bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5624: PD-L1 mediates IFNγ-regulation of glucose but not of tryptophan metabolism in clear cell renal cell carcinoma
Authors: Garige Mamatha , Ghosh Susmita , Norris ALexis , Li Guangyuan , Sourbier Carole 
Published: June 2022

Abstract
The immune checkpoint programmed death-ligand 1 (PD-L1) is expressed on the cell surface of tumor cells and is key for maintaining an immunosuppressive microenvironment through its interaction with the programmed cell death 1 (PD-1). Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic cancer characterized by an aberrant aerobic glycolytic metabolism and is known to overexpress PD-L1. Multiple immunotherapies have been approved for the treatment of ccRCC, including cytokines and immune checkpoint inhibitors. Recently the intrinsic role of PD-L1 and interferon gamma (IFNγ) signaling have been studied in several types of tumor cells, yet it remains unclear how they affect the metabolism and signaling pathways of ccRCC. Using metabolomics, metabolic assays and RNAseq, we showed that IFNγ enhanced aerobic glycolysis and tryptophan metabolism in ccRCC cells in vitro and induced the transcriptional expression of signaling pathways related to inflammation, cell proliferation and cellular energetics. These metabolic and transcriptional effects were partially reversed following PD-L1 transient silencing. Aerobic glycolysis as well as signaling pathways related to inflammation were not induced by IFNγ when PD-L1 was silenced, however tryptophan metabolism and activation of Jak2 and STAT1 were maintained. Our data demonstrate that PD-L1 expression is required to mediate some of IFNγ’s effect in ccRCC cells and highlight the importance of PD-L1 signaling in regulating the metabolism of ccRCC cells in response to inflammatory signals.
Citation Format: Mamatha Garige, Susmita Ghosh, ALexis Norris, Guangyuan Li, Carole Sourbier. PD-L1 mediates IFNγ-regulation of glucose but not of tryptophan metabolism in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5624.
Abstract 5628: Immune repertoire sequencing facilitates gamma delta T cell clonal determination
Authors: Song Chen , Erijman Ariel , Langhorst Bradley W. , Liu Pingfang , Dimalanta Eileen T. , Davis Theodore B. 
Published: June 2022

Abstract
Gamma-delta T cells are a small fraction of T lymphocytes with only 1-5% of the overall T cell population, but they are an important subset that have unique contributions to both innate and adaptive immunity. Gamma-delta T cells can recognize a broad range of antigens to provide rapid responses to pathogens, and can also interact with both immune cells and non-immune tissue cells triggering regulatory and cytotoxic responses. These unique features make them ideal candidates that could be targeted to induce durable immunity in the context of different pathologies. There has been growing interest in understanding the contributions of gamma-delta T cells to immunology and developing efficient gamma-delta T-cell-based therapies for cancer, infectious disease, and autoimmune disease. In this study, we have implemented T cell repertoire sequencing for high throughput characterization. Gamma-delta T cells were enriched from tissues and peripheral blood mononuclear cells (PBMCs). RNA was extracted and used to generate full length TCR libraries. Unique molecular identifiers (UMIs) were incorporated to discretely barcode each mRNA molecule, enabling absolute quantitative ranking of TCR clone abundance. Full length immune repertoire sequencing facilitates the detection of distinct and shared clones in tissue and blood samples, enabling the identification of disease specific clones to evaluate immunotherapy effects. In addition, RNA sequencing was performed for gene expression analysis of gamma-delta T cells to identify cell phenotypes.
Citation Format: Chen Song, Ariel Erijman, Bradley W. Langhorst, Pingfang Liu, Eileen T. Dimalanta, Theodore B. Davis. Immune repertoire sequencing facilitates gamma delta T cell clonal determination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5628.
Abstract 5641: Tumor cell intrinsic factors in colorectal cancer immune evasion
Authors: Wangmo Dechen , Zhao Xianda , Yuan Angelo , Gates Travis , Subramanian Subree 
Published: June 2022

