bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5972: Antiangiogenic activity of FGFR inhibitor erdafitinib in urothelial carcinoma
Authors: Lim Seungtaek , Rha Sun Young , Bae Hyun Joo , Cho Sang Woo , Lee Jii Bum , Kim Tae Soo , Kang Sun Kyung , Kwon Woo Sun , Cho Nam Hoon , Choi Young Deuk , Kim Kunhong , Lee Hoi Young 
Published: June 2022

Abstract
Purpose: Fibroblast growth factors (FGFs) and fibroblast growth factor receptors (FGFRs) are implicated in tumor angiogenesis. Although erdafitinib showed efficacy in urothelial carcinoma (UC) patients harboring FGFR pathway alteration, the anti-angiogenic activity of this compound remains uncertain. Here, we investigated the suppression of UC growth by inhibiting angiogenesis with erdafitinib both in vitro and in vivo.
Materials and Methods: The inhibitory effect of erdafitinib on UC cells was evaluated by wound healing assay, transwell invasion assay, and zymography assay. Tubule formation assay and transwell migration assay was conducted to assess inhibitory effect of erdafitinib on endothelial cells (EC). Transwell migration assay to assess crosstalk of EC co-cultured with UC cell was also performed. For in vivo study, athymic nude mice bearing RT4 cells were randomly divided into a control group, and erdafitinib group. Tumors were then extracted for analysis such as immunohistochemistry.
Results: The results of wound healing assay and transwell invasion assay demonstrated that erdafitinib has inhibitory actions on the migratory and invasive potential of UC cells. Erdafitinib also suppressed tube formation and migratory potential of ECs. Transwell migration assay using EC co-cultured with RT4 showed that migration of EC was significantly inhibited by erdafitinib. For in vivo experiments, immuno-deficient mice (N=14) bearing RT4 xenografts were treated with or without erdafitinib (40mg/kg) orally three times a week for three weeks, and erdafitinib significantly suppressed tumor volumes and weight by 60.0% and 24.4%, respectively. The decrease of both CD31-positive and Ki-67-positive cells indicated that erdafitinib exerted anti-angiogenic activity.
Conclusion: This study demonstrated that erdafitinib has anti-angiogenic activities both in vitro and in vivo. It warrants further investigation for development of new therapeutic strategy.
Citation Format: Seungtaek Lim, Sun Young Rha, Hyun Joo Bae, Sang Woo Cho, Jii Bum Lee, Tae Soo Kim, Sun Kyung Kang, Woo Sun Kwon, Nam Hoon Cho, Young Deuk Choi, Kunhong Kim, Hoi Young Lee. Antiangiogenic activity of FGFR inhibitor erdafitinib in urothelial 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 5972.
Abstract 5993: Inhibition of isorhapontigenin on migration and invasion of bladder cancer cells depends on Sestrin 2 and Beclin 1
Authors: Zhang Zhuo , Li Jingxia , Tu Huailu , Costa Max 
Published: June 2022

