bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5820: Chloroquine inhibited Rab11 mediated E-cadherin transport in collective colon cell migration in Dasatinib resistant cells
Authors: Hou Xiang-Ling , Koo Hui Min , Lin Chia-Wen , Huang Chien-Chi , Tseng Yu-Chi , Tseng Kai-Yu , Chao Wei-Ting 
Published: April 2023

Abstract
In has been demonstrated epithelial mesenchymal transition (EMT) is related to E-cadherin expression level. Recently, studies have been demonstrated the collective cancer cell migration which expresses high E-cadherin is a powerful mechanism of metastasis. Therefore, the role of E-cadherin in cancer metastasis is still not clear. Endocytosis was shown to regulate E-cadherin turnover on the membrane and the function of lysosome is also associated with cell vesicle trafficking. The past studies indicated Src can regulate vesicle trafficking. In this study, HT29 colon cancer cells were treated with Src inhibitor, Dasatinib (DST), to investigate the role of lysosome in regulating E-cadherin dynamics through vesicle trafficking in collective cell migration. In the result, the recycling protein Rab11 and lysosome marker Lamp1 were found localized with E-cadherin in the cell-cell contacts, however, Dasatinib sensitive (DSTS) cells showed less colocalization of Rab11 with E-cadherin. When cells were treated with lysosome inhibitor chloroquine, Rab11 were accumulated in the cell-cell contacts and reduced collective cell migration in Dasatinib resistant (DSTR) cells. These results suggest lysosome inhibition can suppress Rab11 mediated vesicle trafficking of E-cadherin transport for collective cell migration, and chloroquine has therapeutic potential in colon cancer treatment.
Citation Format: Xiang-Ling Hou, Hui Min Koo, Chia-Wen Lin, Chien-Chi Huang, Yu-Chi Tseng, Kai-Yu Tseng, Wei-Ting Chao. Chloroquine inhibited Rab11 mediated E-cadherin transport in collective colon cell migration in Dasatinib resistant cells [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 5820.
Abstract 5821: Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP-TRX signaling
Authors: Gao Jiaming , Yao Yunying , Wang Zaiqi , Zhang Baoyuan , Ren Ruibao 
Published: April 2023

Abstract
CDH1 deficiency is common in triple negative breast cancer and diffuse gastric cancer patients, both of which lack effective therapeutics. Although inhibiting ROS1 function results in synthetic lethality in CDH1-deficient cancers, adaptive resistance limits their potential clinical benefits. Hyperactive focal adhesion kinase (FAK) signaling contributes to adaptive drug resistance, and FAK inhibitors are partially effective against CDH1–deficient cancers. Thus, co-treatment with ROS1 and FAK inhibitors may provide stronger anti-cancer effects by targeting CDH1 deficiency and potentially overcome drug resistance. Here, we evaluated the effects and mechanisms of combined treatment with FAK inhibitor IN10018 and ROS1 inhibitors. Cell-based assays and in vivo animal experiments revealed that FAK and ROS1 inhibitor combination treatment showed stronger anti-cancer effects than either monotherapy. ROS1 inhibitors induced FAK-YAP-TRX signaling, decreasing oxidative stress–related DNA damage, and consequently reducing its anti-cancer effects. However, the combination treatment suppressed the aberrant FAK-YAP-TRX signaling, reinforcing the cytotoxicity of ROS1 inhibitor towards cancer cells. This mechanism of action was confirmed by inhibiting the activity of FAK-YAP-TRX downstream signaling molecules and by pretreatment with oxidative stress scavengers. These findings support the co-administration of FAK and ROS1 inhibitors as a therapeutic strategy in CDH1-deficient triple negative breast cancer and diffuse gastric cancer patients and support further clinical testing of this combination regimen.
Citation Format: Jiaming Gao, Yunying Yao, Zaiqi Wang, Baoyuan Zhang, Ruibao Ren. Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP-TRX signaling [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 5821.
Abstract 592: Therapeutical antibody against LILRB2 enhances antitumor immunity by reprogramming M2 macrophage
Authors: Su Chen , Feng Yanping , Zhao Hui , Zhang Meng , Luo Longtan , Hao Feng , Ning Jinying , Wu Guojin 
Published: April 2023

