bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4232: Exploring chemotherapy resistance in pancreatic cancer: Insights from a 3D organoid model
Authors: Lee Hee Seung 
Published: March 2024

Abstract
Pancreatic cancer is marked by a dismal prognosis, with a 5-year survival rate at approximately 10%. A key contributor to its lethality is the development of chemotherapy resistance, followed by early metastasis. However, studies elucidating the mechanisms behind chemotherapy resistance in pancreatic cancer are limited. Previous research has relied on 2D cell line models, which present limitations, such as uniform cell types that fail to capture tumor heterogeneity and an inaccurate representation of clinical realities, wherein resistance often develops gradually rather than through continuous exposure to high drug concentrations. In this study, we developed a more sophisticated organoid model of chemotherapy resistance. Six organoids from three patients were matched to study chemotherapy resistance in a personalized context. Comprehensive whole-exome sequencing and transcriptomic analyses were performed, along with an examination of chemotherapy resistance protein expression and EMT-related markers. Notably, differential expression levels of CK19 and Vimentin were observed between samples. Our analysis also focused on the expression of the ATP-Binding Cassette Subfamily G Member 2 (ABCG2) gene in chemoresistant organoids. Western blot analysis indicated a significant increase in ABCG2 expression in these organoids compared to controls. According to the Moffitt RNA signature, the primary and corresponding chemoresistant organoids retained their molecular subtype classifications both before and after developing chemoresistance. Gene set enrichment analysis uncovered significant upregulation of pathways related to DNA repair and cell cycle regulation, particularly the G2M checkpoint, in chemoresistant organoids. Furthermore, gene ontology functional analysis suggested a notable overrepresentation of activities related to amino acid transmembrane transport and extracellular matrix constituents, underscoring their potential role in the chemoresistance phenotype.
Citation Format: Hee Seung Lee. Exploring chemotherapy resistance in pancreatic cancer: Insights from a 3D organoid model [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 4232.
Abstract 4240: A comprehensive in vitro tumor model: One-stop simultaneous isolation and culture of tumoroids, CAFs and TILs for advancing immuno-oncology research
Authors: KO YOO RI , Kim Sung Min , Park Hye Seon , Jang Se Jin 
Published: March 2024

Abstract
The tumor microenvironment (TME), composed of a diverse array of cells, jointly participates in tumor formation and has attracted attention as a direct or indirect therapeutic target. Among the tumor-forming cells, cancer cells, cancer-associated fibroblast (CAF), and tumor-infiltrating lymphocytes (TILs) comprise major proportion and players in tumor biology. Therefore, an in vitro tumor model composed of at least above three major cellular players better mimics a patient’s tumor. Here, we developed a patient-derived tumor model containing tumoroids, CAFs and TILs isolated from the patient’s tumor tissue by using one-stop isolation culture system. Our one-stop culture system utilizes a Transwell-based method that concurrently segregates cancer cells, CAFs, and TILs based on distinct characteristics such as cell size, migration speed, and growth. Lung tumoroids, fibroblasts, and TILs segregated in Matrigel-coated upper Transwell chamber, Transwell pores and in the lower chamber, respectively. Lung tumoroids maintain the patient’s lung cancer tissue characteristics and genetic features during extended in vitro cultivation. Fibroblasts extracted from the Transwell pores exhibit significant similarity to CAFs found in patient tissue. TILs in the lower part of the Transwell chamber closely resemble those found in the original cancer tissue analyzed by FACS. We have also refined the functionality of TILs through a two-week expansion process. Patients’ tumor composed of 0.15 to 95.3 % of EpCAM positive tumor cells, 0.14 to 19.4 % of CD90 positive fibroblasts and 3.98 to 91.2 % of immune cells in FACS analysis. By reassembling three main cellular components of the tumor in a proper proportion, we developed a co-culture platform for a patient-derived tumor model reproducing patient-specific TME conditions. The co-culture platform showed a potential not only for an experimental model but also to use a predictive test of personalized immunotherapy responses for lung cancer patients.
Citation Format: YOO RI KO, Sung Min Kim, Hye Seon Park, Se Jin Jang. A comprehensive in vitro tumor model: One-stop simultaneous isolation and culture of tumoroids, CAFs and TILs for advancing immuno-oncology research [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 4240.
Abstract 4247: Miniaturizing patient-derived organoid screening assays for predictive drug testing
Authors: Abouleila Yasmine , Verkerk Roel , Doorn Mayke , Voskuilen Timo , Harada Gakuro , Watanabe Masahiko , Smabers Lidwien , Kyan Hideaki , Kumagai Takahiko , Hikichi Yuichi , Overmeer Rene , Roodhart Jeanine , Matsuno Kiyotaka , Verissimo Carla , Boj Sylvia 
Published: March 2024