Abstract
The poor response of most colorectal cancer (CRC) patients to immunotherapy is a major unmet clinical need. Although early detection through screening has reduced CRC incidence, the prognosis for metastatic CRC is poor. In the past decade, immune checkpoint inhibitors (ICIs) have been a major clinical breakthrough with promising clinical benefits in many cancer types, but its efficacy is limited in most (~85%) CRC patients. ICIs preferentially have robust responses from tumors with pre-existing T cell infiltration. However, most CRC lacks robust T-cell infiltration due to immune evasion mechanisms. Therefore, it is crucial to characterize factors shaping immune evasion to improve the response to ICIs. We hypothesize that targeting tumor-cell intrinsic factors can overcome T cell exclusion and will sensitize the tumor to ICIs. To elucidate the factors underlying ICI resistance, it is critical that preclinical models faithfully recapitulate the tumor physiology and genetics of the human disease. Therefore, we developed a tumor organoid (tumoroids) model system adapted from Jacks lab that harbors shApc, KrasG12D, p53-/- and Smad4-/- (shAKPS) mutations, which are co-mutated with high frequency and associated with poor prognosis. We demonstrated that tumoroids with only shApc and KrasG12D mutations can form a solid tumor in two weeks. Addition of p53-/- and Smad4-/- mutations drives invasiveness and metastasis. The shAKPS tumoroids present key features of advanced CRC that are unresponsive to ICIs including invasive tumor, metastasis, and T cell exclusion. Using CRISPR/Cas9 screening and integrative immune score analysis, we identified potential immune evasive genes. To define their expression profile in the tumor, we performed TCGA data analysis in fourteen different cancer types. Furthermore, we performed correlation tests to determine their role in immune cell infiltration and T cell dysfunction. Our results show that these immune suppressive genes are overexpressed in tumor tissues, and negatively correlate with CD8+ T cell infiltration. Our findings suggest that overexpression of immune suppressive genes in cancer cells may cause T cell dysfunction and exclusion in tumors. Furthermore, the functional role of these immune suppressive genes will be characterized using shAKPS mutant organoids and in vivo orthotopic CRC tumor models.
Citation Format: Dechen Wangmo, Xianda Zhao, Angelo Yuan, Travis Gates, Subree Subramanian. Tumor cell intrinsic factors in colorectal cancer immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5641.
Abstract 5652: A novel anti apoptotic function of CTLA4 in melanoma
Authors: Kazmi Hasan Raza , Mo Xuan , Zhou Bo , Preston-Alp Sara , Gross Scott , Wajeeh Hassaan , Merali Carmen , Soboloff Jonathan , Merali Salim , Zaidi M. Raza 
Published: June 2022

