and patients harbouring certain types of EGFR activating mutation confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Despite promising initial responses, majority of patients develop resistance to treatment and the mechanism of resistance remains unknown in up to 30% of patients. Recent studies revealed that cancer stem cells (CSCs) endowed with stem cell-like properties confer resistance to EGFR-TKI treatment. Identification of pathways maintaining stemness properties potentially provide novel drug targets to overcome treatment resistance. Protein phosphorylation is the most common form of reversible post-translational modification and is frequently involved in the deregulation of signal transductions associated with cancer development and progression. In this study, we have identified Serine/Threonine Kinase 31 (STK31) to be upregulated in enriched lung CSC populations, as well as in the erlotinib resistant derivatives from two LUAD cell lines. Through analysing The Cancer Genome Atlas (TCGA) data, mRNA expression of STK31 is observed to be higher in LUAD tumor when compared with paired normal tissues (p&lt;0.001). High mRNA expression of STK31 was also found to be associated with poorer disease-free survival (p=0.0324) and overall survival (p=0.0012) in LUAD patients. Functional studies using shRNA based knockdown of STK31 in lung cancer cell lines revealed its regulatory role on cancer and stem cell-like properties in vitro and in vivo including tumorigenicity, self-renewal, drug resistance and metastasis. Repressing the expression of STK31 in erlotinib resistant cells re-sensitized the cells to drug treatment. Further studies will be done to delineate the downstream mechanism by which STK31 regulates lung CSCs and erlotinib resistance.
Citation Format: Eunice Yuen-Ting Lau, Isabella Kit-Nam Chin, Alvin Hong-Wai Fong, Victor Wan-San Ma, William Chi-Shing Cho. STK31 contributes to lung carcinogenesis through induction of stemness and resistance to EGFR-TKI therapy [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 1142.
Abstract 1151: A unique layered 3D stromal tissue model for in vitro evaluation of immunologic agents and immune cell infiltration into cancer microenvironment
Authors: Morimura Rii , Tsukamoto Kei , Kitano Shiro , Shinozaki Eiji 
Published: August 2018

Abstract
Background; The modulation of the immune system is a proven key target for cancer therapy, however, the complex interplay between immune cells and cancer cells in cancer microenvironment remains only partially understood. In addition, the currently available in vitro cancer microenvironment models are not designed to study the immunologic agents and a role of immune cells. Here, we developed a unique layered 3D stromal tissue model comprising an allogeneic immune, stromal and cancer cells.
Method; Human umbilical vein endothelial cells (HUVEC) and normal human dermal fibroblasts (NHDF) were coated with collagen and heparin to construct Extracellular matrix (ECM) nanofilm and cultured to form multi-layers. Lung cancer cells were placed between stromal cells. Furthermore, we added Peripheral Blood Mononuclear Cell (PBMC) and Programmed cell death 1 (PD-1) blockade with Nivolumab and evaluated cytotoxic effects of immune cells on cancer cells and immune cell infiltration by immunohistochemistry.
Result; The co-cultured stromal tissues were multi-layered (approximately 20 layers), and the presence of lung cancer cells between stromal cells was observed. Immunohistochemistry revealed CD8 positive immune cell infiltration into the fibroblast layers. PBMC with Nivolumab treatment significantly decreased the viability of lung cancer cells in this 3D co-culture compared with the results in 2D mono-culture. High level of programmed cell death ligand 1 (PD-L1) expression on lung cancer cell lines correlated with a higher response to PD-1 blockade in vitro as well as clinical trials.
Conclusion; In summary, we present a unique 3D cell culture system based on an allogeneic stromal/cancer/immune cell setting to study immunologic agents and immune cell infiltration in cancer microenvironment. This 3D model has the ability to reflect in vivo conditions closer than 2D model and provide a tool for in vitro immunologic agent testing.
Citation Format: Rii Morimura, Kei Tsukamoto, Shiro Kitano, Eiji Shinozaki. A unique layered 3D stromal tissue model for in vitro evaluation of immunologic agents and immune cell infiltration into cancer microenvironment [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 1151.
Abstract 1152: Therapeutic response to PD1/PDL1 axis in a disseminated C1498 syngeneic tumor model
Authors: Mahajan Vivek , Bui Thi , Belle Ian , Wood Edgar , Usher Lindsay , Rainbolt Elizabeth , Kidder Shasta , Synnott Aidan , Harris David 
Published: August 2018

Abstract
The majority of the leukemia cases are diagnosed in adults, of which, acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) are the most common subtypes. Treatment options include chemotherapy, stem cell transplantation and more recently the use of checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 to enhance antitumor responses. In this study we developed a disseminated AML disease model using PD-L1+, C1498 tumor cells to evaluate the therapeutic response to immune checkpoint inhibitors, PD-1, PD-L1 and CTLA-4 and to examine the effect of treatment on infiltration of immune cell populations in selected tissues. C1498 cells were transduced with a lentivirus vector construct containing luciferase and GFP reporter genes. Upon establishment of a clonal population with stable reporter expression, C1498-GFP-Luc expressing cells were implanted intravenously into syngeneic albino C57BL/6 mice and growth of the leukemic tumor cells was monitored via in vivo bioluminescence imaging (BLI) using IVIS Spectrum CT®. In vehicle-treated animals tumor growth was progressive and most animals reached endpoint within 30 days. Luciferase expression was widespread with metastatic development in peripheral organs and tissues. An efficacious response to therapy directed against the PD-1/PD-L1 axis was observed, with anti-PD-L1 showing greater overall efficacy than anti-PD-1. Combination of either PD-1/PD-L1 with anti-CTLA-4 further improved the therapeutic efficacy as measured by prolonged survival and reduced tumor growth. To gain mechanistic insights into how these immunotherapies function in suppressing tumor growth we performed additional studies utilizing flow cytometry and immunohistochemistry to assess the composition and phenotype of immune cell infiltrates in hematological and non-hematological tissues. In summary, comprehensive immunological characterization of the C1498 model revealed the importance of PD1 / PD-L1 pathway in immune evasion and provides a rationale for therapeutic intervention with checkpoint blockade.
Citation Format: Vivek Mahajan, Thi Bui, Ian Belle, Edgar Wood, Lindsay Usher, Elizabeth Rainbolt, Shasta Kidder, Aidan Synnott, David Harris. Therapeutic response to PD1/PDL1 axis in a disseminated C1498 syngeneic tumor model [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 1152.