bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2424: Development of radiation sensitivity evaluation platform in esophageal cancer patient derived organoids
Authors: Kim Jung Eun , Jeong Mi-Hyeon , Ravangnam Thunyaporn , Ju Sunghun , Lee Dong Woo , Ku Bosung , Oh Dongryul 
Published: April 2023

Abstract
Radiation therapy (Radiotherapy) is a highly effective treatment with wide range of cancer curing. Radiotherapy allows the cancer cells to be killed or reduced in number while protecting the majority of other organs and tissues in the body. Radiotherapy is commonly used with chemotherapy or immunotherapy or radiosensitizer drugs for enhancing the treatment efficacy. Predicting individual radiation sensitivity is very important in determining the direction of future treatment after cancer diagnosis. However, it is lack of accurate and relevant preclinical model for evaluation of radiation sensitivity.In this study, we developed the platform for radiosensitivity evaluation using the Esophageal cancer patient derived organoids. Biopsy tissues from Esophageal cancer were digested to single cells and then dispensed with ECM on pillar plate (MBD co.) to forming organoids. After organoid formation, the organoids were exposed to radiation with increasing dosage. Cell viability and radiation sensitivity were calculated by 3D Celltiter glo method and Calcein AM staining. Radiation sensitivity index was determined based on radiation response and organoid growth.We included 22 patients with ESCC treat with radiation therapy from Samsung Medical Center. After surgery, we compared radiation sensitivity index with pathological grade for sensitivity and specificity of radio sensitivity evaluation platform. The sensitivity was 75.00% (95% CI 34.91% - 86.81%) and the specificity was 71.43% (95% CI 41.90% - 91.61%). This resulted in an accuracy in this population of 72.73% (95% CI 49.78% - 89.27%).This study has a very high correlation to patient matched clinical outcomes of radiation sensitive group or non-sensitive group. This radiation sensitivity evaluation platform could contribute to precision medicine in Esophageal cancer patients and it can be helpful to make decision how to cure of cancer.
Citation Format: Jung Eun Kim, Mi-Hyeon Jeong, Thunyaporn Ravangnam, Sunghun Ju, Dong Woo Lee, Bosung Ku, Dongryul Oh. Development of radiation sensitivity evaluation platform in esophageal cancer patient derived organoids [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 2424.
Abstract 2429: AGPAT4 as a novel metabolic driver of oncogenic stemness and dedifferentiation in hepatocellular carcinoma
Authors: Ng Kai Yu , Fong Tsz-Lok , Gao Ya , Wong Tin-Lok , Gao Yuan , Yun Jing-Ping , Guan Xin-Yuan , Liu Ming , Chung Clive YS , Ma Stephanie 
Published: April 2023

