bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5039: SCD1/FADS2 and ferroptosis signalings orchestrate ovarian cancer cell metabolism and metastatic progression in peritoneal metastases
Authors: Xuan Yang , Yung Mingo MH , Chen Arvin FS , Ngan Hextan YS , Chan David W 
Published: September 2020

Abstract
Peritoneal metastases are common and usually associated with poor prognosis in advanced ovarian cancers. Emerging evidence indicates that the ascites microenvironment provides a key reservoir of growth factors and free fatty acids for promoting metastatic recurrence and chemoresistance of ovarian cancers. However, how the metastatic ovarian cancer cells adapt and utilize such a unique tumor microenvironment remains elusive. Here, we report that ovarian cancer cells co-cultured in ascites or omental conditioned medium (OCM) enhance their oncogenic capacities through elevated lipid metabolism. RNA sequencing (RNA-seq) and lipidomic profiling analyses revealed two key mediators of UFAs, Stearoyl-CoA Desaturase-1 (SCD1) and Fatty acid Desaturase-2 (FADS2) were upregulated accompanied with the accumulation of poly- and mono-unsaturated fatty acids (UFAs) in ovarian cancer cells co-cultured in OCM. Enforced expression of either SCD1 or FADS2 promotes cancer stemness, in vitro and ex vivo tumor colony formation, and cell migration/invasion through activation of NFκB signaling. SCD1/FADS2 increases not only UFAs accumulation but also the cell membrane fluidity which is crucial for the epithelial-mesenchymal transition (EMT) and metastatic potentials. On the other hand, RNA-Seq analysis on SCD1/FADS2-depleted ovarian cancer cells showed the ferroptotic activities were inversely correlated with SCD1/FADS2. Of note, either knockout of SCD1/FADS2 or co-treatment of Erastin could enhance cisplatin-induced cytotoxicity through the elevation of iron-mediated reactive oxygen species (ROS), and subsequently led ferroptosis by upregulation of GPX4/xCT expressions in ovarian cancer cells. Higher tumorigenic capacity expressed in iron-rich ovarian cancer cells, which contains sphere formation, EMT potential and cell viability. Taken together, SCD1/FADS2 and ferroptosis signaling pathways orchestrate the metabolic activities, ROS stresses and cellular iron homeostasis during the metastatic progression of ovarian cancer cells in peritoneum microenvironment. Hence, targeting these signaling cascades by the drug cocktail/combination strategy could reduce the risk of metastatic recurrence and chemoresistance in advanced ovarian cancers.
Citation Format: Yang Xuan, Mingo MH Yung, Arvin FS Chen, Hextan YS Ngan, David W Chan. SCD1/FADS2 and ferroptosis signalings orchestrate ovarian cancer cell metabolism and metastatic progression in peritoneal metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5039.
Abstract 504: p27 transcriptionally coregulates STAT3 to drive cancer stem cells
Authors: Razavipour Seyedehfatemeh , Jang Kibeom , Yoon Hyunho , Kim Minsoon , Shin Miyoung , Zhao Dekuang , Slingerland Joyce 
Published: September 2020

Abstract
p27 is a cell cycle inhibitor and a tumor suppressor. It can also regulate cellular processes including migration and transcription through mechanisms independent of its CDK-inhibitory role. In cancers, p27 C-terminal phosphorylation by PI3K-activated kinases, AKT, RSK1, and SGK1 at T157 and T198 alters p27 protein-protein interactions and shifts p27 from CDK-inhibitor to an oncogene. Previously, our group showed that CDK-binding defective p27pT157pT198 phosphomimetic (p27CK-DD) upregulates epithelial-mesenchymal transition (EMT) and the metastatic potential of cancer cell lines. In addition to its action to promote EMT, p27 appears to promote CSC expansion and or maintenance. Here we demonstrated that C-terminally phosphorylated p27 increases CSC properties, including tumor sphere formation and CSC markers. p27CK-DD increases the expression of several embryonic stem cell transcription factors (ES-TFs), including SOX2, NANOG and cMYC, which are known to drive embryonic stem cell self-renewal and to promote CSC expansion. A human phospho-kinase array showed Pyk2 is activated by p27CK-DD. We demonstrated that Pyk2 activation and its binding to p27 are dependent on phosphorylation of p27 at T198 and T157. Treatment with a Pyk2 inhibitor, and PYK2-knockdown by siRNA or shRNA revealed that Pyk2 is a key mediator of the increase in tumor spheres, ALDH1 activity and ES-TFs in cancer cells expressing abundant C-terminally phosphorylated p27. Pyk2 enhances STAT3 phosphorylation and activation. We identified that C-terminally phosphorylated p27 recruits STAT3 to form p27-Pyk2-STAT3 complex leading to STAT3 activation. p27/STAT3 complexes co-localize to the nucleus and co-occupy chromatin. We confirmed by ChIP-qPCR that p27/STAT3 bind and activate the cMYC promotor. Altogether, in breast cancer cells with high p27pT157pT198 or expressing p27CK−DD, STAT3 is partly activated by Pyk2 and interacts with p27. p27 is a STAT3 coregulator, whose assembly and chromatin association is governed by p27 phosphorylation. These data reveal a novel mechanism whereby p27-driven Pyk2 activation promotes CSC expansion and tumor progression via transcriptionally activation of the STAT3 and its target genes.
