bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5845: Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer
Authors: Yoshikawa Mao , Takatsu Fumiaki , Suzawa Ken , Habu Tomohiro , Masayoshi Ohki , Iwata Kazuma , Matsuda Naoki , Thu Yin Min , Shien Kazuhiko , Yamamoto Hiromasa , Toyooka Shinichi 
Published: April 2023

Abstract
Background: Cancer-associated fibroblasts (CAFs) are key players in the tumor microenvironment (TME) due to their abundance in most solid tumors and active crosstalk with cancer cells, and promote the initiation of tumor formation, tumor growth, angiogenesis, metastasis, and therapeutic resistance. In this study, we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC).
Experimental Design: We established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells using in vitro co-culture models, conditioned medium, and in vivo xenograft mouse models. Next, RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we then verified the biological activity of the identified molecule on NSCLC cells in vitro and in vivo mouse model.
Results: Cancer cells showed enhanced cell proliferation, migration, and drug resistance by co-culture with CAFs or CAF-derived conditioned medium. RNA sequencing analysis revealed that CAFs showed higher expressions of POSTN, a matricellular protein, than NFs. Single-cell RNA sequencing data of NSCLC from public database confirmed that POSTN-positive fibroblasts were highly enriched in lung tumor tissues but rarely observed in normal lung tissues, suggesting CAF-specific POSTN expression in lung cancer. Recombinant POSTN increased cell proliferation via NSCLC cells’ ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for Osimertinib treatment.
Conclusion: Our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN in TME could be a potential therapeutic strategy for NSCLC.
Citation Format: Mao Yoshikawa, Fumiaki Takatsu, Ken Suzawa, Tomohiro Habu, Ohki Masayoshi, Kazuma Iwata, Naoki Matsuda, Yin Min Thu, Kazuhiko Shien, Hiromasa Yamamoto, Shinichi Toyooka. Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5845.
Abstract 5848: Identification of mechanosensitive cancer associated fibroblasts in pancreatic cancer
Authors: Xiao Weikun , Eun Chae-Young , Zhao Weian , Hill Reginald 
Published: April 2023

Abstract
The purpose of this study is to investigate whether a subpopulation of cancer associated fibroblasts (CAFs) are responsible for mechanosensation-mediated chemoresistance in pancreatic adenocarcinoma (PDAC). PDAC is one of the most lethal types of cancer with few effective treatments. The abundant stromal cells and the stiff desmoplastic microenvironment constitute more than 90% of the primary tumor bulk. However, there are few easily tunable models to recapitulate this stiff microenvironment. To address this issue, we have developed a Matrigel-based, orthogonally tunable 3-dimensional (3D) culture system to co-culture mouse derived PDAC organoids and host-matching cancer-associated fibroblasts (CAFs). Using this biomimetic model and a mechano-sensation-dependent reporter, we have identified a unique subpopulation of CAFs responsible for mechano-sensing the fibrotic matrix and facilitating CAF-mediated chemoresistance. Moreover, these mechanosensitive CAFs (mecCAFs) respond to increased stiffness through YAP-mediated pathways. Our results also demonstrate how ECM stiffness affects chemoresistance via the hypersecretion CAF-derived exosomes. Moving forward, therapies designed to interrupt the function of mecCAFs could be utilized to overcome matrix-mediated chemoresistance in PDAC.
Citation Format: Weikun Xiao, Chae-Young Eun, Weian Zhao, Reginald Hill. Identification of mechanosensitive cancer associated fibroblasts in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5848.
Abstract 5895: Analysis of microbiome in gastric MALT lymphoma
Authors: Yoo SeungJoo , Shin Dong-Yeop , Byun Ja Min , Hong Junshik , Yun Hongseok , Koh Youngil , Yoon Sung-Soo 
Published: April 2023