Abstract
The liver is an unique organ in that it is responsible for many metabolic functions. During HCC development, these metabolic machineries are extensively reprogrammed to support the insatiable nutrient requirement of HCC. Cancer stem cells (CSCs) are a small and elusive subpopulation of self-renewing cancer cells with remarkable ability to initiate, propagate, and spread the malignant disease. Liver CSCs reprogram their metabolic pathways to match with the increased metabolic needs for cancer cell survival under adverse conditions. Identifying novel metabolic targets that are related to stemness can offer promising strategies for targeting CSCs and hence to kill and to control their growth. In this study, pathway enrichment analysis of genes that linked metabolism and stemness identified aberrant glycerophospholipid metabolism of which AGPAT4 ranked a top-hit. AGPAT4 upregulation in HCC is tightly correlated with aggressive clinical features, including survival, metastasis, and stemness signatures. Expression of AGPAT4 peaked during early liver progenitor development, decreased during hepatocyte maturation and increased progressively from well-differentiated to poorly differentiated HCCs. Enrichment of AGPAT4 in HCC was mediated by promoter binding of SOX9 to drive AGPAT4 transcriptional activity. AGPAT4 inhibition could mitigate tumor initiation, self-renewal, metastasis and sorafenib resistance. Mechanistic studies revealed an AGPAT4-mediated phosphatidic acid production axis to promote HCC through regulating mTOR signaling. Inhibition of Agpat4 by AAV8 shRNA reduced tumorigenicity and stemness, and sensitized HCC tumors to sorafenib. AGPAT4 overexpression was able to predict sorafenib response in the clinic. Through high-throughput screening coupled with activity-based protein profiling, a cysteine-reacting compound with high binding affinity and selectivity towards AGPAT4 was identified and found to work synergistically with sorafenib to supress HCC. To conclude, AGPAT4 is a novel metabolic driver of oncogenic stemness, dedifferentiation and metastasis in HCC. AGPAT4-induced tumor lineage plasticity may represent an Achilles heel for HCC. Inhibition of AGPAT4 may widen the therapeutic window for sorafenib treatment in the clinic.
Citation Format: Kai Yu Ng, Tsz-Lok Fong, Ya Gao, Tin-Lok Wong, Yuan Gao, Jing-Ping Yun, Xin-Yuan Guan, Ming Liu, Clive YS Chung, Stephanie Ma. AGPAT4 as a novel metabolic driver of oncogenic stemness and dedifferentiation in hepatocellular 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 2429.
Abstract 2449: p38β promotes cancer stemness and chemoresistance in hepatocellular carcinoma
Authors: Huang Ianto Bosheng , Xie Yunong , Wong Tin Lok , Lee Terence Kin Wah , Yun Jing-Ping , Ma Stephanie Kwai Yee , Tong Man 
Published: April 2023

Abstract
Protein kinases control a variety of oncogenic functions through a phosphotransfer dependent signal transduction cascade in cancers where potent and selective inhibitors could be developed with favorable pharmaceutical properties. In hepatocellular carcinoma (HCC), increasing evidence suggested that cancer stemness is a driving force of therapy resistance which is tightly controlled by kinase-dependent signaling cascades. However, there are still limited druggable kinase targets that are developed to combat cancer stemness and therapy resistance for HCC treatment. To identify potential kinase targets which promote stemness, survival and therapy resistance in HCC, two datasets profiling kinase genes which are important for HCC survival and chemoresistance in HCC spheres were compared. p38 MAPK beta (p38β) was found to be a common top-ranked kinase important for these functions. Clinically, biopsies of human HCC showed high expression of total and activated forms of p38β, suggesting that p38β could be a potential therapeutic target in HCC. Functionally, we demonstrated that p38β promoted HCC tumor initiation, self-renewal and resistance towards chemotherapy by cisplatin. Using tandem affinity purification coupled with mass spectrometry, we identified BiP, which is a chaperone protein, as a novel binding partner of p38β. Subsequent mechanistic validation and mass spectrometry analysis showed that p38β directly phosphorylates BiP at a previously unrecognized phosphorylation site. Rescue experiments with BiP mutation and inhibition abrogated the stemness and chemoresistant properties observed in p38β overexpressing HCC cells. Taken together, we identified and characterized p38β and its direct phosphorylation target BiP as critical regulators for promoting cancer stemness and chemoresistance in HCC.
Citation Format: Ianto Bosheng Huang, Yunong Xie, Tin Lok Wong, Terence Kin Wah Lee, Jing-Ping Yun, Stephanie Kwai Yee Ma, Man Tong. p38β promotes cancer stemness and chemoresistance in hepatocellular 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 2449.
Abstract 2455: Investigating cancer stem cell plasticity in ovarian cancer
Authors: Metcalfe Tara X. , Zhang Shu , Hassel Christiane , O'Hagan Heather M. , Nephew Kenneth P. 
Published: April 2023