Abstract
Cytotoxic T Lymphocyte Antigen 4 (CTLA4) is an important immune checkpoint protein and has been utilized as an immunotherapeutic target against melanoma. Our previous studies have shown that CTLA4 is expressed at low levels in primary human melanocytes but is upregulated in mutant-BRAF/NRAS melanoma cells and tissues. Despite predominantly intracellular localization of CTLA4, its intracellular function remains highly contradictory and unsubstantiated. We found that ectopic expression of Ctla4 in mouse melanoma cell lines substantially promoted lung colonization in allograft model systems in syngeneic mice. Moreover, similar results were observed in immunocompromised recipient mice, suggesting an intracellular cell-autonomous tumorigenic role of Ctla4 in melanoma. These finding led us to investigated intracellular functions of CTLA4 and its potential roles in melanomagenesis. Through the Ingenuity Pathway Analysis of our proteomics data, we found apoptosis as a major affected pathway in Ctla4-expressing mouse melanoma cells. We treated the cells (B2905-Ctla4-ee and EV control) with doxorubicin to induce apoptosis, followed by assessment by Annexin V assay. We found that Ctla4 expressing mouse melanoma cells were significantly resistant to doxorubicin-induced apoptosis. In reciprocal experiment, we generated (by CRISPR-Cas9) CTLA4-knockout A2058 human melanoma cells that exhibit high endogenous CTLA4 expression and we found that knockout cells showed significantly increased apoptosis than the parental cells. Moreover, we also observed significant upregulation of anti-apoptotic proteins (Bnip3, Birc6, Pak1, Mcl-1, Survivin, Rac1/Cdc42, Bcl-2, and Bnip3l) and downregulation of pro-apoptotic proteins (p53 and Bad) in CTLA4-expressing human melanoma cell lines. CTLA4-expressing cells also showed significantly higher invasion in Matrigel-coated transwell assay. These findings lead us to conclude that CTLA4 plays a significant role in regulating apoptosis and promoting melanoma progression in BRAF/NRAS mutant cells.
Citation Format: Hasan Raza Kazmi, Xuan Mo, Bo Zhou, Sara Preston-Alp, Scott Gross, Hassaan Wajeeh, Carmen Merali, Jonathan Soboloff, Salim Merali, M. Raza Zaidi. A novel anti apoptotic function of CTLA4 in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5652.
Abstract 5660: Anti-proliferation effect of polo-like kinase-4 inhibitor in ovarian cancer via AKT/mTOR/p70S6K pathway
Authors: Tse Ka Yu , Chan Wai Sun , Mo Moxil Xuetang , Lee Horace Hok Yeung , Ip Philip Pun Ching , Mak Tak Wah 
Published: June 2022

Abstract
Background: Chromosomal instability is a hallmark in epithelial ovarian cancer. Polo-like kinases (PLK) play a vital role in cell cycle regulation. In particular, PLK4 is crucial in centriole duplication. PLK4 overexpression causes defect in cytokinesis, which in turn leads to aneuploidy and mitosis catastrophe. Previous studies showed that PLK4 inhibitors are effective against cell growth in different cancers like breast cancer and lung cancer. We hypothesize that the AKT/mTOR and p70S6K pathway is involved in this mechanism.
Methods: The importance of cell proliferation of PLK4 was assessed by its inhibition in ovarian cancer cell lines and patient-derived organoids by CFI-400945. RNA sequencing was performed. The effects of PLK4 inhibition on the AKT/mTOR and p70S6K pathway was demonstrated by qPCR and western blot. Correlation of the mRNA expression level with the IC50 of CFI-400945 in ovarian cancer cell lines.
Results: PLK4 inhibition led to reduced cell proliferation in ovarian cancer cells based on XTT and colony formation assays. The anti-proliferative effect was further confirmed in 12 patient-derived organoids using ATP bioluminescent assay. RNA sequencing showed that PLK4 inhibition led to downregulation of the AKT/mTOR/p70S6K pathway. It was found that the most sensitive cell line had the highest mRNA expression of mTOR and p70S6K, while those less sensitive had lower mTOR and p70S6K mRNA expression. Treatment with CFI-400945 showed a reduction of total and phosphorylated forms of AKT, mTOR and p70S6K in a dose-dependent level. Combined treatment with metformin, a drug that had mTOR inhibition effect, showed a synergistic effect in one ovarian cancer cell line.
Conclusion: PLK4 inhibition caused reduced cell proliferation in in vitro and ex vivo assays, and this was accompanied by a downregulation of the AKT/mTOR/p70S6K pathway. This suggested that this pathway might be one of the downstream effector pathways of PLK4.
Citation Format: Ka Yu Tse, Wai Sun Chan, Moxil Xuetang Mo, Horace Hok Yeung Lee, Philip Pun Ching Ip, Tak Wah Mak. Anti-proliferation effect of polo-like kinase-4 inhibitor in ovarian cancer via AKT/mTOR/p70S6K pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5660.
Abstract 5664: Characterization of OASEP1 as a biomarker and therapeutic target for oral cancer
Authors: Takano Atsushi , Yoshitake Yoshihiro , Shinohara Masanori , Daigo Yataro 
Published: June 2022