Abstract
M2 macrophage is critical in maintaining an immune-suppressive microenvironment inside the tumor. Here we developed a LILRB2 antagonist antibody KA-1769 for reprogramming M2 macrophage to M1 phenotype. KA-1769 binds to LILRB2 with higher affinity (KD=0.67nM) than MK-4830 (KD=7.4nM). And it also binds to LILRB1 with weak affinity (KD=41nM) but not to other LILR family members. KA-1769 blocks bindings of HLA-G to both LILRB1 and LILRB2. Macrophage derived from monocyte with M-CSF stimulation polarizes to M1 phenotype in the presence of KA-1769 by increasing expression of CD86, MHCII, and TNF-α and decreasing expression of CD14, CD206, CD163, and IL-10. KA-1769 accelerates T cell proliferation when co-cultured with macrophage. In a syngeneic Lewis lung carcinoma murine model with LILRB2-transgenic mice, injection of KA-1769 significantly suppressed tumor growth. It decreased the tumor's myeloid-derived suppressor cells (MDSC) and CD4+ CD25+ FoxP3+ Treg population. Based on these preclinical data, KA-1769 is an excellent therapeutical antibody for enhancing antitumor immunity.
Citation Format: Chen Su, Yanping Feng, Hui Zhao, Meng Zhang, Longtan Luo, Feng Hao, Jinying Ning, Guojin Wu. Therapeutical antibody against LILRB2 enhances antitumor immunity by reprogramming M2 macrophage [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 592.
Abstract 5930: Single day workflow for high-quality whole genome analysis of thousands of single cells
Authors: West Jay A. , Blackinton Jeff G. , Hukari Kyle , Dahl Joe 
Published: April 2023

Abstract
DNA sequencing technology provides the capability to tell the story of every cell in a heterogenous sample. ResolveDNA® generates uniform coverage of &gt;95% of a single genome, enabling researchers to generate single-cell genomic data of unparalleled quality. Here, we report an enhancement to the ResolveDNA® workflow that increases the rate of data collection; the ability to reliably generate complete genomic information from up to 1536 cells in parallel from a single experiment. To achieve this, we have coupled a high-throughput automated process to a low volume reaction using the latest ResolveDNA® 2.5-hour chemistry. This establishes the potential for users to go from a single cell, or low-input DNA sample, to ready to sequence libraries in a single day for &gt;3000 samples. As with earlier ResolveDNA® workflows, these reactions generate negligible amounts of contaminating and off target DNA during the reaction. A typical single-cell reaction yields ~ 85 ng of DNA. The single cell’s amplified DNA product is amenable to multiple post amplification library preparation processes. We utilized both BioSkryb ResolveDNA® and Watchmaker Library Preparation kits for Illumina sequencing. We did not identify significant differences in the performance of the two products. Libraries were assessed at a depth of ~ 2million reads and determined to be of high quality, with low rates of chimeric DNA formation and less than 1% mtDNA resulting in the reaction product. A subset of samples was probed at &gt;200 million reads, with &gt;85% of the genome covered at 1x. Consistent with earlier ResolveDNA® workflows, the libraries were characterized with &gt;99% precision and &gt;80% sensitivity. The story told from a single cell’s genome drives discovery and shines a light on the questions surrounding the causes of disease and cellular function. This workflow is designed to empower researchers to probe the genomic landscape of a heterogenous tissue sample.
Citation Format: Jay A. West, Jeff G. Blackinton, Kyle Hukari, Joe Dahl. Single day workflow for high-quality whole genome analysis of thousands of single cells [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 5930.
Abstract 5965: B2M loss of heterozygosity in melanoma is associated with increased numbers of activated NK cells and higher expression of the NK cell inhibitory ligand, HLA-G
Authors: Galvez Mildred , Campbell Katie M. , Medina Egmidio , Ribas Antoni 
Published: April 2023