Abstract
Gastric MALT (mucosa-associated lymphoid tissue) lymphoma is found at a rate of 50% or more among the types of MALT lymphoma. Majority of patients with gastric MALT lymphoma are infected with Helicobacter pylori and also have clinical improvement with eradication therapy. However, it is unclear how H. pylori cause gastric MALT lymphoma. To explore it, we prospectively collected 13 patients who are newly diagnosed with gastric MALT lymphoma with H. pylori. We gathered samples from normal regions and lesions during endoscopy for diagnosis. Samples of lesion were harvested again after eradication of H. pylori. we sequenced 10 of WES (whole exome sequencing) and 13 of WTS (whole transcriptome sequencing) with these samples. With sequencing data, we aligned the sequenced reads to human reference genome (hg19) using BWA and called the variants with Mutect2. We aligned the reads and calculated TPM (Transcripts Per Million) from WTS with STAR and RSEM. We performed DEG (Differentially Expressed Genes) and GSEA (Gene Set Enrichment Analysis) for three comparison groups which are divided into normal, lesion, and after eradication. Gene fusions were detected using STAR-Fusion and Arriba with WTS. To detect potential microbiome from the samples, we used Kraken2, a taxonomic classification tool. We found that MUC6 was mutated from all samples and some samples have mutated MUC3A, KMT2C, ZNF595, CDC27, etc., and two have BIRC3-MALT1 fusion. From DEG and GSEA analysis, G protein-coupled receptor activity was activated in the group of lesion samples and suppressed in normal samples and eradication samples. Lymphocyte activation and immune response were also activated in the cancerous lesion. Kraken2 classified the reads which were not aligned to the human reference genome as reads from microbiota including H. pylori. The reads of H. pylori were more abundant in the lesion group than the other groups. According to the result of differentially expressed species analysis between the groups of lesion and eradication, the following species were also more abundant in the lesion group; Veillonella dispar, Helicobacter hepaticus, Helicobacter winghamensis, etc. We analyzed genetic alterations and differentially expressed genes and also classified non-human reads as microbiome with sequencing data from gastric MALT lymphoma. Our results suggest how H.pylori infection is related to carcinogenesis of gastric MALT lymphoma.
Citation Format: SeungJoo Yoo, Dong-Yeop Shin, Ja Min Byun, Junshik Hong, Hongseok Yun, Youngil Koh, Sung-Soo Yoon. Analysis of microbiome in gastric MALT lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5895.
Abstract 5896: Identification of microbial biomarkers to predict recurrence of oral squamous cell carcinoma
Authors: Lyu Wei-Ni , Lin Mei-Chun , Lou Pei-Jen , Lai Liang-Chuan , Tsai Mong-Hsun 
Published: April 2023

Abstract
Introduction: Oral cancer is a fatal cancer and the sixth most common neoplasm worldwide. Over 90% of oral cancer is oral squamous cell carcinoma (OSCC). OSCC is a global health problem because of its late diagnosis and high rate of relapse and metastasis. Currently, cumulative evidence has suggested the association between oral microbiome and oral cancer. However, the correlation between the oral microbiome and OSCC recurrence remained unclear. Therefore, we investigated the OSCC patients’ oral microbiota to understand the roles of oral microbiome in the recurrence of OSCC.
Materials and Methods: To evaluate the role of the oral microbiome in the recurrence of oral cancer, we compared the oral bacterial composition of tumor samples from the OSCC patients with or without recurrence based on 16S rRNA amplicon sequencing of 54 oral swab samples. Then, the structures of the oral microbiome were analyzed to establish a prediction model for the recurrence of OSCC. To identify microbial signatures capable of distinguishing recurrence from non-recurrence, the 54 tumor samples from OSCC patients were used as a training dataset. Furthermore, 46 external tumor samples from other OSCC patients were used to validate the dataset.
Results: The oral bacterial compositions differed in OSCC patients between with and without recurrence. Compared to nonrecurrence OSCC, periodontitis-related bacteria were enriched in OSCC recurrence. Functional analysis of the oral microbiome showed several functions associated with OSCC recurrence including amino acid metabolism, carbohydrate metabolism, lipid metabolism, glucose utilization, and drug resistance. Subsequently, we established a random forest prediction model with high accuracy (accuracy = 0.963) to discriminate OSCC recurrence from the original OSCC based on five specific microbial signatures. Moreover, the prediction model achieved an accuracy of 0.761 in another independent cohort (46 OSCC patients). On the other hand, the accuracy predicted by the current clinical-used model was 0.519 with the training dataset. Thus, our novel model could improve the prediction accuracy of OSCC recurrence.
Conclusions: In this study, we elucidated the relationship between oral bacteria and the recurrence of OSCC. Moreover, we established a novel bacteria-based prediction model for the recurrence of OSCC. Thus, the present study provided a new insight and treatment strategy for the clinical prediction of OSCC recurrence.
Citation Format: Wei-Ni Lyu, Mei-Chun Lin, Pei-Jen Lou, Liang-Chuan Lai, Mong-Hsun Tsai. Identification of microbial biomarkers to predict recurrence of oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5896.
Abstract 5998: Global DNA methylation analysis of cancer-associated fibroblasts reveals extensive epigenetic rewiring linked with RUNX1 upregulation in breast cancer stroma
Authors: Halperin Coral , Hey Joschka , Weichenhan Dieter , Stein Yaniv , Mayer Shimrit , Lustik Pavlo , Plass Christoph , Scherz-Shouval Ruth 
Published: April 2023