Abstract
Most women diagnosed with late-stage high grade serous ovarian cancer (HGSOC) develop recurrent, platinum-resistant tumors. Ovarian cancer stem cells (OCSCs) are hypothesized to contribute to the emergence of these resistant tumors. CSCs have been postulated to reside in a plastic state, which can allow for the conversion of non-CSC to CSC. This process of dedifferentiation continues during tumor development and chemotherapeutic agents like platinum can exaggerate CSC plasticity. We have previously demonstrated that acute platinum treatment enriched for OCSCs. However, whether platinum transforms non-OCSCs into OCSCs to contribute to this subpopulation of cells remains unclear, and the underlying mechanism remains incompletely understood. To examine OCSC plasticity, aldehyde dehydrogenase (ALDH; functional marker) and fluorescence activated cell sorting were used to isolate OCSCs (ALDH+) and non-OCSCs (ALDH-) from HGSOC cell lines, OVCAR5 and OVCAR3. To determine the stability of the non-OCSC phenotype, ALDH- cells were cultured for 3 and 5 days and ALDH activity was measured using flow cytometry. At both timepoints examined, ALDH- cells remained ALDH-, with approximately less than 1% being ALDH+ (p&lt;0.05). To determine if platinum can induce conversion of non-OCSC to OCSC, ALDH- cells were treated with cisplatin (12µM for 16h), and the percent of ALDH+ cells was measured using flow cytometry. Treatment of ALDH- cells with cisplatin resulted in conversion of approximately 3-4% of ALDH- cells into ALDH+ cells (p&lt;0.05). Furthermore, increased expression (p&lt;0.05) of stemness genes BMI1, NANOG, OCT4, and SOX2, analyzed using qRT-PCR, was observed in converted OCSCs compared to parental ALDH+ and whole cell populations treated with cisplatin (12µM for 16h), suggesting that platinum induced the observed differences in the stemness phenotype. With the goal of targeting key genes and pathways to inhibit platinum-induced OCSC conversion, we are carrying out RNA-sequencing analysis of the converted OCSCs and investigating the genes and pathways driving the platinum-induced conversion on non-OCSCs to OCSCs. Understanding the mechanisms involved in OCSC plasticity is critical to developing targeted therapies to block the persistence of OCSCs and ultimately reduce mortality in patients.
Citation Format: Tara X. Metcalfe, Shu Zhang, Christiane Hassel, Heather M. O'Hagan, Kenneth P. Nephew. Investigating cancer stem cell plasticity in ovarian 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 2455.
Abstract 2456: Transcriptional signatures of stem cell phenotypes in normal and clonal hematopoiesis
Authors: Soldatov Ruslan , Schiroli Giulia , Kharchenko Peter , Scadden David 
Published: April 2023

Abstract
Clonal hematopoiesis (CH) is an age-related clonal expansion of hematopoietic stem cells (HSCs). Factors that shape the progression of CH are only beginning to be characterized. HSCs are a heterogeneous population of cells with distinct clonal outputs over time, which are hypothesized to be largely scripted in epigenetic and transcriptional cell state. Molecular properties of HSC states that mediate clonal behaviors of two major driver mutations in CH - DNMT3A and TET2 - represent potential therapeutical targets. Recent studies have identified the landscape of human CH mutant cells compared to non-mutated ones. However, the notion of a specific molecular target identified in CH cells associated with selective advantage or predisposition for subsequent transformation requires a formal validation by longitudinal studies. To uncover molecular underpinnings of CH-driven clonal phenotypes in human HSCs in vivo, we combined clonal analysis using heritable expressed DNA barcodes with single-cell transcriptomics using transplant in immunodeficient mice. We developed a statistical approach to associate transcriptional differences of HSCs with the clone phenotypes, such as size and HSC density, across more than a hundred of detected clones. It revealed robust transcriptional signatures underlying clone size and HSC density, which are largely complementary to transcriptional programs activated in TET2 and DNMT3A mutant HSCs. Of note, the clone size and density of HSCs in the clone tend to be uncoupled and associated with distinct transcriptional processes.
Citation Format: Ruslan Soldatov, Giulia Schiroli, Peter Kharchenko, David Scadden. Transcriptional signatures of stem cell phenotypes in normal and clonal hematopoiesis [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 2456.
Abstract 2470: ARG1 is potential prognostic biomarker for development of distant metastatic endometrial cancer in mice with Pten deficiency
Authors: Jeong Jae-Wook , Tran Dinh , Rozen Valery , Kim Tae Hoon , Yoo Jung-Yoon 
Published: April 2023

