bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6098: Analysis of the impact of ZEB1 expression on pathway enrichment and immune cell abundance in prostate cancer
Authors: Chaves Luiz Paulo , Caliari André Luiz , Lautert-Dutra William , Silva Francisco Cesar Souza , Melo Camila Morais , Saggioro Fabiano Pinto , Borges dos Reis Rodolfo , Squire Jeremy Andrew 
Published: June 2022

Abstract
Prostate cancer (PCa) reactivates a latent embryonic program called epithelial-mesenchymal transition during disease progression. The mesenchymal phenotype contributes to invasion, metastasis and therapy response variation. In this study, we characterize the downstream effects of ZEB1 expression based on cohort dichotomization of quartiles of expression comparing the 25% of tumors with high ZEB1 expression to the 75% of tumors with lower ZEB1 expression. Differential gene expression (DGE), gene set enrichment analysis (GSEA) and immune cell abundance prediction were accessed using PCa expression data from TCGA (n=488). ZEB1 high status based on gene expression was stratified based on ZEB1 expression values higher than the 3rd expression quartile value (n=122). Contingency analysis showed that PTEN loss is more frequent in the ZEB1 high group (Chi-square, p=0.0005) which supports previously presented data from our group that showed an inverse correlation between ZEB1 and PTEN protein expression but showed no difference between the groups regarding presence of the TMPRSS2-ERG fusion. DGE showed that more than 13,000 genes are differentially expressed in the ZEB1 high group while GSEA showed that signaling pathways such as HALLMARK TGF BETA, HALLMARK IL2 STAT5, HALLMARK INFLAMMATORY RESPONSE and HALLMARK NOTCH were upregulated in the ZEB1 high group compared to the low group. Yet inflammatory response related pathways were observed enriched in the ZEB1 high group, CIBERSORT analysis showed that effector immune cells such as CD8+ T cells and T helper cells (Holm-Sidak, p=000003 and p=0.000613, respectively) were enriched in the ZEB1 low group in comparison to the ZEB1 high group, which supports previous studies that suggest that ZEB1 cooperates with PTEN loss and TMPRSS2-ERG fusion to promote an immune evasive phenotype in PCa. Collectively, these findings demonstrate that gene expression changes associated with increased ZEB1 expression may involve clinically relevant pathways such as modulation of the tumor immune microenvironment and NOTCH-dependent tumor progression.
Citation Format: Luiz Paulo Chaves, André Luiz Caliari, William Lautert-Dutra, Francisco Cesar Souza Silva, Camila Morais Melo, Fabiano Pinto Saggioro, Rodolfo Borges dos Reis, Jeremy Andrew Squire. Analysis of the impact of ZEB1 expression on pathway enrichment and immune cell abundance in prostate 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 6098.
Abstract 6101: K6-K14 keratin fusion variant (K6-K14/V7) in OSCC cells promotes tumor microenvironment remodeling through activating inflammatory CAFs
Authors: Kuo Brian Yu-Ting , Lin Yen-Ting , Ravichandran Senthilkumar , Sheu Jim Jinn-Chyuan 
Published: June 2022

Abstract
Keratin intermediate filament is one major cytoskeleton architecture in epithelial cells, providing necessary mechanical support to maintain cell shape and tissue integrity. In a previous study, we discovered the existence of a novel K6-K14 keratin fusion variant (K6-K14/V7) in oral squamous cell carcinoma (OSCC) cells which can promote cancer stemness and aggressiveness. However, the underlying mechanism remains to be elucidated. Here, we report that overexpression of K6-K14/V7 in OSCC cells can influence the mechanical properties of the cells, leading to cell protrusion and enhanced extracellular vesicle (EV) secretion. Consequently, the expression levels of inflammatory cytokines (e.g. IL-6, TGF-[[Unsupported Character - Symbol Font β]]) in the culture medium can be also increased. Normal oral fibroblast cells co-cultured with K6-K14/V7-expressing OSCC cells can be converted into a pro-inflammatory type of cancer-associated fibroblasts (iCAFs). Those findings suggest the ability of K6-K14/V7-expressing OSCC cells in remodeling tumor microenvironment. In this study, we will discuss how K6-K14/V7-expressing OSCC cells educate iCAFs to promote cancer cell migration and invasion via intercellular communication by EVs. The key signaling cascades and the associated regulatory networks will be also discussed. Our study, therefore, uncovers the pro-tumorigenic functionality of K6-K14/V7 by creating an inflammatory tumor microenvironment.