Abstract
Cancer cells recruit and rewire normal cells in their microenvironment to support and protect them by creating a pro-tumorigenic tumor microenvironment (TME). We lack an overarching view of how, despite being genomically stable, stromal cells in the tumor microenvironment are heterogeneously reprogrammed across time and space to promote the evolution of aggressive disease. Recent work by us and others has shown that fibroblasts in the tumor microenvironment are transcriptionally rewired to become protumorigenic cancer associated fibroblasts (CAFs). Transcriptional regulation plays a major role in this reprogramming, but the extent to which epigenetic modifications of DNA also contribute to the rewiring of CAF transcription is not clear. Here we address this question by dissecting the epigenetic landscape of breast CAFs. We applied a sensitive method of whole genome bisulfide sequencing on a model of triple-negative breast cancer in mice to evaluate the methylome profile of CAFs compared to normal mammary fibroblasts (NMFs). we found that fibroblasts undergo massive DNA methylation changes as they transition into CAFs in mice. These changes inversely correlated with transcriptional changes between CAFs and NMFs. We characterized potential regulators of this process, and tested their expression in CAFs in human breast cancer patients, to confirm relevance of our findings to human disease. Our findings suggest that epigenetic alterations contribute to the transcriptional rewiring of fibroblasts to CAFs. This work presents a comprehensive map of DNA-methylation in CAFs, and reveals a previously unknown facet of the dynamic plasticity of the stroma.
Citation Format: Coral Halperin, Joschka Hey, Dieter Weichenhan, Yaniv Stein, Shimrit Mayer, Pavlo Lustik, Christoph Plass, Ruth Scherz-Shouval. Global DNA methylation analysis of cancer-associated fibroblasts reveals extensive epigenetic rewiring linked with RUNX1 upregulation in breast cancer stroma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5998.
Abstract 6005: Promoter methylation occurs at high frequencies regardless of mutation status of tumor-associated genes in oral malignancies
Authors: Abe Masanobu , Hoshi Kazuto , Ushijima Toshikazu 
Published: April 2023

Abstract
Background: Genetic and epigenetic alterations are both important in tumorigenesis. However, their association in oral carcinogenesis has not been fully investigated yet. In this study, we analyzed somatic mutations of tumor-related genes and promoter methylation of tumor-suppressor genes (TSGs) in oral malignancies/premalignancies, and analyzed their association.
Materials and Methods: 39 oral squamous cell carcinomas (OSCCs) and 2 oral epithelial dysplasias (OEDs) were obtained as fresh-frozen?. Somatic mutations of 46 tumor-related genes, 13 TSGs and 33 oncogenes, were analyzed by targeted next-generation sequencing (NGS). Promoter methylation of five TSG: (p16/INK4A, CMTM3, EGFLAM, NKX2-3, and RBP4) were determined by methylation-specific PCR (MSP).
Results: Somatic mutations of tumor-related genes were observed in 63.4% of 41 OSCCs/OEDs. Particularly, mutations of p53 and PIK3CA were observed 39.0% and 31.7%, respectively, of the 41 OSCCs/OEDs. Promoter methylation of p16/INK4A, CMTM3, NKX2-3, RBP4, and EGFLAM were observed in 34.1%, 48.8%, 41.5%, 68.3%, and 36.6%, respectively, of the 41 OSCCs/OEDs. No differences in the frequency of promoter methylation of the five genes were observed between tumors with and without somatic mutations of p53 and PIK3CA.
Conclusions: Promoter methylation was observed at high frequencies regardless of mutation status of p53 and PIK3CA in OSCCs/OEDs. Oral tumorigenesis appears to be difficult to be explained solely by genetic events indicating involvement of epigenetic events.
Citation Format: Masanobu Abe, Kazuto Hoshi, Toshikazu Ushijima. Promoter methylation occurs at high frequencies regardless of mutation status of tumor-associated genes in oral malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6005.
Abstract 6007: p16 epimutation modulates the tumor microenvironment and promotes malignancy of Apc-mutant colon cancer
Authors: Yang Li , Chen Xiaomin , Lee Christy , Shi Jiejun , Lawrence Emily B. , Zhang Lanjing , Li Yumei , Gao Nan , Jung Sung Yun , Creighton Chad J. , Li Jingyi Jessica , Cui Ya , Arimura Sumimasa , Li Wei , Shen Lanlan 
Published: April 2023

