bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6065: ASF1B potentiates stem cell traits and tumor progression in hepatocellular carcinoma via histone H3.3-dependent transcriptional reprogramming
Authors: Fang Xiaona , Liu Beilei , Liu Shan , Zhang Yu , Gong Lanqi , Yan Qian , Guan Xinyuan 
Published: June 2022

Abstract
Hepatocellular carcinoma (HCC) is one of the frequently diagnosed cancers worldwide and has emerged as the main cause of cancer-related death with a very poor prognosis, which is closely related to cancer stem cell (CSC), a subset of cells known to be a root of tumor recurrence, metastasis, and chemoresistance in HCC. However, the characteristics of CSCs in hepatocellular carcinoma (HCC) are still elusive. Our previous in vitro hepatocyte differentiation model revealed that the expression of anti-silencing function 1B histone chaperone (ASF1B) was remarkably upregulated in the stem cell-like stages. In HCC patients, ASF1B was highly expressed in cancer tissues compared with normal counterparts and was positively correlated with poor survival. Functional assays indicated that ASF1B could considerably promote the self-renewal, growth, and metastasis of HCC both in vitro and in vivo. Mechanistically, ASF1B could directly bind to histone H3 Variant H3.3 and enhance its incorporation into the promoter regions of certain stemness- and metastasis-associated genes including SOX9, KLF4, and TBX3, contributing to their augmented transcriptional and protein expression levels. H3.3 knock-down decreased the expression of these stemness and metastasis-associated genes, eliminating the stemness and oncogenic properties of ASF1B. Overall, our study revealed that ASF1B could facilitate HCC stemness and progression via H3.3-dependent transcriptional reprogramming. ASF1B might be a novel diagnostic and prognostic biomarker for HCC patients.
Citation Format: Xiaona Fang, Beilei Liu, Shan Liu, Yu Zhang, Lanqi Gong, Qian Yan, Xinyuan Guan. ASF1B potentiates stem cell traits and tumor progression in hepatocellular carcinoma via histone H3.3-dependent transcriptional reprogramming [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 6065.
Abstract 6068: Restoring the balance between WNT and retinoic acid signaling to promote differentiation of cancer stem cells in treatment of colorectal cancer
Authors: Facey Caroline O. , Hunsu Victoria O. , Osmond Brian T. , Opdenaker Lynn M. , Boman Bruce M. 
Published: June 2022

Abstract
Given that the stem cell (SC) marker ALDH is a key component of the retinoic acid (RA) signaling pathway and since APC mutation leads to increased WNT signaling and overpopulation of ALDH+ SCs in colorectal cancer (CRC), we hypothesized that human CRC evolves due to an imbalance between dysregulated RA and WNT signaling. Herein, we investigated how to target the link between these two pathways to restore proper WNT and RA signaling, and promote differentiation of CSCs along the neuroendocrine cell (NEC) lineage. Accordingly, we conducted in vitro experiments to determine if restoring wt-APC in APC-mutant CRC cells reduces Wnt/β-catenin signaling, increases sensitivity to retinoids, reduces cell proliferation, reduces expression of stem cell markers, reduces the number of ALDH+ cells, and enhances NEC maturation. We utilized Nanostring profiling, TCF reporter assay, western blot, and fluorescence activated cell sorting analyses to ascertain the effects of restoring WNT in HT29 CRC cells. We found that induction of wt-APC expression decreased WNT/β-catenin signaling and reduced protein expression of WNT-target genes. Notably, inducing wt-APC decreased ATRA-induced expression of the WNT target gene CYP26A1 (by 50%), which is predicted to increase RA signaling by lowering the degradation of RA. Indeed, wt-APC increased sensitivity of CRC cells to ATRA-induced inhibition of cell proliferation in a dose-dependent manner. Expression of ALDH1A1 decreased 3-fold by ATRA treatment and inducing wt-APC furthered the decrease by an additional 2-fold. Furthermore, we found an increase in the protein expression of several NEC markers including CHGA, GLP2R, NSE (ENO2), and SSTR1, and an increased number of GLP2R+ NECs upon inducing wt-APC. Thus, the link between WNT and RA signaling at the level of CYP26A1, provides a mechanism that can explain how mutant APC leads to decreased maturation of ALDH+ SCs along the NEC lineage and an increased number of ALDH+ SCs. Therefore, discovering ways to increase differentiation of SCs along the NEC lineage in vivo might lead to new more effective treatment strategies involving retinoids for CRC patients.
Citation Format: Caroline O. Facey, Victoria O. Hunsu, Brian T. Osmond, Lynn M. Opdenaker, Bruce M. Boman. Restoring the balance between WNT and retinoic acid signaling to promote differentiation of cancer stem cells in treatment of colorectal 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 6068.
Abstract 6073: First-in-class Doublecortin-like kinase 1 (DCLK1) inhibitor for targeting cancer stem cell in hepatocellular carcinoma
Authors: Yoon Daseul , Jung Seung Hee , Jang Ju Young , Ahn Ji-Young , Jo Seung Jin , Ko Donghyun , Kim Dong-kyu , Yu Su Jong 
Published: June 2022