Citation Format: Seyedehfatemeh Razavipour, Kibeom Jang, Hyunho Yoon, Minsoon Kim, Miyoung Shin, Dekuang Zhao, Joyce Slingerland. p27 transcriptionally coregulates STAT3 to drive cancer stem cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 504.
Abstract 5045: Predictive factors for successful growth of patient derived xenograft (PDX)
Authors: Hernandez Tatiana , Baños Natalia , Bonilla Victoria , del Puerto Laura , Doger Bernard , Garcia-Foncillas Jesus , Wick Michael , Moreno Victor 
Published: September 2020

Abstract
Background: PDXs have become a core component of translational cancer research. Developing these models can become challenging since little is known about which factors influence engraftment rates. We sought to determine which clinical, pathological or molecular factors may predict a higher chance of success for PDX development.
Methods: Between March 2017 and August 2019, biopsies obtained from patients with primary or metastatic cancer were implanted into athymic nude mice. Statistical analyses were performed to identify factors that could correlate with final engraftment defined as tumor volume of 150 mm3 in at least three consecutive measurements. We focus on clinical (patient factors) pathological (tumor sample) and molecular characteristics (tumor sample). Information regarding sampling process was also analyzed.
Results: 440 tumor samples were collected and implanted. 15 failed due lack of tumor cells. Of 425 tumor-positive samples, 143 PDXs achieved successful growth at time of analysis. The following clinical characteristics were correlated with engraftment success: systemic steroid administration within 2 weeks of sampling (45.5% (30/66) within the steroids-receiving group achieved growth vs 31% (113/359) no-steroids) (p: 0.027). High neutrophils/lymphocytes (NLR) ratio (&gt;5) (42.3% (47/111) of tumors with NLR&gt;5 achieved growth vs 30% (96/313) in the NLR&lt;5 group; P:0,018). Regarding pathological tumor characteristics, higher ki67 levels were correlated with better engraftment rates (Low (Ki67&lt;15%): 10% (5/46) vs. Medium (Ki67:15-30%): 25% (7/28) and high (Ki67&gt;30%): 34% (16/47) (p:0.029). The presence of mucinous cells (signet ring cells) was also correlated with higher chance of tumor engraftment (50% (19) vs. 32% (124/387) (p: 0.022). Negativity for estrogen receptors could also be a positive predictive marker (14% (8/57) of ER+ achieved growth vs 46.7% (7/15) ER negative (p: 0.011). Lastly, sampling source (either primary of metastatic tumors) was not correlated with successful growth.
Conclusions: tumors with higher Ki67, mucinous features and ER expression negative have higher chance of PDX development. Some clinical characteristics can also interfere with PDXs development such as use of steroids or NLR.
Citation Format: Tatiana Hernandez, Natalia Baños, Victoria Bonilla, Laura del Puerto, Bernard Doger, Jesus Garcia-Foncillas, Michael Wick, Victor Moreno. Predictive factors for successful growth of patient derived xenograft (PDX) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5045.
