bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 287: Analysis for the role of antigen-presenting cancer-associated fibroblasts in tumor microenvironment of colorectal cancer
Authors: Fukui Yasuhiro , Kasashima Hiroaki , Wang Zizhou , Yonemitsu Ken , Kitayama Kishu , Miki Yuichiro , Yoshii Mami , Fukuoka Tatsunari , Tamura Tatsuro , Shibutani Masatsune , Toyokawa Takahiro , Tanaka Hiroaki , Lee Shigeru , Yashiro Masakazu , Maeda Kiyoshi 
Published: March 2024

Abstract
A new subset of cancer associated fibroblasts (CAFs) called antigen presenting CAF (apCAF) was recently identified, and modulation of the tumor immunity might be associated with tumor progression. We examined the markers of apCAF, such as IRF5, HLA-DRA and HLA-DQA1 by bioinformatics analyses of human colorectal cancer (CRC) datasets. The expression of apCAF markers were upregulated in CAFs isolated from human CRCs and liver metastases compared with their normal counterparts. Kaplan-Meir analysis of 172 human CRC samples clarified that the patients with apCAF marker positive expression in the tumor stroma had worse prognosis than that with negative expression. In addition, the origin of apCAFs was reported to be mesothelial cells, therefore, we established cancer-associated mesothelial cells (CAmes) from ascites of human CRC patients with peritoneal dissemination. Consistently, the expression of antigen-presentation markers was highly upregulated in CAmes, however, allo-mixed lymphocyte reaction analysis demonstrated that their stimulating activity of CD4+ T lymphocytes was diminished. In an in vivo study, we applied a rectal orthotopic transplant model with mouse tumor organoid (MTO) to investigate the effect of apCAF on tumor progressions. Using fluorescence-activated cell sorting (FACS), we examined the ratios of apCAF, myCAF, and iCAF in orthotopic rectal tumors. The percentage of apCAF was highest in the 6-week-tumors and the percentage of myCAF was highest in the 9-week-tumors. Interestingly, the percentage of apCAF was higher in liver metastases than in primary tumor, consistent with bioinformatics analysis. The apCAF increased during the stage of tumor growth, and the percentage of myCAF increase in the later stage of tumor progression with fibrosis. In summary, apCAF might be associated with tumor progression in CRC.
Citation Format: Yasuhiro Fukui, Hiroaki Kasashima, Zizhou Wang, Ken Yonemitsu, Kishu Kitayama, Yuichiro Miki, Mami Yoshii, Tatsunari Fukuoka, Tatsuro Tamura, Masatsune Shibutani, Takahiro Toyokawa, Hiroaki Tanaka, Shigeru Lee, Masakazu Yashiro, Kiyoshi Maeda. Analysis for the role of antigen-presenting cancer-associated fibroblasts in tumor microenvironment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 287.
Abstract 2901: The apoptotic peptide TB511 targets activated CD18 and suppresses solid tumor progression
Authors: Choi Ilsoeb , Han Ik-Hwan , Kim Soyoung , Yang Juwon , Kim Hye Yeon , Park Daehwan , Choi Hongseo , Choi Jeongyoon , Lee Heekyung , Shin Jin Sun , Kim Jinho , Moon Jihwan , Bae Hyunsu 
Published: March 2024

Abstract
Tumor-associated macrophages (TAMs) primarily exist in the M2-like phenotype in the tumor microenvironment (TME). M2-TAMs contribute to tumor progression by establishing an immunosuppressive environment. However, TAM targeting is hindered, mainly owing to a lack of specific biomarkers for M2-TAMs. Herein, we verified that TB511, a fusion peptide comprising a TAM-targeting peptide and the pro-apoptotic peptide dKLA, could preferentially bind to active CD18 in M2-TAMs, inducing apoptosis; it was less toxic to other tissue-resident macrophage lineages. TB511 suppressed tumor progression in various cancer models and humanized mouse models. Removal of M2-TAMs by TB511 significantly increased the infiltration of tumor-killing cells, such as granzyme B-positive CD8+ T cells and natural killer cells, in the TME. Collectively, our findings suggest that targeting CD18 in M2-TAMs using peptide drugs is a potential strategy for immunotherapy in various tumors, including non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, and prostate cancer.
Citation Format: Ilsoeb Choi, Ik-Hwan Han, Soyoung Kim, Juwon Yang, Hye Yeon Kim, Daehwan Park, Hongseo Choi, Jeongyoon Choi, Heekyung Lee, Jin Sun Shin, Jinho Kim, Jihwan Moon, Hyunsu Bae. The apoptotic peptide TB511 targets activated CD18 and suppresses solid tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2901.
Abstract 2906: Inducing and disabling COX-2 S-nitrosylation to investigate its role in breast cancer progression
Authors: Hoffmann Reuben J. , Bensen AeSoon , de Wilde Elise , Korkola James E. , Schedin Pepper 
Published: March 2024