Abstract
Cancer stem cells (CSCs) have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. Doublecortin-like kinase 1 (DCLK1) was recently identified as CSC marker is upregulated in several solid tumors, which distinguishes between cancer and normal stem cell. However, the role of DCLK1 in hepatocellular carcinoma (HCC) is unclear. According to the open database like TCGA, overexpression of DCLK1 is reported to be associated with poor prognosis in HCC patients. It was also observed that DCLK1 expression was significantly increased in the advanced stage of HCC. In addition, as a result of measuring the serum DCLK1 levels obtained from patients with liver cirrhosis or HCC treated at Seoul National University Hospital, it was confirmed that the expression of DCLK1 was significantly increased in patients with HCC compared to those with liver cirrhosis. It was also confirmed that DCLK1 was expressed in human HCC cell lines and that the expression levels of DCLK1 mRNA and protein were further increased in CSC rich human HCC cell lines. Moreover, cell death was increased at the cellular level when DCLK1 was blocked via inhibiting expression of CSC markers such as CD133 and EpCAM. After evaluating the effect of DCLK1 inhibition in CSC rich human HCC cells lines, it was found that spheroid formation decreased by suppressing CSCs markers including LGR5 and CD133. In addition, it was confirmed that cell migration decreased when DCLK1 was blocked. Even in the murine HCC model, it was found that the antitumor effect was showed when administered with DCLK1 inhibitor, DCLK1-IN-1, in xenograft model with CSC rich HCC cell lines. Our results support that DCLK1 can be used as a biomarker for the detection of HCC and may be a candidate for developing targeted therapeutics to eradicate HCC.
Citation Format: Daseul Yoon, Seung Hee Jung, Ju Young Jang, Ji-Young Ahn, Seung Jin Jo, Donghyun Ko, Dong-kyu Kim, Su Jong Yu. First-in-class Doublecortin-like kinase 1 (DCLK1) inhibitor for targeting cancer stem cell in hepatocellular 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 6073.
Abstract 6099: Differential gene expression related to TMPRSS2-ERG fusion, CDK12, RB1, TP53, AR and ZEB1 based on transcriptomic analysis of the TCGA PRAD cohort
Authors: Lautert-Dutra William , Melo Camila Morais , Chaves Luiz Paulo , Caliari André Luiz , Silva Francisco Cesar Souza , Squire Jeremy Andrew 
Published: June 2022