Abstract 5066: Investigating the role of IL-6 to modulate the immunosuppressive tumor microenvironment of EGFR mutant NSCLC
Authors: Patel Sonia A. , Nilsson Monique , Cho Sungnam , Le Xiuning , Heymach John 
Published: September 2020

Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death with a less than 15% five-year survival. Approximately 15% of NSCLC cases in the US harbor epidermal growth factor receptor (EGFR) activating mutations and are initially highly sensitive to EGFR tyrosine kinase inhibitors (TKI). Unfortunately, the vast majority of tumors acquire EGFR TKI resistance, and treating resistant disease remains a clinical challenge. Additional therapeutic modalities, such as immunotherapy, are needed to improve clinical outcome. While immunotherapy has shown clinical activity in multiple cancer types including NSCLC, a lack of efficacy has been observed in EGFR mutant NSCLC patients. The biological mechanisms driving immunotherapy resistance in EGFR mutant NSCLC are not well understood, and additional EGFR mutant NSCLC patients. We previously reported that IL-6 is upregulated in NSCLC cells with acquired resistance to EGFR TKIs. Given the role of IL-6 as an immunomodulatory cytokine, we evaluated the effects of IL-6 signaling on immunosuppression in genetically engineered mouse models (GEMMs) of EGFR mutant NSCLC. IL-6 knockout (EGFRL858R/IL-6KO) resulted in decreased PD-L1 expression on the surface of EGFR mutant tumor cells compared to tumors in IL-6 proficient mice. Additionally, we observed a modest increase in PD-1 expression on CD8+ T cells in EGFRL858R/IL-6KO mice compared to EGFRL858R mice, suggesting that IL-6 acts on both tumor and immune populations to facilitate a “cold” immunosuppressive tumor microenvironment. We next analyzed immune populations in EGFR mutant tumors from mice with or without knockout of IL-6 by single cell RNA sequencing and validated these findings by immunohistochemistry. Tumors in EGFRL858R/IL-6KO mice displayed decreased B-cell (CD20) populations, increased macrophages (F480), and increased natural killer cells (NKp46) compared to tumors from IL-6 expressing EGFRL858R mice. Our data suggests that the increased expression of IL-6 in EGFR TKI resistant NSCLC may alter immune cell populations within the tumor microenvironment and impact immunosuppression, and that therapeutic approach targeting IL-6 merit further investigation for EGFR-mutant NSCLC.
Citation Format: Sonia A. Patel, Monique Nilsson, Sungnam Cho, Xiuning Le, John Heymach. Investigating the role of IL-6 to modulate the immunosuppressive tumor microenvironment of EGFR mutant NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5066.
Abstract 5086: The aged tumor microenvironment promotes melanoma metabolic plasticity and therapy
Authors: Alicea Gretchen Marie , Rebecca Vito W. , Goldman Aaron , Fane Mitchell , Behera Reeti , Webster Marie , Ecker Brett , Blair Ian , Speicher David , Schug Zachary , Weeraratna Ashani 
Published: September 2020

Abstract
“Aged” melanoma patients (&gt;55 years old) have poorer prognosis and reduced response rates to targeted therapy relative to “young” patients (&lt;40 years old). Here, we report an altered metabolic landscape in the aged tumor microenvironment (TME) as critical for melanoma aggressiveness. Aged fibroblasts uptake high levels of glucose compared to their young counterparts, which fuels lipid production. Melanoma cells cultured in an aged TME in vitro or in vivo display elevated intracellular lipid levels and increased metastatic potential relative to melanoma cells in a young TME. Further, lipidomics reveal an elevated lipid profile (i.e., triglycerides, ceramides, and cholesterol) preferentially secreted by aged fibroblasts relative to young. In turn, we show that melanoma cells adaptively increase extracellular fatty acid scavenging via the lipid transporter FATP2 in the lipid rich aged TME. Melanoma cells cultured in the aged TME also display an increased oxygen consumption rate (OCR) relative to those grown in young TME, which could be ablated when fatty acid transport into the mitochondria is blocked with etomixir. Notably, melanoma cells in the aged TME treated with BRAFi/MEKi in combination with a FATP2 inhibitor display decreased OCR relative to BRAFi/MEKi inhibitor alone, which paralleled the increased overall survival of aged mice treated with BRAFi/MEKi/FATP2i relative to either agent alone. To rule out off-target effects of the FATP2 inhibitor, we used a doxycycline inducible system for FATP2 knockdown in melanoma cells and reproduced the abrogation of tumor growth and extension of survival in aged immune-competent mice when combined with BRAFi/MEK therapy. Additionally, elevated FATP2 levels correlate with worse response in human patients. We hypothesize the aged TME triggers adaptive metabolic plasticity of melanoma cells critical for therapy escape.