Abstract
β2-microglobulin (B2M) is a critical subunit of antigen presenting major histocompatibility complex (MHC) class I molecules. Its genetic inactivation in tumor cells has been implicated in tumor-intrinsic immune escape and immunotherapy resistance. Currently, the impact of B2M dysregulation on tumor-immune dynamics requires furthers characterization. Using a clinical dataset of patients with melanoma treated with immune checkpoint blockade (ICB), whole-exome sequencing and bulk RNA-sequencing data from baseline tumor biopsies (n=295) were analyzed to identify somatic B2M alterations and evaluate correlative clinical outcomes, infiltrating immune cells, and gene expression patterns. No loss-of-function mutations in B2M were found; however, 50% of tumors had B2M alterations in the form of homozygous loss (n=2), loss of heterozygosity (LOH; n=56), or copy number gains (n=88). B2M LOH events were overrepresented in tumors from patients who progressed during ICB therapy compared to those who responded (34% versus 19%; Pearson chi-square test, p=0.035). Additionally, tumors with B2M LOH had lower B2M expression compared to B2M-unaltered tumors (Wilcoxon test, p=0.05). Gene set enrichment analysis revealed reduced expression of immune and inflammatory signatures in B2M-LOH tumors. Furthermore, immune cell deconvolution showed that B2M-LOH tumors had lower total immune cell counts, but greater numbers and proportions of activated natural killer (NK) cells (Wilcoxon test, numbers p=0.021, proportions p=0.032). Differential gene expression analysis revealed concordant higher expression of human leukocyte antigen G (HLA-G), an NK cell inhibitory ligand, in B2M-LOH tumors (Wilcoxon test, p=0.0035). Moreover, B2M-LOH progressive tumors had the highest median HLA-G expression and trended toward a positive correlation between increasing HLA-G expression and increasing numbers of activated NK cells (Pearson correlation, r=0.55, p=0.015). In conclusion, melanoma biopsies with B2M LOH were associated with non-response to ICB, had increased presence of activated NK cells, and demonstrated a compensatory increase in HLA-G. These results suggest that in melanoma B2M alterations may be implicated in modulating NK cell interactions and point toward HLA-G potentially playing a role in inhibiting NK cell anti-tumor activity.
Citation Format: Mildred Galvez, Katie M. Campbell, Egmidio Medina, Antoni Ribas. B2M loss of heterozygosity in melanoma is associated with increased numbers of activated NK cells and higher expression of the NK cell inhibitory ligand, HLA-G [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 5965.
Abstract 5966: Cathepsin S mediates interleukin 7 to sculpture the tumor immunity in head and neck cancer
Authors: Chang Yung-Chieh , Chen Shan-Hung , Chang Kwang-Yu , Chang Jang-Yang 
Published: April 2023

Abstract
Cathepsin S (CTSS) is a lysosomal enzyme that belongs to cysteine proteases. It is associated with progression of different types of cancer, mediating the antigen presentation, extracellular matrix degradation, angiogenesis, and metastasis. In recent studies, CTSS was suggested as a therapeutic target for cancer treatment. We found that, with a CTSS inhibitor RJW-58 treatment over tumor-bearing mouse, the serum showed an enhanced anti-tumor cytokine releasing of interleukin 7 (IL-7). In the mRNA array results of 40 pair head and neck patients’ sample, we found the negative correlation between CTSS and IL-7 comparing to the normal head and neck tissue. Moreover, we also found that the level of CD8 T cell infiltration is negatively correlated with the expression of CTSS in 20 head and neck cancer patients’ slides. In cell model, targeting CTSS by siRNA or RJW-58 promoted IL-7 secretion in different head and neck cancer cell lines. We demonstrated that cathepsin S decreased the secretion level of IL-7 through downregulating IL-7 receptor, a receptor that mediating IL-7 secretion, protein expression level resulting in activating lysosomal degradation pathway. Promoting cell proliferation of activated CD8 T cells was proved when CD8 T cells were treated with the condition medium from CTSS-knockdown head and neck cancer cells. In conclusion, this is the first study demonstrated that CTSS acted as a negative regulator in mediating IL-7 resulting in inducing an immune cell-suppressed microenvironment in head and neck cancer cells. (This work is supported by the NSTC grand number: MOST 110-2314-B-400-035)
Citation Format: Yung-Chieh Chang, Shan-Hung Chen, Kwang-Yu Chang, Jang-Yang Chang. Cathepsin S mediates interleukin 7 to sculpture the tumor immunity in head and neck 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 5966.
Abstract 5972: CDK1 bridges NF-kB and b-catenin signaling in response to H. pylori infection in gastric tumorigenesis
Authors: Al-Mathkour Marwah M. , Zhu Shoumin , Cao Longlong , Khalafi Shayan , Chen Zheng , Poveda Julio , Peng Dunfa , Lu Heng , Soutto Mohammed , Hu Tianling , McDonalnd Oliver , Zaika Alexander , El-Rifai Wael 
Published: April 2023