Abstract
Prostate Cancer (PCa) is considered an immunologically excluded tumor, unable to generate an effective T-cell response against cancer cells. Inactivating mutations of the PTEN tumor suppressor are one of the most common events in human malignancies that contribute to tumorigenesis by affecting many cancer Hallmark pathways. The CDK12, RB1, TP53, AR and ZEB1 genes have been variously implicated in pathways of PCa progression and immune evasion. Here, we present a comprehensive analysis of The Cancer Genome Atlas derived PCa cohort (n=488, 96 homozygous and 64 hemizygous PTEN loss). Differential gene expression (DGE) and pathway enrichment analysis were performed for all five genes using the DESeq2 tool from the Bioconductor package for R. All comparisons were designed to compensate for gene expression changes caused by PTEN loss (Table 1).
Functional pathway analysis showed that fusion positive samples presented several downregulated pathways, including leukocyte mediated cytotoxicity, IFN type I response and IFN-γ production. AR high presented upregulation of pathways such as DNA replication and chromatin remodeling, while AR low presented upregulation of pathways such as T cell activation and lymphocyte proliferation. ZEB1 high presented a wide range of enriched pathways, including upregulation of mesenchymal cell differentiation and T cell activation. CDK12-Hom group exhibited upregulation of T cell activation, T cell differentiation and IFN-γ production. TP53 mutation revealed upregulation of various pathways including DNA replication and cell division. RB1 loss showed enrichment of pathways such as T cell activation and lymphocyte activation. Our analysis showed that variation in these five genes can promote gene expression changes associated with clinically relevant pathways independently of PTEN and that AR, CDK12, TMPRSS2-ERG fusion, ZEB1 and RB1 status are potential biomarkers for immunotherapy response.
Table 1. Differential genes expression results summary Comparison # of upregulated (LFC&gt;0) # of downregulated (LFC&lt;0) Fusion positive vs. Fusion negative 2997 5418 AR low vs. AR medium 4133 4167 AR high vs. AR medium 4365 2589 CDK12-Hom vs. CDK12 WT 2416 713 CDK12-Hem vs. CDK12 WT 704 387 ZEB1 high vs. ZEB1 normal 6439 6792 RB1 mut vs. RB1 WT 78 335 TP53 mut vs. TP43 WT 859 1193
Citation Format: William Lautert-Dutra, Camila Morais Melo, Luiz Paulo Chaves, André Luiz Caliari, Francisco Cesar Souza Silva, Jeremy Andrew Squire. Differential gene expression related to TMPRSS2-ERG fusion, CDK12, RB1, TP53, AR and ZEB1 based on transcriptomic analysis of the TCGA PRAD cohort [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 6099.
Abstract 6105: Single high-dose irradiation induced iRhom2 up-regulation promotes macrophage anti-tumor activity through cGAS/STING signaling
Authors: Zhao Xiaomei , Du Shisuo , Wang Biao , Zeng Zhaochong 
Published: June 2022

Abstract
Clinical application of Stereotactic body radiotherapy (SBRT) allows high dose of radiation to be delivered to extracranial target within the body safely, however, high dose per fraction and with fewer fractions(hypofractionation) opened up the radiation oncology field to new questions on variety of dose-fractionation schedules, especially, the immunomodulatory effects of radiotherapy, which changes following the variety of dose-fractionation schedules. In the present study, we excluded the direct antitumor effect of radiation by comparing three different fractionation schedules –8*2Gy, 3*4.5Gy, 1*10Gy, which have the same biologically effective dose (BED). We found the fractionation schedules 1*10Gy had a significant higher antitumor effect, suggesting that a single high-dose induced a more enhanced anti-tumor immunity compared to the conventionally fractionation(8*2Gy) and moderately fractionation (3*4.5Gy). However, in STING deficiency mice, we failed to find a different tumor control effect among the three dose-fractionation schedules, suggesting cGAS/STING signaling was involved in regulating immunomodulatory effects that leading to different anti-tumor immunity. Further mechanism investigation revealed that single high-dose irradiation induced up-regulation of iRhom2 in infiltrated macrophage, and iRhom2 promoted cGAS/STING signaling via maintaining stability of STING and facilitating STING trafficking from ER to perinuclear microsomes. Meanwhile, a positive feedback loop between iRhom2 and TNFα sharpened the signaling responses, and amplified antitumor immunity induced by cGAS-STING-IFN pathway after single high-dose irradiation. Taken together, these results suggest that single high-dose irradiation induced iRhom2 up-regulation promotes macrophage anti-tumor activity through cGAS/STING signaling.
Citation Format: Xiaomei Zhao, Shisuo Du, Biao Wang, Zhaochong Zeng. Single high-dose irradiation induced iRhom2 up-regulation promotes macrophage anti-tumor activity through cGAS/STING signaling [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 6105.
Abstract 6122: Different characteristics of tumor immune microenvironment between LUSC and LUAD
Authors: Li Na , Hu Mengna , Zhang Ding , Ji Xiaoyu 
Published: June 2022