Abstract
Bladder cancer is the fourth most common cancer in men in the United States. It has been reported that about 83,730 new cases of bladder cancer and 17,200 deaths from bladder cancer occurred in 2021. Therefore, the discovery of new alternative medication becomes extremely important for reduction of cancer mortality. Isorhapontigenin (ISO), a phytopolyphenol, is derivative stilbene isolated from the Chinese herb Gnetum cleistostachyum. It has been reported that ISO exhibits multiple anticancer activities in human high grade invasive bladder cancer cells. Our previous study has demonstrated that ISO treatment increased methyltransferase 14, N6-adenosine-methyltransferase subunit (METTL14), subsequently decreased vimentin, a key member of epithelial mesenchymal transition (EMT), resulting in reduced invasion of bladder cancer T24T cells. Autophagy maintains normal cell homeostasis through the removal of oncogenic protein substrates, toxic unfolded proteins and damaged organelles. Tumor-promoting or tumor-inhibiting functions of autophagy depends on the cancer type and stage. Sestrin 2, a member of stress-inducible protein family which is essential for maintaining metabolic homeostasis, is involved in the autophagy initiation. Beclin 1, a key autophagy regulator, is involved in multiple stages of autophagy. The present study investigated the mechanisms of ISO-inhibited migration and invasion in bladder cancer cells by focusing on Sestrin 2 and Beclin 1 pathways. Our results showed that ISO treatment in bladder cancer T24T decreased both migration and invasion as assessed by using transwell assays. However, in T24T cells with Sestrin 2 knockdown or Beclin 1 knockdown ISO lost the inhibitory effect on migration and invasion. The results from immunoblotting analysis showed that knockdown of Sestrin 2 or Beclin 1 increased N-cadherin and vimentin, two important members of EMT. While treatment with ISO in T24T wildtype cells decreased N-cadherin and vimentin, ISO did not have any effect on N-cadherin or vimentin in T24T cells with Sestrin 2 or Beclin 1 knockdown. Furthermore, ISO treatment reduced protein levels of Atg7 and Bcl-2 in T24T wildtype cells. ISO failed to decrease Atg7 and Bcl-2 in those T24T cells with Sestrin 2 or Beclin 1 knockdown. The present study suggested that ISO inhibits migration and invasion of bladder cancer cells and the inhibition of ISO is dependent on Sestrin 2 and Beclin 1, and induction of autophagy by ISO reduces migration and invasion of bladder cancer cells. The present study provides evidence that ISO can be a candidate of chemotherapy.
Citation Format: Zhuo Zhang, Jingxia Li, Huailu Tu, Max Costa. Inhibition of isorhapontigenin on migration and invasion of bladder cancer cells depends on Sestrin 2 and Beclin 1 [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 5993.
Abstract 60: Functional mapping reveals widespread remodelling and unrecognized pathway dependencies in recurrent glioblastoma
Authors: Chokshi Chirayu R. , Brown Kevin , Venugopal Chitra , Moffat Jason , Singh Sheila K. 
Published: June 2022

Abstract
Glioblastoma is a highly fatal brain cancer. The underlying functional drivers of treatment resistance and disease recurrence are unclear. By applying a genome-wide CRISPR-Cas9 library to patient-derived glioblastoma stem cell models, we systematically map genetic dependencies in patient-matched pre-treatment primary and post-treatment recurrent tumor cells. These insights reveal a large-scale remodelling of genetic dependency profiles at disease recurrence, arming recurrent tumor cells with newly-acquired genetic drivers and further loss of tumor suppressors. These analyses support parallel tumor-intrinsic mechanisms of treatment resistance which rely on acquisition of immunosuppressive capacity, including a defective mismatch repair pathway, ablation of PTEN activity, and a novel combination of de novo mutations in SWI/SNF components. We map a multilayered genetic and functional response to drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel driver of self-renewal, proliferation and tumorigenicity at glioblastoma recurrence. Mechanistically, genetic perturbation and a small molecule inhibitor of PTP4A2 results in greater survival and reduced tumor growth in patient-derived models of recurrent glioblastoma.
Citation Format: Chirayu R. Chokshi, Kevin Brown, Chitra Venugopal, Jason Moffat, Sheila K. Singh. Functional mapping reveals widespread remodelling and unrecognized pathway dependencies in recurrent glioblastoma [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 60.
Abstract 6025: Baseline cytokine profiling in naïve and tumor-bearing Balb/c and C57BL/6 Charles River mice
Authors: Munroe Kenneth , Eberle Christoph S. , Mihalek Robert , Festin Stephen 
Published: June 2022