Abstract
Methylation of the p16 promoter resulting in mitotically stable gene silencing—known as p16 epimutation—is the most common epigenetic event in human colorectal cancer (CRC) and is also common in normal-appearing colonic mucosa of aging individuals. However, the functional role of p16 epimutation in CRC carcinogenesis is not completely understood. Here, using a mouse model of engineered p16 promoter hypermethylation, we show that p16 epimutation cooperates with mutant Apc to promote colon cancer development. Mice carrying combined Apc mutation and p16 epimutation display significantly shortened survival and increased tumor growth compared to those with Apc mutation only. Moreover, colon tumors from these animals express increased levels of programmed death-ligand 1 (Pdl1). Single-cell RNA sequencing (scRNA-seq) analysis further revealed the presence of dysfunctional cytotoxic CD8+ T cells together with Foxp3+ Tregs and γδT17 cells, which promote an immunosuppressive tumor microenvironment (TME). Lastly, we show that a combined therapy using an inhibitor of DNA methylation and a PD-L1 immune checkpoint inhibitor is more effective for improving survival in tumor-bearing mice than anti-PD-L1 treatment alone. These findings provide a mechanistic rationale for targeted epigenetic and immunotherapy in CRC patients, with the potential to improve colon cancer treatment.
Citation Format: Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B. Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J. Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Wei Li, Lanlan Shen. p16 epimutation modulates the tumor microenvironment and promotes malignancy of Apc-mutant colon cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6007.
Abstract 6015: Methylation synthetic lethality: CHFR methylation and KRAS inhibition in gastric cancers
Authors: Takeshima Hideyuki , Ebata Takahiro , Furuichi Yumi , Yamashita Satoshi , Ushijima Toshikazu 
Published: April 2023

Abstract
Synthetic lethality is a promising therapeutic strategy, but the number of founder mutations is limited. In contrast, DNA methylation is frequently present in many types of cancers, and can be a potential target for a synthetic lethality. So far, BRCA1 methylation with a PARP inhibitor is known as a synthetic lethality [Kawachi et al., Breast Cancer Res Treat, 181:323-329, 2020]. In this study, we aimed to identify a novel methylation synthetic lethal combination in gastric cancers. Founder methylation was searched for in 8,008 genes with putative promoter CpG islands (CGIs), and 137 genes which were 1) heavily methylated and 2) frequently methylated in primary gastric cancers (10 or more of 50 cases) were selected. The association analysis between DNA methylation and gene expression showed that 10 of 137 genes were completely silenced in gastric cancer cell lines with methylation of their promoter CGIs, but were expressed in those without. Among these 10 genes, we focused on CHFR, a known tumor-suppressor gene in gastrointestinal cancers, and genes lethal for CHFR methylation were screened for using the sgRNA screening database (The Cancer Dependency Map, DepMap). Comparison of gene dependencies of 17,645 genes between four cell lines with CHFR methylation and 12 cell lines without revealed that knockout of KRAS reduced cell growth specifically in cell lines with methylation. This synthetic lethality could be experimentally confirmed in two cell lines with CHFR methylation, AGS and 44As3, and three cell lines without, HSC41, HSC42, and MKN74. These cell lines included those not used in the screening, validating the usefulness of the combination. These results showed that gastric cancers with CHFR methylation were sensitive to KRAS inhibition, and that methylation synthetic lethality is a promising therapeutic strategy.
Citation Format: Hideyuki Takeshima, Takahiro Ebata, Yumi Furuichi, Satoshi Yamashita, Toshikazu Ushijima. Methylation synthetic lethality: CHFR methylation and KRAS inhibition in gastric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6015.
Abstract 602: Single cell evaluation of intratumoral B cells across solid tumor indications
Authors: Fahl Shawn P. , Colwell Kerri , Smith Casey , Ott Cavin , Moore Alex , Williams Kayla 
Published: April 2023

Abstract
The immune system is a critical component of the tumor microenvironment that has both tumor-promoting and tumor-eradicating activity based on the specific immune cell subtype and their activation status. T lymphocytes represent the largest lymphocyte population within the tumor, and numerous immunotherapies have been developed to specifically target this cellular subset. B cells are the next most abundant lymphocyte subset within the tumor microenvironment, and recent studies have identified crucial roles for intratumoral B cells in the production of tumor-reactive antibodies. Using human dissociated tumor cells (DTCs) samples, we have profiled intratumoral B cells to determine their frequency and subset breakdown across thirteen different solid tumor indications. Intratumoral B cells were prevalent in lung cancer and cancers of the gastrointestinal tract (esophageal, gastric, and colorectal), while they were rarer in cancers of the female reproductive tract (endometrial and ovarian). The transcriptional profile and B cell repertoire of the intratumoral B cell subsets were evaluated to provide a deeper understanding of the biology of these tumor-infiltrating lymphocyte subsets. Additionally, spatial transcriptomics were utilized to understand the spatiotemporal location of these subsets within the tumor microenvironment. These studies will provide critical insight for the development of the next generation of immunotherapies.
Citation Format: Shawn P. Fahl, Kerri Colwell, Casey Smith, Cavin Ott, Alex Moore, Kayla Williams. Single cell evaluation of intratumoral B cells across solid tumor indications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 602.