Citation Format: Gretchen Marie Alicea, Vito W. Rebecca, Aaron Goldman, Mitchell Fane, Reeti Behera, Marie Webster, Brett Ecker, Ian Blair, David Speicher, Zachary Schug, Ashani Weeraratna. The aged tumor microenvironment promotes melanoma metabolic plasticity and therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5086.
Abstract 509: Discovery of novel small molecule inhibitors of Wnt signaling through in silico molecular docking
Authors: Low Joo-Leng , Du Weina , Gocha Tenzin , Gokce Oguz , Zhang Xiaoqian , Yim Daniel G. , Ramasamy Adaikalavan , Fan Hao , DasGupta Ramanuj 
Published: September 2020

Abstract
Canonical Wnt signaling is one of the crucial pathways involved in embryonic development and tissue homeostasis. However this pathway is often dysregulated in cancers and thus developing effective inhibitors of Wnt signaling is of great interest in the field. Our strategy for inhibition of Wnt signaling involves disruption of the β-catenin (β-cat)-Tcf4 protein-protein interaction (PPI) complex, which is the key effector for nuclear Wnt signaling activity. Towards this goal, we developed a computational model of β-cat for predicting small molecule binders. Application of our computational model to an in silico screen against a library of more than 10,000 compounds predicted 27 compounds as good binders to β-cat. Through in vitro validation experiments such as Wnt reporter assays, co-immunoprecipitation, and surface plasmon resonance (SPR) studies, we identified compound GB1874 as our most promising candidate for inhibiting the β-cat-Tcf4 PPI. Compound GB1874 also affected the proliferation of Wnt-addicted colorectal cancer (CRC) cells in vitro and in tumor xenograft models in vivo. Notably the in vivo efficacy was associated with minimal systemic toxicity. In summary, we report the identification of a novel disruptor of β-cat-Tcf4 interaction, GB1874, which can serve as a promising small molecule candidate for a Wnt signaling inhibitor. Moreover, our study demonstrates the feasibility of using computational modeling to identify new inhibitors of PPI.
Citation Format: Joo-Leng Low, Weina Du, Tenzin Gocha, Oguz Gokce, Xiaoqian Zhang, Daniel G. Yim, Adaikalavan Ramasamy, Hao Fan, Ramanuj DasGupta. Discovery of novel small molecule inhibitors of Wnt signaling through in silico molecular docking [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 509.