Abstract
Background: Syngeneic studies are still the backbone of oncology research. These rely on immunocompetent mice to model anti-cancer immune responses elicited by experimental treatments. Cytokines mediate these responses through cell signaling, which contributes to an immunosuppressive milieu in the tumor microenvironment. Determining the secretion patterns of these protein modulators can help understand pathogenesis, disease progression and resistance to targeted therapies. To evaluate biological effects of potential interventions, we compared systemic cytokine activities in naïve and untreated tumor-bearing Balb/c and C57BL/6 mice.
Study Details: Charles River wild type Balb/c (n=9) and C57BL/6 (n=10) mice were used for all experiments. CT26 and B16.F10 tumor cell lines for inoculations were purchased from ATCC (Manassas, VA). Serum samples were collected from colon carcinoma (Balb/c) and melanoma (C57BL/6) bearing mice as well as tumor-free animals. For rapid multiplex measurements on the Meso Scale Discovery platform the V-PLEX Proinflammatory Panel 1 Mouse Kit was used (cat no. K15048D-1). IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, KC/GRO, IL-10, IL-12p70, and TNF-α were detected simultaneously by electrochemiluminescence within the manufacturer’s specification for each analyte.
Results: Sera from CT26 and B16.F10 tumor-bearing mice exhibited higher average concentrations of IFN-γ, IL1-β, IL-4, IL-10, KC/GRO and TNF-α, when compared to naïve mice of the Balb/c or C57BL/6 background, respectively; however, IL-2 production was found increased in tumor-bearing Balb/c and decreased in tumor-bearing C57BL/6 mice. Though known to be promoting tumor growth, IL-6 was only measurable in three out of ten B16.F10-bearing mice and below the limit of detection in CT26-bearing mice. IL-5 and IL-12 p70 levels showed no difference between CT26-bearing and naïve Balb/c mice, whereas both cytokines were elevated in the B16.F10 model over naïve C57BL/6 mice.
Conclusions: Circulating serum cytokines have been quantified in commonly used syngeneic mouse strains with and without tumor burden. These reference data provide baseline levels to compare soluble proinflammatory biomarkers suitable for assessing potential immunomodulatory effects of experimental cancer treatments in combination with other pharmacodynamic readouts.
Citation Format: Kenneth Munroe, Christoph S. Eberle, Robert Mihalek, Stephen Festin. Baseline cytokine profiling in naïve and tumor-bearing Balb/c and C57BL/6 Charles River mice [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 6025.
Abstract 6049: Identifying shared features of low-H3K27me3 pediatric brain tumors
Authors: Pun Matthew , Pratt Drew , Venneti Sriram 
Published: June 2022

Abstract
Brain tumors have the worse survival rates of all childhood malignancies, and a better understanding of their biology is needed for therapeutic development. Two especially devastating subtypes of pediatric brain tumors—diffuse midline gliomas, H3K27M-mutant (DMGs) and posterior fossa ependymomas, group A (PFAs) are both characterized by a hallmark of global reduction of histone 3 lysine 27 trimethylation, a mark associated with transcriptional repression. DMGs primarily harbor mutations of histone 3 (H3K27M) that inhibit the function of the H3 methyltransferase enhancer of zeste homolog 2 (EZH2)-containing polycomb repressive complex (PRC2). Most PFAs overexpress EZH inhibitory protein (EZHIP), resulting in a similar effect on PRC2 activity. Intriguingly, a small subset of DMGs found to be lacking H3K27M mutations express EZHIP, and a fraction of histological PFAs lacking EZHIP expression harbor H3K27M mutations. Given the highly similar putative driving alterations and epigenetic features in these two tumor types, we undertook a systematic evaluation of the clinical and molecular features of each tumor class to elucidate additional shared features and potential targetable vulnerabilities. We performed detailed analyses of genomic aberrations, gene expression, and epigenomic landscapes to identify key similarities and differences in tumor biology. From preliminary studies, our findings demonstrate similar H3K27me3 landscapes with convergence of residual tri-methylated loci between PFA and DMG tumors. We additionally found shared recurrent copy number gain of the long arm of chromosome 1 (1q) and identified several 1q genes whose expression correlated with survival differences in cohorts of both tumors. Together, these findings better define the commonalities and differences of these highly aggressive, low-H3K27me3 pediatric brain tumors and will provide a framework for understanding which therapeutic strategies may translate from one tumor to the other.
Citation Format: Matthew Pun, Drew Pratt, Sriram Venneti. Identifying shared features of low-H3K27me3 pediatric brain tumors [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 6049.
Abstract 6050: JMJD6 regulates super-enhancer mediated transcriptional dependencies in group 3 medulloblastoma
Authors: Kling Matthew , Ray Sutapa , Coulter Don W. , Chaturvedi Nagendra 
Published: June 2022