Abstract
Background: Patients with lung squamous cell carcinoma (LUSC) have higher tumor mutation burden (TMB) and PD-L1 expression than those with lung adenocarcinoma (LUAD). Several studies showed that tumor immune microenvironment (TIME), mainly the tumor-infiltrating immune cells, may affect the efficacy of immunotherapy. However, the comparison of tumor immune microenvironment between LUAD and LUSC is little known.
Methods: 14 patients with LUSC and 21 patients with LUAD were enrolled in the retrospective analysis of multiple immunofluorescence staining to assess the number of immune cells. Genomic profiling of DNA was performed on formalin-fixed paraffin-embedded tumor samples from 3752 LUAD and 459 LUSC patients by NGS with 733 cancer-related genes panel. TMB is defined as the total counts of single nucleotide variants and indels in the exon region.
Results: Overall, as the most abundant tumor-infiltrating immune cells in both groups, CD3+ cells are more in LUAD [median (number/mm2 in LUSC vs in LUAD): 312 vs 918, p = 0.02]. However, there were no significant differences in CD8+ T cells (median: 48 vs 36, p = 0.74), indicating higher infiltration of T lymphocytes rather than cytotoxic T lymphocytes (CTLs) in LUAD than that in LUSC. Unlike in tumor, LUAD patients had both more T lymphocytes (p &lt; 0.001) and CTLs (p &lt; 0.01) in stroma. Besides, LUSC was correlated with fewer M2 tumor-associated macrophages (TAMs) and PD-1+ immune cells (p &lt; 0.001; p = 0.02), while no significant differences were found in tumor-infiltrating FOXP3+ cells (p = 0.41) and B lymphocytes (p = 0.61). In addition, natural killer cells were the fewest among the tumor-infiltrating lymphocytes detected in both groups (median: 2 vs 13). Similar to the previous studies, TMB level was higher in LUSC (median: 8.94 vs 3.36, p &lt; 0.0001). Although LUSC patients had a larger proportion of positive PD-L1 expression (45% vs 30.5%, p &lt; 0.0001) and strong PD-L1 expression in tumor cells (20.9% vs 10.7%, p &lt; 0.0001), the number of CTLs and TAMs expressing PD-L1 is significantly lower than that in LUAD ( p = 0.04; p = 0.0001).
Conclusion: LUAD had more immune invasion, while LUSC was related to higher TMB and PD-L1 expression. It suggested that the mechanisms affecting the benefits of immunotherapy may be different. The immune microenvironment of tumor and stroma should be considered simultaneously to explore the mechanism of immunotherapy and the respective thresholds should be selected according to the types of immune cells.
Citation Format: Na Li, Mengna Hu, Ding Zhang, Xiaoyu Ji. Different characteristics of tumor immune microenvironment between LUSC and LUAD [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 6122.
Abstract 6133: Intratumoral budding in pretreatment biopsies can predict prognosis and neoadjuvant therapy response among the tumor microenvironmental components in colorectal adenocarcinoma
Authors: Yim Kwangil , Jang Won Mo , Chong Yosep , Shin OK Ran , Seo Kyung Jin 
Published: June 2022

Abstract
Purpose: Neoadjuvant therapy has been used as one of a treatment option in locally advanced rectal cancer and unresectable colorectal cancers (CRCC) with oligo-metastasis. Considering that radical specimen has been deformed due to this treatment, predicting prognosis is more complex. We evaluated several tumor microenvironmental factors in the pretreatment biopsies; those were known as prognostic factors in radical specimen.
Methods: From 2010 to 2021, 85 patients with neoadjuvant therapy and surgery for CRCC were enrolled in Uijeongbu St. Mary’s hospital. Intratumoral budding (ITB), tumor stromal ratio, presence of immature stroma and Klintruo-Makinen grade for inflammatory cells were evaluated in pretreatment biopsies by three pathologists, independently.
Results: Only high grade ITB (OS: p = 0.030, CSS: p = 0.005, DFS: p &lt; 0.001) was poor survival factor in univariate analysis. In addition, high grade ITB was related with pathological stage (p = 0.017), lymphatic invasion (p = 0.010) and chemoresistance in non-metastatic CRCC group (p = 0.046). Presence of immature fibrosis was related with clinical stage (p = 0.045) and pathological stage (p = 0.033). In multivariate analysis, high grade ITB was independent poor survival factor (OS: p = 0.031, CSS: p = 0.009, DFS: p = 0.001).
Conclusion: Our study revealed that high grade ITB in pretreatment biopsied was poor survival factor in CRCC with neoadjuvant treatment. In our observation, we recommend that ITB result should be included in the pathology report when considering neoadjuvant treatment.
Citation Format: Kwangil Yim, Won Mo Jang, Yosep Chong, OK Ran Shin, Kyung Jin Seo. Intratumoral budding in pretreatment biopsies can predict prognosis and neoadjuvant therapy response among the tumor microenvironmental components in colorectal adenocarcinoma [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 6133.
Abstract 6139: GPR4 promotes the development of colitis-associated colorectal cancer in an experimental mouse model
Authors: Marie Mona A. , Sanderlin Edward J. , Hoffman Alexander , Yang Li V. 
Published: June 2022