Abstract 5091: TIMP-1 in tumor-associated fibroblasts drives tumor progression in lung adenocarcinoma through CD63 interaction
Authors: Duch Paula , Gabasa Marta , Ikemori Rafael , Arshakyan Marselina , Hillberg Frank , Reguart Noemí , Radisky Derek , Alcaraz Jordi 
Published: September 2020

Abstract
Tumor associated fibroblasts (TAFs) are important regulators of tumor growth and resistance to therapies. We have recently shown that lung TAFs in vitro respond to the antifibrotic drug nintedanib in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). We also showed that the tumor-promoting effects of TAFs are driven by different mechanisms in ADC and SCC, which remain to be elucidated. Tissue inhibitor of metalloproteinases 1 (TIMP-1) has been associated with poor prognosis in lung cancer, its expression is downregulated by nintedanib, and our preliminary results reveal that its putative receptor, CD63, is overexpressed in ADC patients compared to SCC, supporting a selective crosstalk between TAFs and cancer cells in ADC through TIMP-1 and CD63. The aim of this study was to test this hypothesis using in vitro preclinical models. Primary fibroblasts were obtained with the patient informed consent, and using protocols approved by the Ethics Committee of the Hospital Clinic. ADC-TAFs and SCC-TAFs were stimulated with TGF-β1 in the presence or absence of nintedanib, and the TIMP-1 content in their conditioned medium was determined by ELISA. TIMP-1 was knocked-down in ADC-TAFs by siRNA, and the corresponding conditioned medium was used to stimulate growth and invasion of the high-CD63 ADC cell line, H1437. Likewise, CD63 expression in H1437 cells was reduced by siRNA. Our in vitro results showed that TIMP-1 secretion induced by TGF-β1 is significantly larger in ADC-TAFs compared to SCC-TAFs. Likewise, nintedanib elicited a higher downregulation of secreted TIMP-1 in ADC-TAFs compared to SCC-TAFs. Of note, TIMP-1 from ADC-TAFs was necessary to induce growth and invasion of H1437 cells. Likewise, knocking-down CD63 in H1437 ADC cells was sufficient to reduce the growth and invasion elicited by the conditioned medium of TGF-β1 activated ADC-TAFs. Collectively, our results unveil a novel stroma-carcinoma crosstalk driven by TIMP-1 and CD63 selectively in lung ADC, and support that such heterotypic crosstalk may underlie the aberrant tumor-promoting effects of ADC-TAFs that are selectively downregulated by nintedanib.
Citation Format: Paula Duch, Marta Gabasa, Rafael Ikemori, Marselina Arshakyan, Frank Hillberg, Noemí Reguart, Derek Radisky, Jordi Alcaraz. TIMP-1 in tumor-associated fibroblasts drives tumor progression in lung adenocarcinoma through CD63 interaction [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5091.
Abstract 5115: Cancer-associated fibroblasts under the influence of melanoma cells might stimulate the lymphatic vessel formation
Authors: Maeda Shusaku , Yashiro Masakazu , Motomura Hisashi , Hatano Takaharu , Fujikawa Heishiro 
Published: September 2020

Abstract
Introduction: Cancer-associated fibroblasts (CAFs) in tumor microenvironment have an interaction with tumor cells and play an important role for the progression and metastasis. Tumor lymphangiogenesis may be controlled by not only tumor cells but also tumor microenvironment, and some reports suggested that CAFs may promote tumor lymphangiogenesis. In malignant melanoma, lymph node metastasis is important prognostic factor. However, no study about the interaction among CAFs, tumor cells, and human lymphatic endothelial cells (HLECs) was found. In this study, we evaluated the effect of CAFs on lymphatic vessel formation in malignant melanoma. Materials and methods: We used CAFs established from a primary malignant melanoma, HLECs, and two melanoma cell lines (MMAc, COLO679). CAFs and melanoma cell lines were cultured with DMEM. Serum-free conditioned medium (CM) was obtained from CAFs (CAF-CM) and two melanoma cells (MMAc-CM, COLO679-CM). Also, CM from CAFs cultured with MMAc-CM (MMAcCAF-CM) and COLO679-CM (COLO679CAF-CM) was obtained. HLECs were cultured by endothelial growth medium (EGM) in combination with 50% of each CM. Control group was cultured with 50% EGM and 50% of serum-free endothelial basal medium. The effect of each CM on the proliferation of HLECs was examined by CCK assay and tube formation assay. Tube formation was assessed by counting total tube length, number of tubes and junctions at 12 hours of incubation. Result: Both MMAcCAF-CM and COLO679CAF-CM significantly increased the proliferation of HLECs in compared with the control or CAF-CM alone, after 24, 48 and 72 hours of incubation. In tube formation assay, both tube length and number of tubes formed by HLECs were significantly longer and larger in MMAcCAF-CM and MMAc-CM group than control group. The tube length, number of tubes and junctions treated by MMAcCAF-CM or COLO679CAF-CM were longer and larger than in control and CAF-CM group. Conclusion: CAFs under the influence of melanoma cells might have a more progressive effect on HLECs, resulting in promotion of lymphangiogenesis.
Citation Format: Shusaku Maeda, Masakazu Yashiro, Hisashi Motomura, Takaharu Hatano, Heishiro Fujikawa. Cancer-associated fibroblasts under the influence of melanoma cells might stimulate the lymphatic vessel formation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5115.