Abstract
Background: We aim to assess the effect of S-nitrosylation of COX-2 on tumor attributes in models of early breast cancer. COX-2 is involved in tumor progression in many solid cancers. It is a known oncogene in murine breast cancer models, and targetable by NSAIDs. In women, its clinical correlation to breast cancer progression as well as its efficacy as a therapeutic target have yielded mixed results. These incongruities may be due, in part, to a post-translational modification, as COX-2 undergoes S-nitrosylation on Cys-526. Commercially-available antibodies selectively bind to either the S-nitrosylated (SNO-COX-2) or non-nitrosylated (nCOX-2) forms, and immunohistochemical staining of human tissue reveals that the two forms of COX-2 localize to different cellular sites in normal breast tissue and have opposite associations with breast cancer progression (PMID 33298921).
Hypothesis: S-Nitrosylated and non-nitrosylated COX-2 have distinct roles in cancer progression.
Approach: MCF10DCIS.com is a human breast cancer cell line chosen due to its ability to form DCIS-like (“stage 0”) lesions in culture and xenografting, which can progress to invasion when induced by signals from the tumor microenvironment (TME).
Approach 1: Detect extracellular matrix (ECM) and ligand factors that upregulate SNO-COX-2, independently or in ECM/ligand pairs. We utilized a 2D microenvironment microarray (MEMA) and tested 357 TME conditions.
Approach 2: Validate TME conditions in 3D culture.
Approach 3: Develop a mutant MCF10DCIS.com line in which COX-2 cannot be S-nitrosylated by inducing a single disabling missense mutation at Cys-526 via CRISPR.
Results: The MEMA revealed several conditions in which SNO-COX-2 was upregulated, including fibular collagens and SSP1. In 3D culture, increased SNO-COX-2 was associated with the presence of markers for EMT and an invasive growth phenotype, whereas nCOX-2 was not. Following CRISPR transformation, 59 individual MCF10DCIS.com clones were isolated and the target site of each sequenced. We identified 10 heterozygotic clones with the desired mutation, including a classical heterozygote that also retained the WT allele.
Ongoing: Current studies include a second round of CRISPR to produce a homozygous mutant cell line as well as validation of the mutant protein. The resulting cell lines will model the loss of COX-2 S-nitrosylation in breast cancer cells while retaining otherwise-functional COX-2.
Citation Format: Reuben J. Hoffmann, AeSoon Bensen, Elise de Wilde, James E. Korkola, Pepper Schedin. Inducing and disabling COX-2 S-nitrosylation to investigate its role in breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2906.
Abstract 2907: Therapeutic targeting miR-146a and miR-21 induce malignant cell death and regulate CD8+ T-cell function in mycosis fungoides with large-cell transformation
Authors: Han Zhen , Swiderski Piotr , Wu Xiwei , Yuan Yate-Ching , Wu Jun , Su Chingyu , Qin Hanjun , Rosen Steven , Querfeld Christiane 
Published: March 2024