Abstract
Medulloblastoma (MB) is a heterogenous cerebellar tumor that comprises four molecular and clinically significant subgroups. MB is the most common brain malignancy in children with a five-year survival of 70%, however, Group 3 MB patients have the poorest survival due to the amplification of MYC and overexpression of key oncogenes that underly the Group 3 phenotype. Recently, epigenetic modifications bearing super-enhancer, H3K27ac, marks have been suggested to contribute to transcriptional dependencies that define Group 3 MB and represents an emerging target for therapeutic intervention. Currently, the mechanism that establishes and maintains these modifications to the DNA architecture remains unclear. In our study, we hypothesize that an epigenetic modifying protein, JMJD6, regulates the promoter-pause release associated with super-enhancer mediated oncogene addiction in Group 3 MB. This hypothesis is based on evidence in the literature showing that JMJD6 regulates the transcriptional pause release at enhancer regions. Moreover, the promoter-pause release has been shown to be critical for super-enhancer mediated transcription. In our preliminary studies, we demonstrate elevated levels of JMJD6 in Group 3 MB and survival analysis indicating JMJD6 as a predictor for poor prognosis in MB patients. Immunoprecipitation revealed that JMJD6 forms complexes with proteins involved in maintaining and regulating the promoter-pause at super-enhancers. Inducible knockdown of JMJD6 decreased MYC expression, cellular proliferation and stemness in vitro while inhibiting tumor formation and promoting survival in mice. Together, these studies identify JMJD6 as a promising therapeutic target for treating aggressive epigenetically driven Groups 3 MB tumors.
Citation Format: Matthew Kling, Sutapa Ray, Don W. Coulter, Nagendra Chaturvedi. JMJD6 regulates super-enhancer mediated transcriptional dependencies in group 3 medulloblastoma [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 6050.
Abstract 6109: Clonal relationship of B cells between tertiary lymphoid structures (TLSs) and tumor infiltrating lymphocytes (TILs) in advanced endometrial cancer
Authors: Suzuki Haruka , Hamanishi Junzo , Qin Meng , Ukita Masayo , Ueda Akihiko , Kawahara Shunsuke , Yamanoi Koji , Miyamoto Taito , Takamatsu Shiro , Taki Mana , Hosoe Yoko , Kobayashi Takashi , Yamaguchi Ken , Mandai Masaki 
Published: June 2022

Abstract
Objective: Tertiary lymphoid structures (TLSs) are known to be a marker of peripheral inflammation. While high densities of TLSs were reported to be associated with longer patient survival in several cancer types, there is no direct evidence where B cells in TLSs(TLBs) are derived from and whether these clones are consistent with tumor infiltrating B cells (TIBs), in endometrial cancer.
Methods: We analyzed the pathological distribution of TLSs and TIBs in human endometrial cancer samples using immunohistochemistry of a series of B cell markers and evaluated the relationship with patients’ clinical outcomes. Additionally, we micro-dissected six pairs of tumor nests and their neighbor TLSs and analyzed the clonal consistency between TLBs and TIBs using the sequencing of complementarity-determining region (CDR) of B cell receptor (BCR).
Results: In 104 patients with endometrial cancer, TLSs were detected in 81 patients (78%), and the absence of TLS was related to worse progression-free survival (PFS) (HR, 0.15, P &lt;0.01). Among TLS-detected cases, the high number of TIBs was significantly associated with better PFS (P&lt;0.05). BCR analyses in the six patients found that three patients with advanced stage had a unique B cell clones in common between TLBs and TIBs, while the other three patients with early stage did not have any common B cell clones. The frequency of common B cell clones in the former three patients were 10.3% (5250/51146 reads), 9.7% (1873/19369 reads) and 3.0% (1034/34618 reads).
Conclusion: TLSs and TIBs are associated with better prognosis in endometrial cancer. Common B cell clones were found in the advanced stage cases, suggesting that B cells may have gradually acquired immunospecificity in TLSs.
Citation Format: Haruka Suzuki, Junzo Hamanishi, Meng Qin, Masayo Ukita, Akihiko Ueda, Shunsuke Kawahara, Koji Yamanoi, Taito Miyamoto, Shiro Takamatsu, Mana Taki, Yoko Hosoe, Takashi Kobayashi, Ken Yamaguchi, Masaki Mandai. Clonal relationship of B cells between tertiary lymphoid structures (TLSs) and tumor infiltrating lymphocytes (TILs) in advanced 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 6109.
Abstract 6123: High-fat diets promote lung metastasis of breast cancer by activating lung fibroblasts
Authors: Chen Huiping , Huang Penghan , Chen Jianing , Song Erwei 
Published: June 2022