Abstract
This study aims to identify new biomarkers and therapeutic targets for oral cancer. Our strategies are as follows: i) Identification of overexpressed genes in oral cancers by gene expression array analysis, ii) Validation of clinicopathologic significance of their protein expression by tissue microarray, iii) Examination of their growth effect on cancer cell by siRNAs. We identified a secreted protein, OASEP1 (oral cancer-associated serum protein 1) as a candidate. Immunohistochemical staining showed that OASEP1 protein expression was observed in 120 (75.4%) of 159 oral cancers that had undergone curative surgery. High level of OASEP1 expression was associated with poor prognosis for oral cancer patients (P = 0.0054, by log-rank test). Multivariate analysis revealed that strong OASEP1 expression was an independent prognostic factor. Suppression of OASEP1 expression by siRNA specific for OASEP1 significantly inhibited the growth of oral cancer cell lines through apoptosis as detected by apoptosis assays and time lapse imaging. In addition, siRNAs for the receptor of OASEP1 also significantly inhibited the growth of oral cancer cells. Enforced OASEP1 expression significantly enhanced the growth of cancer cells. Addition of OASEP1 protein significantly increased the growth of oral cancer cells in a dose dependent manner, suggesting that the interaction between OASEP1 and its receptor regulated the growth of oral cancer cells. Microarray analysis coupled with siRNAs for OASEP1 demonstrated various OASEP1-related oncogenic pathways in oral cancer cells. Our data suggest that OASEP1 is a possible prognostic biomarker and therapeutic target for oral cancer.
Citation Format: Atsushi Takano, Yoshihiro Yoshitake, Masanori Shinohara, Yataro Daigo. Characterization of OASEP1 as a biomarker and therapeutic target for oral cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5664.
Abstract 5666: MyD88 in myofibroblasts regulates aerobic glycolysis-driven hepatocarcinogenesis via ERK-dependent PKM2 nuclear relocalization and activation
Authors: Yuan Qi , Zhang Jinhua 
Published: June 2022

Abstract
Hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). MyD88 controls the expression of several key modifier genes in liver tumorigenesis; however, whether and how MyD88 in myofibroblasts contributes to the development of fibrosis-associated liver cancer remain elusive. Here, we used an established hepatocarcinogenesis mouse model involving apparent liver fibrogenesis, in which MyD88 was selectively depleted in myofibroblasts. Myofibroblast MyD88-deficient (Fib-MyD88 KO) mice developed significantly fewer and smaller liver tumor nodules. MyD88 deficiency in myofibroblasts attenuated liver fibrosis and aerobic glycolysis in hepatocellular carcinoma tissues. Mechanistically, MyD88 signaling in myofibroblasts increased the secretion of CCL20, which promoted aerobic glycolysis in cancer cells. This process was dependent on the CCR6 receptor and ERK/PKM2 signaling. Furthermore, liver tumor growth was greatly relieved when the mice were treated with a CCR6 inhibitor. Our data revealed a critical role for MyD88 in myofibroblasts in the promotion of hepatocellular carcinoma by affecting aerobic glycolysis in cancer cells and might provide a potential molecular therapeutic target for HCC.
Citation Format: Qi Yuan, Jinhua Zhang. MyD88 in myofibroblasts regulates aerobic glycolysis-driven hepatocarcinogenesis via ERK-dependent PKM2 nuclear relocalization and activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5666.
Abstract 5671: Thermotherapy interferes with XRCC1/PARP1-mediated DNA repair and confers sensitization of ovarian cancer to oxaliplatin
Authors: Shen Fangrong 
Published: June 2022