Citation Format: Brian Yu-Ting Kuo, Yen-Ting Lin, Senthilkumar Ravichandran, Jim Jinn-Chyuan Sheu. K6-K14 keratin fusion variant (K6-K14/V7) in OSCC cells promotes tumor microenvironment remodeling through activating inflammatory CAFs [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 6101.
Abstract 6116: Tumor immune environment in liver metastasis of colorectal cancer and its correlation with recurrence free survival
Authors: Zhou Jiamin , Xu Weiqi , Wang Miao , Zhang Siqi , Zhang Ding 
Published: June 2022

Abstract
Introduction: The liver is a common site of metastases of colorectal cancer. Tumor infiltrating lymphocytes (TILs) play an important role in the process of colorectal cancer liver metastasis (CRCLM). A comprehensive investigation into TILs will provide more prognostic information for patients with colorectal liver metastases after liver resection.
Methods: 15 CRC patients with liver metastases from our hospital were enrolled in the study. The density and percentage of the TILs [CD8+, CD3+, CD4+, CD20+, tumor associated macrophages (TAMs), dim CD56+NK, bright CD56+NK, PD-1+etc.] in the liver metastasis samples from operation were analyzed by multiplex immunofluorescence technique (3DMedcines Inc.). The level of the density and percentage of immune cells were determined by dichotomy method. The correlation between recurrence free survival (RFS) and immune cells were analyzed using the Kaplan-Meier curve and Log-rank test.
Results: The existence of dim CD56+ NK cells in the stroma was associated with significant improvement in RFS (p=0.0461). The median RFS was 26.1 months (95% CI, 14.9 to 33.5) with the existence of dim CD56+ NK cells in the stroma versus 1.7 months (95% CI, -18.0 to 32.4) without dim CD56+ NK cells in the stroma. Nevertheless, dim CD56+ NK cells in the tumor-enriched segments was not significantly associated with improved outcome. The existence of bright CD56+ NK cells in the stroma was associated with significant improvement in RFS (p=0.0307) but not in the tumor-enriched segments. The median RFS was 34.6 months (95% CI, 15.0 to 35.2) with the existence of bright CD56+ NK cells in the stroma versus 7.9 months (95% CI, -5.3 to 23.1) without bright CD56+ NK cells in the stroma. However, low FoxP3+ cells in the tumor-enriched segments (p=0.0037) was significantly associated with improved outcome but not in the stroma. The median RFS was 36.5 months (95% CI, 23.1 to 40.1) with low FoxP3+ cells versus 8.2 months (95% CI, 0.5 to 21.8) with high FoxP3+ cells in the tumor-enriched segments. Low CD3+CD4+FoxP3+ cells (p=0.074) and the existence of PD-L1+CD68+ cells (p=0.0524) in the tumor-enriched segments showed a trend towards better RFS. No significant correlation was achieved for CD8+, CD3+, CD3+CD4+, CD20+, CD68+CD163+, CD68+CD163-, PD-1, PD-1+CD8+ cells either in the tumor-enriched segments nor in the stroma.
Conclusion: We identified that CD56+ NK cells in stroma are associated with improved outcome in CRCLM. Nevertheless, FoxP3+ cells are associated with poor prognosis in CRCLM.
Citation Format: Jiamin Zhou, Weiqi Xu, Miao Wang, Siqi Zhang, Ding Zhang. Tumor immune environment in liver metastasis of colorectal cancer and its correlation with recurrence free survival [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 6116.