Abstract
Metastasis is the main cause of patient death among many tumor types including breast cancer and breast cancer patients with obesity have higher risk of distant metastases during 10-year follow-up. Diet is one of the main and manageable factors that cause obesity and regular intake of high-fat diets can induce obesity. In addition, fibroblasts, as the most abundant stromal cell type in tumor microenvironment, are involved in cancer metastasis. However, the role of fibroblasts and the downstream mechanism in metastasis of patients with high-fat diet remains unclear. In this study, we fed MMTV-PyMT transgenic mice with high-fat diet to obtain a high-fat tumorigenesis model, and isolate primary lung fibroblasts and then coculture them with breast cancer cells to explore the interaction. We found that a high-fat diet can significantly promote progression of primary breast cancer and lung metastasis, and that before weight difference shows, there is a different chemotactic influence of lung fibroblasts on breast cancer cell between high-fat diet and normal diet group. And we observed increased chemotactic function of primary lung fibroblasts in high-fat diet group. Moreover, tumor cells treated with primary lung fibroblasts in high-fat diet group show increased ability of adhesion, suggesting that high-fat diet chemoattracts breast cancer cell colonization by activating lung fibroblasts. Collectively, we explored the functional differences of lung fibroblast and the key factors for the lung colonization of recruited breast cancer cells. Our findings suggest that dietary patterns are associated with the risk of breast cancer metastasis and targeting activated fibroblasts in pre-metastatic microenvironment may serve as potential early therapeutic strategy to reduce breast cancer lung metastasis.
Citation Format: Huiping Chen, Penghan Huang, Jianing Chen, Erwei Song. High-fat diets promote lung metastasis of breast cancer by activating lung fibroblasts [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 6123.
Abstract 6156: High-fat diet-induced gut dysbiosis promotes prostate cancer growth through mast cells and histamine 1 receptor
Authors: Fujita Kazutoshi , Matsushita Makoto , Motooka Daisuke , Hase Takuaki , Banno Eri , De Velasco Marco , Kato Taigo , Kawashima Atsunari , Uemura Motohide , Nakamura Shota , Tsujikawa Kazutake , Morii Eiichi , Yoshimura Kazuhiro , Uemura Hirotsugu 
Published: June 2022

Abstract
Introduction and Objective High-fat diet (HFD) induce prostate inflammation and promote cancer growth. However, the mechanism of this inflammation has not been entirely clear. We provide the evidence of new histamine-mediated mechanism and the crucial role of the gut microbiota on HFD-induced prostate cancer (PCa) growth.
Methods We compared between HFD-fed and control diet (CD)-fed prostate-specific Pten KO mice at 22 weeks of age as PCa models. HFD-fed mice were given histamine receptor antagonist. Tumor growth was evaluated by prostate weight and Ki67 staining. Gut microbiota compositions were analyzed by 16S rRNA gene sequencing. Histamine signaling in PCa was assessed at gene and protein level.
Results HFD significantly increased prostate weight (0.25 vs. 0.46g, P = 0.01) and Ki67-positive cancer cell ratio (0.15 vs. 0.36, P = 0.01). cDNA microarray of PCa showed that expression of Hdc encoding histidine decarboxylase (HDC), which is responsible for histamine production, was upregulated in HFD-fed mice (Fold change = 2.71). The elevated expression of Hdc was also confirmed by quantitative PCR (P &lt; 0.01). Infiltrating mast cells highly produced HDC protein, and mast cell counts around cancer foci were significantly increased in HFD-fed mice. Fexofenadine (Fexo), an H1 blocker, inhibited HFD-induced PCa growth, while ranitidine, an H2 blocker, had no inhibitory effect. Fexo reduced MDSC counts and suppressed IL6-STAT3 signaling in PCa of HFD-fed mice. In vitro, both histamine and Fexo did not affect the proliferation of DU145. HFD altered the composition of gut microbiota, and Shannon index suggesting diversity of gut microbiota was reduced in HFD-fed mice. Serum lipopolysaccharide (LPS) levels were elevated in 11-week-old HFD-fed mice, and LPS injection resulted in upregulation of Hdc in PCa.
Conclusions We found that HFD caused gut microbiota dysbiosis and elevated systemic LPS level, which could promote inflammatory PCa progression through mast cells and histamine H1 receptor signaling. These results suggest the existence of “Gut-Prostate Axis.”
Citation Format: Kazutoshi Fujita, Makoto Matsushita, Daisuke Motooka, Takuaki Hase, Eri Banno, Marco De Velasco, Taigo Kato, Atsunari Kawashima, Motohide Uemura, Shota Nakamura, Kazutake Tsujikawa, Eiichi Morii, Kazuhiro Yoshimura, Hirotsugu Uemura. High-fat diet-induced gut dysbiosis promotes prostate cancer growth through mast cells and histamine 1 receptor [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 6156.