Abstract
Background: Cell cycle dysregulation is a hallmark of cancer, resulting in unregulated cell proliferation and, eventually, tumor development. Cyclin-dependent kinase 1 (CDK1) is a cell cycle regulatory protein that is involved in cell cycle maintenance. CDK1 has been discovered to be substantially elevated in a several tumors and is linked to poor overall and relapse-free survival. The aim of this study is to understand the regulation role of Helicobacter Pylori infection and inflammation on CDK1 expression in gastric cancer.
Methods: Using TCGA data and our integrated comprehensive gene expression analysis, we found a significant overexpression of CDK1 in gastric cancer human and mouse tissues. We detected overexpression of CDK1 in human and mouse gastric glands in response to H. pylori infection. Our data demonstrated that H. pylori infection induced phosphorylation (S536) and activation of NF-kB in vitro and in vivo. Furthermore, H. pylori infection and TNF-α treatment increased the CDK1 mRNA and protein levels in gastric cancer cell lines. Using the ChIP assay, we detected direct biding of NF-κB on the CDK1 promoter regulating its transcription. CDK1 promoted activation of the β-catenin signaling pathway. Using the pTOP/pFOP luciferase reporter assays, as a measure of β-catenin/TCF transcription activity, we confirmed CDK1-dependent activation of β-catenin in response to H. pylori infection. Pharmacologic and genetic inhibition of CDK1 reversed these effects and decreased number and size of gastric tumors organoid from mouse and human.
Conclusion: Our findings demonstrate NF-kB-mediated induction of CDK1 expression in response to H. pylori infection with subsequent activation of tumorigenic β-catenin signaling. This novel regulatory link between infection, CDK1, and β-catenin suggests the importance of considering CDK1 inhibitors in gastric cancer.
Citation Format: Marwah M. Al-Mathkour, Shoumin Zhu, Longlong Cao, Shayan Khalafi, Zheng Chen, Julio Poveda, Dunfa Peng, Heng Lu, Mohammed Soutto, Tianling Hu, Oliver McDonalnd, Alexander Zaika, Wael El-Rifai. CDK1 bridges NF-kB and b-catenin signaling in response to H. pylori infection in gastric tumorigenesis [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 5972.
Abstract 6085: Molecular profile by next generation sequencing in papillary thyroid carcinoma, Colombian Cohort at Fundacion Santa fe de Bogota University Hospital
Authors: Rodriguez Paula , González Sebastián , Cruz Sergio , Juez Yesith , Becerra David , Baldión Margarita , Perdomo Sandra , Beltran Angela , Hakim Jose , Gonzales Deyanira 
Published: April 2023