Abstract 6135: Microbiome profiling through the various gastrointestinal environment of gastric cancer
Authors: Lee Jieun , Shin Sunguk , Lee Seung-been , Yoo Yieri , Lee Sangjun , Kang So Hyun , Lee Eunju , Park Young Suk , Ahn Sang-Hoon , Park Kyoung Un , Kim Hyung-Ho , Kwon Nak Jung , Suh Yun-Suhk 
Published: June 2022

Abstract
The association between cancer and microbiome dysbiosis across anatomically related multiple body sites has not been comprehensively investigated. The purpose of our study is to profile microbial diversity and composition through the various gastrointestinal environment of gastric cancer (GC). We performed V3-V4 16S rRNA gene sequencing analysis for matched samples of gastric tumor, normal gastric mucosa, gastric juice and stool from 30 GC patients. Amplicon sequence variant (ASV) profile was compared among the four body sites at genus level. In this study, we found that mean alpha diversity was lowest in normal gastric mucosa and stool exhibited the largest amount of alpha diversity compared with others. Beta-diversity analysis showed significant differences in microbiota composition for each sample. The microbiome dysbiosis was significantly independent in gastrointestinal environment of gastric cancer. Helicobacter abundance in tumor tissue was significantly lower than in matched normal tissue and gastric juice while the trend was opposite for Lactobacillus. Additionally, the level of Helicobacter was considerably lower in patients with lymphatic invasion. The bacterial community that significantly correlated with tumor samples compared to normal mucosa, gastric juice, and stool were 49, 27, and 11 genus, respectively. Lactobacillus and Delftia had higher abundance and Rothia and Collnsella had lower abundance in tumor tissue compare with normal mucosa. Especially, Delftia was seen only in the tumor tissue not normal gastric mucosa, gastric juice and stool. Pentose phosphate pathway was significantly enriched in tumor tissue and normal mucosa. There is a unique microbiome pattern through the various gastrointestinal environment of gastric cancer. Our analysis shows enriched Delftia abundance only in the tumor tissue except other sample type.
Citation Format: Jieun Lee, Sunguk Shin, Seung-been Lee, Yieri Yoo, Sangjun Lee, So Hyun Kang, Eunju Lee, Young Suk Park, Sang-Hoon Ahn, Kyoung Un Park, Hyung-Ho Kim, Nak Jung Kwon, Yun-Suhk Suh. Microbiome profiling through the various gastrointestinal environment of gastric 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 6135.
Abstract 615A: HuGEMM࣪ modelling toxicology of species-specific immune checkpoint inhibitors
Authors: He Daniel XF 
Published: June 2022

Abstract
Background: Immune checkpoint inhibitors, including anti-PD-1 and anti-CTLA-4 monoclonal antibodies, have led to impressive clinical outcomes in treating certain cancers. However, the overall success rate of immunotherapeutic drugs remains low, due to poor efficacy (cancer immunotherapeutic effect [CITE]) or unexpected safety risks such as immune-related adverse events (irAEs), underlining the importance of predictive preclinical animal models. Notably, most immunotherapies cannot be modeled in xenograft tumor models, due to their immunodeficient phenotype, or syngeneic models, as most biologics are usually species-specific. Given these limitations, genetically engineered humanized mouse models (HuGEMM࣪) and syngeneic cell lines (HuCELL࣪), where human drug target gene(s) replace the original mouse ortholog(s), have been broadly used to assess species-restricted biologics for CITE. Since most irAEs in biologics are on-target toxicities, it is potentially possible to model the irAEs of biologics using non-tumor bearing HuGEMMs. In this study, the PD-1/CTLA-4 double knock-in (dKI) HuGEMM is used as an example to provide more insights into irAE evaluation in preclinical models.
Methods: The PD-1 and CTLA-4 HuGEMM in BALB/c backgrounds were developed by substituting the mouse extracellular domains with their human counterparts, followed by crossbreeding to create dKI mice for both targets. The juvenile dKI mice (age 4-5 weeks) were treated with the vehicle control, anti-human PD-1, and a combination therapy of anti-human PD-1/anti-human CTLA-4. The models were monitored for toxicity parameters, including general welfare, body weight, mortality, gross pathology (arthritis, skin inflammation, and colitis scoring), and histopathology of different organs at study termination.