Abstract
Large cell transformation of mycosis fungoides (LCT-MF) occurs in 20-50% of advanced MF and is associated with an aggressive clinical course and poor survival not to overcome by any standard treatment regimen. We have previously identified a distinct miRNA expression profile in LCT-MF from that of non-transformed MF with significant upregulation of miR-21 and miR-146a. Our analyses demonstrated the involvement of genes for immune checkpoint pathways such as ICOS-ICOSL and PD1-PDL1 signaling (Di Raimondo C et al. Cancers 2021). Here, we aimed to investigate the efficacy of antagomiR-146a and -21 (amiR-146a, and -21) on the tumor growth and CD8+ tumor infiltrating lymphocyte exhaustion in LCT-MF. The amiR-146a, and -21 were synthesized in our DNA/RNA Synthesis Core by linking CpG-D19. In vitro, CTCL cell lines (Myla and HH) were treated with amiR-146a and -21, the cell viability was assessed by the 2,5-diphenyl-2H-tetrazolium bromide assay and cell apoptosis was evaluated using apoptosis assay. We found that
amiR-146a, and -21 synergistically inhibited the proliferation of MyLa and HH cells due to the activation of apoptosis through Caspase3/7 pathways and inducing cell cycle arrest by blocking STAT3/CDK1/Cyclin B1 pathway. Our RNA-seq data indicated that the exhausted CD8+ T cells express elevated amounts of STAT3, IRF4, and BATF in LCT-MF compared with non-LCT MF. To evaluate the functional importance of amiR-146a, and -21 on CD8+ T cell exhaustion, we induced an exhausted state of CD8+ T cells with high level of immune checkpoints and dysfunctional cytokine production by continues anti-CD3/DC28 beads and culture supernatant (MyLa or HH cell) exposure. Our data revealed that amiR-146a and -21 attenuated the CD8+ T cell exhaustion by blockade of immune checkpoints and STAT3/IRF4/BATF pathway to trigger the cytotoxic immune response. Collectively, the findings of our study suggest that targeting miR-146a and -21 is a promising and novel therapeutic strategy for LCT-MF.
Citation Format: Zhen Han, Piotr Swiderski, Xiwei Wu, Yate-Ching Yuan, Jun Wu, Chingyu Su, Hanjun Qin, Steven Rosen, Christiane Querfeld. Therapeutic targeting miR-146a and miR-21 induce malignant cell death and regulate CD8+ T-cell function in mycosis fungoides with large-cell transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2907.
Abstract 2939: Harnessing in vivo CRISPR screen to uncover metabolic dependencies during cancer progression
Authors: Ng Seow Qi , Wu Zhengwei , Lidster Jessica A. , Tam Wai Leong 
Published: March 2024

Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with the worst prognosis and limited treatment options. TNBC cells undergo metabolic reprogramming in response to nutrient limitations and changes in the tumor microenvironment throughout cancer progression. In the early stages, tumor cells are found to prioritize nutrient uptake and biosynthesis, but as they grow, intensified competition for nutrients fosters the emergence of subpopulations of cancer cells that excel in utilizing specific nutrients. The substantial metabolic pathways and genes that regulate each phase of cancer progression remain poorly understood. To address this, we have developed a stable integration, site-specific, and inducible CRISPR-Cas9 system that allows for temporal control of genetic perturbation. We conducted an unbiased in vivo loss-of-function CRISPR screen aimed at identifying metabolic vulnerabilities at different phases of cancer progression of TNBC. The inducible CRISPR system was activated only at the desired study period of each phase, thus capable of uncovering metabolic dependencies for TNBC proliferation at each distinct phase of cancer progression. As many large-scale CRISPR screens have previously been performed to identify gene dependencies for cancer progression in vitro, our CRISPR screen could address the shortcomings of in vitro screens by identifying novel essential metabolic genes that are significantly important for cancer growth in vivo. Preliminary data from our CRISPR screen revealed different pathways to be significantly important for tumor growth and proliferation at different phases of TNBC progression. For example, we find that ferroptosis is altered during the early lag phase of TNBC cancer progression, whereas, at the later stage of cancer progression, metastatic tumors upregulate serine metabolism, suggesting that secondary tumors could have distinct metabolism from the primary sites. Altogether, the findings from this study could provide valuable insights into stepwise metabolic dependencies arising from microenvironmental limitations and identify potential therapeutic targets at each phase of cancer progression. Moreover, our CRISPR-Cas9 model holds promise for dissecting the complex mechanisms of other cancer progressions.
Citation Format: Seow Qi Ng, Zhengwei Wu, Jessica A. Lidster, Wai Leong Tam. Harnessing in vivo CRISPR screen to uncover metabolic dependencies during cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2939.
Abstract 2960: Deciphering the role of miRNA146-a and its crosstalk with cellular redox state in senescence escape in breast cancer cells
Authors: Pervaiz Shazib , Liew Angeline Q. , Clement Marie-Veronique 
Published: March 2024