Abstract
Objective/aim: To describe the main molecular alterations in a Colombian Cohort of patients diagnosed with Papillary Thyroid Carcinoma (PTC) at Fundacion Santa Fe de Bogota University Hospital between 1993 and 2011
Methods: A total of 231 surgically intervened patients at our institution and diagnosed with PTC with available paraffin blocks were analysed. DNA and RNA extraction was performed from FFPE samples using Quick-DNA & RNA FFPE MiniPrep Kit (Zymo Research). Next Generation Sequencing analysis was performed using SOPHiA Solid Tumor Solutions Kit (SOPHiA GENETICS, Saint Sulpice, Suiza), which detects 42 DNA genes and 137 fusion genes with the platform MiSeq System (Illlumina, San Diego, California). Data underwent QA and QC and variants were analysed through Sophia commercial pipeline for somatic aberrations.
Results: Among 231 patients, 82% were women, average age 45 +/- 13 y-o, 97% from Colombia, with institutional pathologic diagnosis of PTC. The most frequent histological subtypes were Classic PTG (33%), Follicular Infiltrative (29%) and Tall cell (23%). Identification of clinically relevant molecular alterations was done (see table 1). The most frequent SNV mutations were BRAF-V600E (72%), TP53 (9%) and IDH1-R132H (8%). The most frequent insertions or deletions (INDELS) were found in KIT (75%). We identified 8 fusion genes (most frequent were RET-CCD6 and ETV6-NTRK3). Interestingly, we detected 3 MSI positive cases.
Conclusions: PTC molecular profile by NGS can allow us to improve molecular understanding of the disease and identify possible prognostic factors and treatment targets.
Table 1. Molecular alterations detected by next-generation sequencing in Papillary carcinoma Molecular alterations Gene n % INDEL (n=20) KIT 15 75,0 NRAS 1 5,0 PTPN11 1 5,0 TP53 3 15 SNV (n=226) BRAF 163 72,1 FGFR1 1 0,4 HRAS 2 0,9 IDH1 19 8,4 KIT 2 0,9 KRAS 2 0,9 NRAS 9 4,0 PDGFRA 1 0,4 PIK3CA 3 1,3 SMAD4 4 1,8 TP53 20 8,8 Fusion genes (n=6) CCDC6-RET 2 25,0 ETV6-NTRK3 2 25,0 GOLGB1-TACC3 1 12,5 MYH14-BICC1 2 25,0 GOPC-RET 1 12,5 MSI (n=231) MSI-L 3 1,3 Negative 228 98,7
Citation Format: Paula Rodriguez, Sebastián González, Sergio Cruz, Yesith Juez, David Becerra, Margarita Baldión, Sandra Perdomo, Angela Beltran, Jose Hakim, Deyanira Gonzales. Molecular profile by next generation sequencing in papillary thyroid carcinoma, Colombian Cohort at Fundacion Santa fe de Bogota University Hospital [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 6085.
Abstract 6227: Tumor cell heterogeneity may cause treatment failure of GPA33-targeted therapy in colorectal cancer
Authors: Börding Teresa , Janik Tobias , Morkel Markus , Sers Christine , Horst David 
Published: April 2023

Abstract
Purpose: Glycoprotein A33 (GPA33) is a membrane protein almost exclusively expressed in intestinal epithelia and in more than 95% of colorectal cancers (CRCs). This renders GPA33 a promising antigen for targeted therapy, but trials did not meet pre-specified response rates. We investigated intratumoral heterogeneity as a reason for low treatment efficacy, GPA33 regulation and the potential for pharmacological induction of GPA33 expression in vitro and in vivo to enhance treatment response.
Methods: We assessed intratumoral heterogeneity of GPA33 in tissue specimens of 223 stage II CRCs using immunohistochemistry and immunofluorescence, and obtained scRNAseq transcriptomic analysis from 12 primary CRCs. We then manipulated WNT and PPARγ signaling pathways and transcription factor expression in colon cancer cells using specific inhibitors, siRNAs or inducible dominant negative TCF4 (dnTCF4), and analyzed the effects on GPA33 protein and RNA expression. Furthermore, we investigated the effects of WNT inhibition on GPA33 in vivo in NOD/SCID xenografts. Additionally, we developed anti-GPA33 CAR-T cells and measured their activation after co-cultivation with colon cancer cells using flow cytometry.
Results: In the CRC cohort we found that GPA33 expressing cells had a differentiated phenotype and low WNT activity. GPA33-negative subpopulations were located at the infiltrative tumor edge and showed increased nuclear β-catenin. Downregulation of WNT pathway activity using inhibitors, siRNAs or inducible dominant negative TCF4 (dnTCF4), as well as activation of PPARγ signaling induced GPA33 expression in vitro. Forced expression of dnTCF4 also enhanced GPA33 expression in vivo in previously GPA33-negative tumor cell subpopulations in colon cancer xenografts. siRNA mediated knockdown of CDX1 and KLF4, two transcription factors that were previously implicated in GPA33 regulation, only moderately reduced GPA33 expression levels in vitro. Anti-GPA33 CAR-T cells activated in response to co-culture with GPA33-expressing CRC cells in vitro.
Conclusion: Our analysis highlights a heterogenous expression of GPA33 in vivo as a limiting factor for anti-GPA33 therapy. WNT inhibition or PPARγ activation induced GPA33 expression in vitro and in vivo. Depletion of CDX1 and KLF4 had moderate effects on GPA33 only, indicating a complex regulation in colon cancer. We suggest that pharmacological induction of GPA33 expression may increase the efficacy of anti-GPA33 targeted therapy in patients with CRC.
Citation Format: Teresa Börding, Tobias Janik, Markus Morkel, Christine Sers, David Horst. Tumor cell heterogeneity may cause treatment failure of GPA33-targeted therapy in colorectal 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 6227.