Abstract
Endometrial cancer is the most common gynecologic malignancy. The most common histological type is endometrioid endometrial cancer (EEC). While the majority of patients present with early-stage and low-grade EEC and have an excellent prognosis, a subset has metastatic disease at presentation, or develops distant recurrence after initial treatment of the primary. However, the lack of prognostic biomarkers for metastatic EEC is a critical barrier. We have developed a genetically engineered mouse model for metastatic EEC that implicates coexistent Pten and Mig-6 mutations in EEC. Pten mutation in the uterus is not sufficient for distant metastasis, but mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. Arginase 1 (ARG1) regulates the last step of the urea cycle, and an increase in ARG1 has been correlated as a poor prognostic factor in a variety of cancers including ovarian carcinoma, colorectal cancer, and neuroblastoma. In the present study, ARG1 expression was evaluated with immunohistochemistry in endometrial hyperplasia and cancer of mice with Pten mutation as well as Pten and Mig-6 double mutations. Our immunostaining analysis revealed that the expression of ARG1 in early stage of EEC from mice deficient in Mig-6 and Pten mutations significantly increased compared to Pten mutation in the uterus. High levels of ARG1 are associated with distant metastatic endometrial cancer. The results demonstrate that a high level of ARG1 is associated with poor prognosis in association with EEC of mouse. ARG1 has the potential to identify patients that require additional treatment at an early stage of endometrial cancer.
Citation Format: Jae-Wook Jeong, Dinh Tran, Valery Rozen, Tae Hoon Kim, Jung-Yoon Yoo. ARG1 is potential prognostic biomarker for development of distant metastatic endometrial cancer in mice with Pten deficiency [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 2470.
Abstract 2579: The tumor landscape is molded by quantitative and qualitative signaling differences between different oncogenic KRAS mutations
Authors: Roux Ozgun Le , Counter Christopher M. 
Published: April 2023

Abstract
Despite over 50 possible oncogenic RAS mutations, cancers tend to have a bias towards a specific subset, often unique to each cancer type. As RAS mutation occur early, if not being the first mutations, these mutation patterns ostensibly reflect the selection of specific RAS mutations in each tissue to initiate tumorigenesis. Different RAS mutations can affect the level of active oncprotein and/or the type of pathways activated thereof. To attempt to determine the contribution of these two forms of signaling on the process of RAS mutation patterns in cancer, we generated four conditional murine Kras alleles containing one of two distinct oncogenic mutations, G12D or Q61R, encoded by native rare or common codons to induce low or high protein expression, respectively. These four alleles were globally activated throughout the mouse, revealing different tissue susceptibilities to the oncogenic Kras alleles. We observed that hematolymphopoietic lesions were preferentially initiated by the level of active RAS, squamous tumor were preferentially induced by one mutation over the other, while pulmonary carcinomas are susceptible to both activity level and the mutation type of the Kras allele. To further explore the signaling responses to the oncogenic Kras allele, we performed RNAseq analysis at the moment of tumor initiation, revealing that each allele induced a unique cellular response, ranging from transcriptional features of a plastic state to high oncogenic signaling and a stress response. We thus suggest that distinct RAS mutations impart a unique quantitative or qualitative signaling response that are selected in a tissue-specific fashion to initiate tumorigenesis, which has implications for early detection, interception, and prevention.
Citation Format: Ozgun Le Roux, Christopher M. Counter. The tumor landscape is molded by quantitative and qualitative signaling differences between different oncogenic KRAS mutations [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 2579.
Abstract 261: Whole genome sequencing provides a more comprehensive genetic characterization of lung cancer compared to a targeted panel sequencing
Authors: Park Ji-Hyung , Kim Young Tae , Connolly-Strong Erin , Ju Young Seok 
Published: April 2023