Results: No body weight loss was observed throughout the study in all treatment groups. No mortality was observed in models treated with a monotherapy, while in the combination group (anti-human PD-1/anti-human CTLA-4), five mice displayed lethargy and tachypnea symptoms, and four mice experienced severe adverse effects. Per gross pathology analysis, combination treatment caused significant arthritis in the feet of the mice at study end. Histopathology analysis of the combination treatment group samples demonstrated colon epithelia damage and heart lymphocyte infiltration at termination. These observations for toxicity or irAE profiles are in line with those observed in patients undergoing the same treatment regimen.
Conclusions: HuGEMM engineered to express human targets could be used in preclinical studies to test for assessing irAE of biologics.
Citation Format: Daniel XF He. HuGEMM࣪ modelling toxicology of species-specific immune checkpoint inhibitors [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 615A.
Abstract 6160: Tie2-mediated AMPK activation by ferritin-based protein C nanoparticles inhibits advanced prostate cancer development through induction of vasodilation
Authors: Lee You Mie , Jeong Ji-Hak , Jang Hyunha , You Jihye 
Published: June 2022

Abstract
Prostate cancer (PCa) is one of the most common malignancies and the second-leading cause of cancer-related mortality in men in Western countries. Androgen deprivation therapy (ADT) is an initial systemic therapy for advanced PCa, but almost all cancer eventually becomes castration resistant. Recently, we introduced ferritin-based protein C nanoparticles (PCNs), known as TFG and TFMG, which enhance normalization of the tumor vasculature. However, the exact underlying mechanism how PCNs induces AMP-activated protein kinase (AMPK) activation and anti-tumor activity in castration-resistant prostate cancer (CRPC) remains unknown. Here, we investigated the role of PCNs for CRPC development in endothelial cells. We found that TFMG inhibits prostate cancer castration resistance by activating AMPK through the Tie2-mediated signaling pathway. TFMG treatment increased AMPK phosphorylation at Thr172 and acetyl-CoA carboxylase (ACC) at Ser79 in EA.hy926 cells. TFMG treatment also significantly increased the phosphorylation of endothelial nitric oxide synthase (eNOS) with inducing nitric oxide (NO) production in EA.hy926 cells. In addition, TFMG treatment induced the vasodilatory effect in isolated rat mesenteric resistance arteries (MRAs), which was blocked by NO synthase inhibitor L-NAME. Interestingly, these effects were all abolished by pretreatment with Compound C (an AMPK inhibitor), rebastinib (selective Tie2 Inhibitor), AMPK knockdown using siRNA, or dominant negative AMPKα recombinant adenovirus. Finally, we found that TFMG functionally abrogates CRPC development in mouse model. In summary, TFMG exerted vasodilatation through activating Tie2/AMPK/eNOS signaling in endothelial cells, which leads to the overcoming vasoconstriction induced ADT. This study provides the potential value of TFMG in vasodilation of blood vessels leading suppression of CRPC development.
Citation Format: You Mie Lee, Ji-Hak Jeong, Hyunha Jang, Jihye You. Tie2-mediated AMPK activation by ferritin-based protein C nanoparticles inhibits advanced prostate cancer development through induction of vasodilation [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 6160.