Abstract
Senescence serves as a double-edged sword in cancer as studies revealed that senescence exhibits both tumor-suppressing and tumor-promoting effects. A subpopulation of cancer cells that enters senescence can evade senescence to proliferate, thereby resulting in tumor regrowth, which has been associated with chemoresistance and tumor aggressiveness. Unlike senescent cells, the senescence-escaped cells harbor low levels of reactive oxygen species (ROS), however, the mechanism(s) underlying this redox dichotomy in senescence and senescence evasion remains elusive. In this regard, recent reports have highlighted the pivotal role of miRNAs in regulating cellular senescence. To that end, miR-146a has been reported as a biomarker of senescence probably via modulating pro-inflammatory and antioxidant pathways. We set up a model of doxorubicin-induced senescence in MDA-MB-231 breast carcinoma cells to study the role and involvement of miRNA146a in senescence induction and its regulation. Senescence induction was confirmed by upregulation of p21, increase in senescence-associated beta galactosidase and C12FDG staining, as well as propidium iodide positivity. We show that, following the initial phase of apoptotic cell death, as evidenced by increased yH2AX and cleaved caspase 3, a population of senescent cells escaped growth arrest to re-enter cell cycle and proliferate. Senescence-escaped cells harbored lower ROS levels compared to senescent cells, which correlated with upregulation of antioxidant enzymes such as MnSOD and CuZnSOD as well as increased transcription of NRF2 and NQO1. Our results also provide evidence for a novel senescence associated redox state, which implicates intracellular peroxynitrite as a driver of cellular senescence. Interestingly, in our model system, p21 upregulation was not associated with intracellular ROS accumulation, which was reported in earlier findings. Interestingly, these changes coincided with a significant increase in miR-146 expression (during senescence), which was previously shown to downregulate ROS in other model systems. While modulating miR-146a did not seem to change ROS levels upon doxorubicin-induced senescence in MDA-MB231 cells, the precise crosstalk between cellular ROS, miR146-a and senescence evasion is currently being pursued.
Citation Format: Shazib Pervaiz, Angeline Q. Liew, Marie-Veronique Clement. Deciphering the role of miRNA146-a and its crosstalk with cellular redox state in senescence escape in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2960.
Abstract 3009: ATRX loss blocks the differentiation of mesenchymal stem cells and promotes undifferentiated sarcoma development
Authors: Cai Yiming , Yao Jun , Pan Dean N. , Jin Yanqiang , You James M. , Yao Wantong , Ying Haoqiang 
Published: March 2024

Abstract
Soft tissue sarcomas (STSs) are a collection of rare tumor types originated from the mesenchymal tissues. Among the over 70 histological subtypes of STS, undifferentiated sarcoma (US), which lacks any discernible morphological features of differentiated tissues, accounts for over 20% of all STSs and is correlated with high tumor grade and poor prognosis. Recent genomic profiling in US has identified p53 and ATRX among the most frequently mutated or deleted genes. ATRX is a SWI/SNF2 type of chromatin remodeling factor which functions in a histone variant H3.3-specific chaperone complex to orchestrates replication-independent nucleosome assembly at repetitive heterochromatic DNA regions including telomeres. Loss-of-function mutations occur frequently in many tumor types and is associated with the development of alternative lengthening of telomere (ALT). However, how loss of ATRX function may contribute to tumorigenesis is largely unknown. Here, we demonstrated that ATRX is required for the terminal differentiation of mouse mesenchymal stem cells (MSCs) into multiple lineages, such as adipocytes and osteocytes. Targeted deletion of Atrx in mouse MSCs, but not terminally differentiated mesenchymal lineage cells, accelerated sarcoma initiation induced by loss of p53 and significantly shortened the overall survival. Atrx-deficient tumors express high level of MSC markers such as CD44 and CD29 and exhibit pathological features highly reminiscent of human high-grade US. Transcriptomic analysis indicates that Atrx deficiency is associated with enhanced proliferation. Together, our data indicates that ATRX deficiency contributes to undifferentiated sarcoma development by inhibiting mesenchymal stem cell differentiation.
Citation Format: Yiming Cai, Jun Yao, Dean N. Pan, Yanqiang Jin, James M. You, Wantong Yao, Haoqiang Ying. ATRX loss blocks the differentiation of mesenchymal stem cells and promotes undifferentiated sarcoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3009.
Abstract 3041: The small MAF transcription factor MAFG is a potent driver of melanoma
Authors: Vera Olga , Martinez Michael , Soto-Vargas Zulaida , Xu Xiaonan , Karreth Florian 
Published: March 2024