Abstract
GPR4 is a proton-sensing G protein-coupled receptor expressed in endothelial cells as well as other cell types. Endothelial cell adhesion, blood vessel permeability, leukocyte infiltration, and angiogenesis are regulated by the proinflammatory functions of GPR4. Inhibition of GPR4 ameliorates inflammatory bowel disease (IBD) in mouse models. GPR4 expression is upregulated in the intestinal tissues of IBD and colorectal cancer patients and is associated with a worse prognosis. Herein, we studied the role of GPR4 in colitis-associated colorectal cancer (CAC) by inducing CAC in GPR4 knockout (KO) and wild-type (WT) mice using azoxymethane (AOM)/dextran sulfate sodium (DSS). The severity of CAC development was higher in WT mice than GPR4 KO mice when treated with AOM/DSS. Blood vessel density was significantly higher within the tumors of WT mouse colons compared to GPR4 KO mice. GPR4 KO tumors showed a significant increase in tumor necrosis in comparison to WT tumors. Fecal blood/diarrhea score, colon shortening, and mesenteric lymph node size were aggravated in WT mice compared to GPR4 KO mice treated with AOM/DSS. Our data demonstrate that GPR4 increases intestinal inflammation and angiogenesis, enhancing tumor development in the CAC mouse model, suggesting that GPR4 inhibition may reduce the risk of developing colitis-associated colorectal cancer.
Citation Format: Mona A. Marie, Edward J. Sanderlin, Alexander Hoffman, Li V. Yang. GPR4 promotes the development of colitis-associated colorectal cancer in an experimental mouse model [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 6139.
Abstract 6158: Rewiring cancer associated fibroblasts using nanomedicines improves immunotherapy efficacy
Authors: Elzoghby Ahmed , Freag May , Mohammed Mostafa , Maremanda Krishna , Jang Hae Lin , Sengupta Shiladitya 
Published: June 2022

Abstract
The failure of large number of patients to respond to cancer immunotherapy remains a formidable challenge. The immunosuppressive tumor microenvironment (TME) can hinder the capability of cytotoxic T cells to fight cancer. In this regard, cancer associated fibroblasts (CAFs) are among the most abundant stromal cells in TME responsible for immunosuppression. Therefore, reversal of the immunosuppressive phenotype of CAFs and is a major therapeutic goal. Cancer cells secrete exosomes and other factors to reprogram fibroblasts and induce their differentiation into pro-tumorigenic CAFs. Also, cancer cells maintain the activated fibroblast phenotype via triggering major signaling pathways e.g., TGFβ1, FGFR, or β-catenin pathways in the fibroblasts. Here, our goal was to maintain a normalized quiescent phenotype of fibroblasts to enhance the efficacy of immune checkpoint blockade. We demonstrated that a tumor-targeted EpCAM antibody modified shikonin/GW4869 combination liposomes synergistically reduces the biogenesis and release of exosomes from A549 lung cancer cells which significantly inhibits differentiation of MRC5 lung fibroblasts into CAFs. In parallel, we showed the efficacy of TAS-120/ICG-001 FGFR-Wnt/β-catenin inhibitor combination liposomes decorated with GPR77 and CD10 targeting antibodies to switch the acquired activated CAFs phenotype to a quiescent one. Co-administration of both liposomes in low drug doses significantly enhanced the infiltration of cytotoxic CD8+ T cells and improved the antitumor efficacy of αPD-L1 antibody in LLC syngeneic mice model of lung cancer. In conclusion, simultaneous blockage of the tumoral exosome-mediated activation of fibroblasts and FGFR-Wnt/β-catenin signaling may constitute an outstanding immunotherapeutic modality.
Citation Format: Ahmed Elzoghby, May Freag, Mostafa Mohammed, Krishna Maremanda, Hae Lin Jang, Shiladitya Sengupta. Rewiring cancer associated fibroblasts using nanomedicines improves immunotherapy efficacy [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 6158.