Abstract 6192: ERK/AKT pathways may be the wrong effectors for KRAS signaling inhibition in colorectal cancers
Authors: Cheah Peh Yean , Lam Kuen Kuen , Tang Choong Leong , Tan Emile , Wong Siew Heng 
Published: June 2022

Abstract
Colorectal cancer (CRC) is the third highest incident cancer worldwide and a major cause of cancer death. KRAS protein gain-of-function point mutations play major roles in colorectal tumorigenesis. However, direct inhibition of KRAS is challenging as its protein structure is inadmissible to inhibitor docking. Efforts have been diverted to inhibit downstream RAF/MEK/ERK and PI3K/Akt signaling. Nevertheless, none of these inhibitors has progressed to clinical use in CRC despite extensive trials over the past few decades. We examined levels of phospho-ERK1/2(T202/Y204) and phospho-Akt1/2/3(S473) in human colorectal tumor and matched mucosa at least 10 cm away with quantitative near infrared western blot and immunofluorescence imaging. Surprisingly, 75.5% (25/33) of tumors has lower or equivalent phospho-ERK1/2 and 96.9% (31/32) of tumors has lower phospho-AKT1/2/3 compared to matched mucosa, irrespective of KRAS mutation status and tumor stage. In contrast, we discovered KRAS-dependent SOX9 upregulation in 28 of the 31 (90.3%) tumors. CPTAC phosphoproteomics data similarly showed significantly lower phospho-ERK1/2 levels in tumor compared to matched mucosa. Analysis of transcriptome data from TCGA and GEO series GSE95132 also showed no activation of RAF/MEK/ERK signaling in CRC tumors. These data indicate that the pursue of targeted therapy inhibiting RAF/MEK/ERK and PI3K/Akt signaling is unlikely to be effective in sporadic CRC and possibly harmful as phospho-ERK1/2 are highly expressed in the matched mucosa suggesting a role in normal colonic homeostasis. The widespread use of RAF/MEK/ERK or PI3K/Akt signaling downregulation as a biomarker in drug testing on CRC cell lines needs to be re-evaluated. The data suggest further that SOX9 could be an alternative effector and biomarker of KRAS signaling.
Citation Format: Peh Yean Cheah, Kuen Kuen Lam, Choong Leong Tang, Emile Tan, Siew Heng Wong. ERK/AKT pathways may be the wrong effectors for KRAS signaling inhibition in colorectal cancers [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 6192.
Abstract 6214: Detecting and characterizing extrachromosomal DNA in medulloblastoma at single-cell resolution
Authors: Chapman Owen , Sridhar Sunita , Larson Jon D. , Wechsler-Reya Robert J. , Mesirov Jill , Chavez Lukas 
Published: June 2022

Abstract
Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive cancers, including medulloblastoma (MB), the most common malignant pediatric brain tumor. To assess the clinical import of ecDNA in MB, we applied computational methods to detect ecDNA to the genomes of a cohort of 468 MB patients and 31 MB model systems. Among patients, ecDNA was detected in 18% of tumors and carried threefold greater risk of mortality. Between sequential patient biopsies at initial diagnosis and subsequent relapse, we observed frequent structural variation at ecDNA loci and generation of new ecDNA sequences. Among model systems, ecDNA was found in 19 of 31 genomes (61%). Although ecDNA was far more prevalent among MB models than patients, the ecDNA genomic sequence was conserved between most patient-derived xenograft (PDX) models and their origin human tumors. EcDNA promotes high oncogene copy number, accelerated evolution of drug resistance and poor prognosis. Mechanistically, these behaviors are hypothesized to be consequences of intratumoral heterogeneity of ecDNA copy number; however, there are currently no methods to quantify the abundance and distribution of ecDNA across single cells in a tumor. We have previously identified a primary TP53-mutant SHH medulloblastoma tumor, which harbors multiple distinct lineages of ecDNA originating from different chromosomes. We have now simultaneously analyzed the accessible chromatin and gene expression in single cells of the human tumor and of a orthotopic mouse xenograft (PDX) derived for this tumor, using multiome single-cell ATAC-seq and gene expression (10X Genomics). By measuring scATAC-seq read depth at the ecDNA loci relative to the rest of the genome, we estimate ecDNA copy number in single cells. We observe substantial variation in the ecDNA copy number of cells in both the human tumor and the PDX, and strong association with transcription of ecDNA-amplified genes. We anticipate that this approach will illuminate mechanisms of ecDNA-mediated drug resistance, by revealing the sensitivity and population dynamics of ecDNA-containing cells under treatment pressure.
Citation Format: Owen Chapman, Sunita Sridhar, Jon D. Larson, Robert J. Wechsler-Reya, Jill Mesirov, Lukas Chavez. Detecting and characterizing extrachromosomal DNA in medulloblastoma at single-cell resolution [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 6214.