Abstract
While common mutations in potent proto-oncogenes and tumor suppressors induce melanoma formation, no recurrent mutations associated with the late stages of melanomagenesis have been identified. Instead, non-mutational mechanisms such as the deregulation of transcriptional or epigenetic programs typically promote the malignant progression and metastasis of melanoma. We have previously identified the small MAF transcription factor MAFG as a critical target of the melanoma suppressor miRNA miR-29, prompting an in-depth evaluation of the role of MAFG in melanoma. MAFG expression is elevated in melanoma compared to melanocytes and increases with tumor stage. Ectopic expression of MAFG in human melanocytes and melanoma cells enhances proliferation in vitro and promotes melanoma growth in vivo. Moreover, MAFG overexpression in BrafV600E; PtenFL/+ mice accelerated melanomagenesis, significantly shortening overall survival. Despite being a critical NRF2 dimerization partner, NRF2 was dispensable for the effects of MAFG. Moreover, MAFG overexpression in melanoma cells had no effect on the activity of NRF2 transcriptional reporters, nor did it induce transcriptional programs associated with NRF2. RNA sequencing and pathway analysis revealed MAFG-mediated effects on melanoma-associated processes such hypoxia, the PI3K/AKT pathway, and pigmentation. Indeed, MAFG induced HIF1a under normoxic conditions, enhanced AKT phosphorylation, and downregulated MITF and its target genes in the pigmentation pathway in melanoma cells. Interestingly, MAFG also potently enhanced AXL expression, suggesting that MAFG may promote melanoma, at least in part, by affecting the MITF/AXL balance that is associated with melanoma phenotype switching. We next analyzed whether MAFG is required for melanoma. Interestingly, silencing MAFG in human melanoma cells robustly inhibited growth in vitro. Moreover, the CRISPR/Cas9-mediated knockout of MAFG in an aggressive BrafV600E; PtenFL/FL model potently prevented melanoma formation. Given the mild phenotype of MAFG whole-body knockout mice, our results suggest targeting of MAFG or its downstream pathways as a viable therapeutic approach in melanoma. In conclusion, our study establishes MAFG as a potent driver of melanoma development and nominates it as a therapeutic target.
Citation Format: Olga Vera, Michael Martinez, Zulaida Soto-Vargas, Xiaonan Xu, Florian Karreth. The small MAF transcription factor MAFG is a potent driver of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3041.
Abstract 3061: A positive feedback loop between GLS1 and c-Myc drives tumor aggressiveness
Authors: Yang Jianqiang , Chen Fanghui , Yang Fan , Teng Yong 
Published: March 2024

Abstract
Both GLS1 and c-Myc are upregulated in head and neck squamous cell carcinoma (HNSCC) primary tumors and further increased in metastatic tumors. However, the regulation between these two molecules remains largely unknown. GLS1 is a critical enzyme that regulates glutamate, which plays an important role in cancer metabolism that supports cancer growth and survival. Our bioinformatic analysis of the TCGA HNSCC cohort revealed a strong correlation between c-Myc and GLS1 expression. We describe the importance of c-Myc in regulating GLS1 and vice versa. c-Myc protein directly binds to the promoter of the GLS1 gene and upregulates its expression at the transcriptional level. Interestingly, blocking GLS1 signaling in HNSCC cells by lentiviral shRNA knockdown or CB-839 treatment downregulates USP1, one of the best characterized human DUBs, which in turn reduces c-Myc protein stability via the ubiquitin-proteasome pathway. The GLS1-c-Myc axis thus represents a novel positive feedback loop that is critical for driving the aggressiveness of HNSCC. As the treatment of HNSCC remains a major challenge, these novel findings provide the molecular basis for combining GLS1-specific inhibitors with c-Myc-targeted therapy for the treatment of HNSCC patients.
Citation Format: Jianqiang Yang, Fanghui Chen, Fan Yang, Yong Teng. A positive feedback loop between GLS1 and c-Myc drives tumor aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3061.