Abstract
At present, hyperthermia combined with chemotherapy has become a clinical treatment means Despite some research reports investigating the effects of heat elevation on inducing the DNA damage response and interfering with various DNA repair pathways, but the underlying coalition mechanisms of combined with PARP inhibitorss are not yet completely elucidated. In this study, We use a variety of OC cell lines treat by thermo-chemotherapy and then the proliferation, colony formation ability, apoptosis, and cell cycle distribution of OC cells were measured. Here, We found that in heat sensitive cell line A2780cells treat by thermo-chemotherapy combined wint PARPi, could induces Ppromote OC cells apoptosis and inhibit proliferation, aggravate DNA damage and arrests OC in the cell cycle S phase, buthowever, in heat resistance cell line SKOV3 cells there exhibited an Constant tendency. Western blot analysis shows hyperthermia down-regulated the levels of PARP1 and XRCC1.In addition, hyperthermia combined with chemotherapy could increase the expressions of ATM and NBS1 in the double-stranded DNA damage pathway. Meanwhile, The expression of DNA damage-related proteins increased after PARP1 inhibitors eliminated single-strand repair. Based on these results, we conclude hyperthermia confers sensitization of ovarian cancer to oxaliplatin via interference with XRCC1/PARP1-mediated base excision repair be consumed and Promotes DNA double strand breakage, thereby inhibiting OC development.
Citation Format: Fangrong Shen. Thermotherapy interferes with XRCC1/PARP1-mediated DNA repair and confers sensitization of ovarian cancer to oxaliplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5671.
Abstract 5686: Integrative genomic analysis reveals hypermethylation triggered GPER1 loss is associated with genomic instability of endometrial cancer
Authors: Feng Xuan , Huang Ting , Shen Boqiang , Hao Juan , Wang Jiaqi , Dong Yangyang , Zhou Jingyi , Wang Jianliu 
Published: June 2022

Abstract
Objective: Endometrial cancer is a common gynecologic malignancy, yet carcinogenesis remains elusive. Evidence showed that aberrant genomic methylation profiling contributes to the development of endometrial cancer. G protein-coupled estrogen receptor (GPER1), a membrane-associated estrogen receptor, was reported to play a multifaceted role in tumors. Its function in endometrial cancer is little known. Here, we conducted an integrated analysis of RNA expression, DNA methylation, and somatic mutations data from TCGA to investigate GPER1 upstream regulator and its influence in endometrial cancer biological process.
Methods: RNA-seq, DNA methylation, and clinical information of endometrial cancer (n=554) and normal control (n=33) were obtained from TCGA database. RNA-seq profiles of GPER1 low and high groups were analyzed by R 4.1.0 software. KEGG and GSEA based on GPER1 expression were conducted. Correlation analysis of GPER1 and genomic instability were displayed. G1, the GPER1 agonist, was added to observe cell viability and metastatic ability in vitro. DNA methylation data was analyzed.
Results: GPER1 expression was decreased in endometrial cancer compared with normal tissues. GPER1 was associated with poor overall survival (HR=0.52, p=0.003) (Figure 1). Low expression group showed a more frequent mutation landscape, higher tumor mutation burden (TMB), and micro-satellite instability (MSI) (Figure 2). Several hypermethylation loci on GPER1 CpG island were revealed. Methylation status is negatively correlative to RNA expression of GPER1 (Figure 3). P-value &lt;0.05 and log2FC &gt;1.5, 473 up-regulated and 114 down-regulated genes were screened. Up-regulated DEGs enriched in the Estrogen signaling pathway, Endometrial cancer, wnt signaling pathway, etc. Down-regulated DEGs enriched in Cell cycle, p53 signaling pathway, etc. (Figure 4). GSEA analysis showed that GPER1 low expression group was enriched in several biological processes including cell cycle checkpoint, Recombinational repair, etc. G1 inhibited endometrial cancer cell growth in a dose-dependent manner, and reduced cell metastatic ability (Figure 5).
Conclusions: GPER1 exhibited decreased expression in endometrial cancer and DNA hypermethylation in promoter CpG island locus. The low GPER1 expression group showed prominent genomic instability. GPER1 agonists inhibit endometrial cancer cell growth and metastasis, which may serve as a therapeutic target.
Citation Format: Xuan Feng, Ting Huang, Boqiang Shen, Juan Hao, Jiaqi Wang, Yangyang Dong, Jingyi Zhou, Jianliu Wang. Integrative genomic analysis reveals hypermethylation triggered GPER1 loss is associated with genomic instability of endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5686.