Abstract
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death in the United States despite a decline in mortality. Adenocarcinoma of the lung usually evolves from the mucosal glands and represents about 40% of all lung cancers. A significant proportion of lung adenocarcinoma patients present alterations in oncogenic driver genes. Next-Generation Sequencing (NGS) allows the sequencing of several genomic regions in a single test. There are multiple NGS approaches including Targeted Panel Sequencing (TPS), Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS). Methods: The detection of actionable genomic mutations in 60 lung adenocarcinoma surgical specimens was evaluated through two NGS approaches TPS and WGS. TPS was performed using the Seoul National University Hospital (SNUH) TPS consisting of 75 total genes, with a total coverage of 1.92Mb (exon 0.69Mb, intron 1.23Mb). WGS was performed using Illumina’s NovaSeq 6000 platform and data were processed with BWA and variant callers including Mutect2 and Delly. Functional mutations were determined by Ensembl VEP, while putative driver mutations were identified via the Genome Insight pipeline (San Diego). Results: A total of 120 driver mutations were detected by TPS. WGS identified 114 out of the 120 driver mutations (95% match). An additional 9 driver mutations were detected by WGS, along with thousands of additional non-driver mutations. (Table 1) Conclusion: An NGS-based approach allows for the identification of actionable molecular changes which leads to more informed clinical decision making. These results validate that Genome Insight’s WGS workflow and pipeline are comparable to TPS in detecting key driver mutations. Furthermore, this study demonstrated that WGS provides a more comprehensive genetic characterization of lung cancer, which may impact the therapeutic options and patients’ prognosis.
Table 1. Driver mutations # of mutations detected by TPS # of mutations detected by WGS Detected by TPS EGFR 20 19 KRAS 9 9 TP53 30 30 Fusion oncogenes 17 17 PIK3 genes 1 1 BRAF 2 2 Secondary drivers detected by TPS 41 36 Sub-total 120 114 Missed by TPS Other drivers not detected by TPS 0 9 Total 120 123
Citation Format: Ji-Hyung Park, Young Tae Kim, Erin Connolly-Strong, Young Seok Ju. Whole genome sequencing provides a more comprehensive genetic characterization of lung cancer compared to a targeted panel sequencing [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 261.
Abstract 2870: Inhibition of DNA methylation and histone deacetylation synergistically reprograms M2-polarized macrophages and inhibits tumor growth by upregulating miR-7083-5p
Authors: Murugan Poongkavithai Vadevoo Sri , Rangaswamy Gunassekaran Gowri , Lee Byungheon 
Published: April 2023

Abstract
Reactivation of epigenetically suppressed miRs, in tumors, have become increasingly relevant in clinical practice. But less epigenetic studies have been performed on tumor associated M2 macrophages that plays a key role in the functional regulation of epithelial cancer development. In this study, we used 5-Aza-2’5’Aza-deoxycytidine (Aza) or decitabine (5-Aza) plus Trichostatin A (TSA) as epigenetic drugs to study the M2 macrophage modulation in the tumor microenvironment. Epigenetic therapy, not only modulated the M2 macrophages to a tumoricidal phenotype, but also strengthened the tumor immune surveillance and eventually attenuated tumor growth. In vitro studies on M2 macrophages, showed that these epigenetic modifiers, namely 5Aza+TSA, fine-tuned the M2 macrophages into a ‘no more tumor friendly’ phenotype. Using comparative miR profiling, we identified nearly 79 miRs that were upregulated in M2 macrophages after epigenetic drug treatment. Of all miRs, miR-7083-5p showed 32 fold upregulation in M2 after epigenetic therapy and csf2ra, a GM-CSF receptor that helps in IL3 and GM-CSF signaling to M2 polarization, and CD43,a leukocyte marker, were one two of the important genes targeted by this miR-7083-5p. Nevertheless, re-expression of miR-7083-5p in M2 Macrophages in vitro, modulated M2 Macrophage to an anti-tumor phenotype and 4T1 tumor tissues showed inversed correlation between the expression of miR-7083-5p and its target,csf2ra and CD43,implying the pathological relevance of targeting. Considering the vital role of M2-TAM in tumor growth and metastasis, epigenetic drug mediated reactivation of miRs in M2-TAM could act as a promising therapeutic approach in cancer treatment.
Citation Format: Poongkavithai Vadevoo Sri Murugan, Gunassekaran Gowri Rangaswamy, Byungheon Lee. Inhibition of DNA methylation and histone deacetylation synergistically reprograms M2-polarized macrophages and inhibits tumor growth by upregulating miR-7083-5p [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 2870.