Abstract
Colorectal cancer (CRC) ranks as the third leading cause of both cancer incidence and cancer-related mortality. A significant portion of CRC patients diagnosed with de novo metastatic disease face limited benefits from conventional treatment options, often accompanied by substantial side effects. This underscores the pressing need for more effective preclinical models to predict patient responses in clinical settings. Patient-derived organoids (PDOs or HUB Organoids®) represent a pivotal breakthrough in preclinical modeling. These organoids are directly derived from patient tissue, faithfully mirroring the patient's disease. While HUB Organoid Technology is currently applicable for preclinical drug screening, it is essential to expedite the transition from patient diagnosis to the delivery of PDO-based results to directly benefit patients. In a collaborative effort with Yamaha Motor, we have optimized the Yamaha CELL HANDLERTM for the automated transfer of organoids, offering enhanced precision and efficiency in handling a significantly reduced number of organoids per screening plate, compared to conventional methods. Moreover, we have developed an image-based readout system that enables precise quantification of organoid numbers, ensuring high assay quality. Utilizing this developed automated platform, we conducted a proof-of-concept investigation into PDO responses to chemotherapy in comparison to corresponding patient responses. The correlation between PDO and patient responses demonstrated a strong connection, highlighting the potential of the developed automated platform for predictive drug testing. In summary, this work signifies the development of an automated workflow that synergizes patient-representative HUB Organoids® with cutting-edge robotics from Yamaha Motor. The described workflow reduces the number of organoids needed per screening well, streamlining patient response prediction, potentially leading to faster diagnoses, and ultimately optimizing patient outcomes.
Citation Format: Yasmine Abouleila, Roel Verkerk, Mayke Doorn, Timo Voskuilen, Gakuro Harada, Masahiko Watanabe, Lidwien Smabers, Hideaki Kyan, Takahiko Kumagai, Yuichi Hikichi, Rene Overmeer, Jeanine Roodhart, Kiyotaka Matsuno, Carla Verissimo, Sylvia Boj. Miniaturizing patient-derived organoid screening assays for predictive drug testing [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 4247.
Abstract 4253: High expression of specific gene profiles in organoids from African American pancreatic cancer tumors
Authors: Lyn-Cook Beverly D. , Emamzaden Fatemeh Nouri , Word Beverly , Hammons George 
Published: March 2024

Abstract
Pancreatic cancer remains one of the leading causes of cancer-related deaths in the United States with limited therapies for advanced stages of this disease. African Americans have the highest morbidity and mortality rates of pancreatic cancer compared to other racial groups. Many factors are known to contribute to this disparity such as, socioeconomic and lifestyle factors. One of the major factors contributing to this disparity is the lack of African Americans with pancreatic cancer in clinical trials or genomic databases. In order to gain insight into the biology or genetic differences that may exist in signals driving the aggressiveness of this cancer in this population more studies are needed. Innovative in vitro models are needed to investigate possible differences in molecular changes that may exist in African Americans. Studies have shown that organoids developed from metastatic and primary tumors can give sights into genetic and epigenetic changes detected in several type of cancers. Using a Human Pancreatic Adenocarcinoma TagMan Array 96 (Applied Biosystems), which contained 76 genes known to be expressed in pancreatic cancer, pancreatic organoids from African American metastatic tumors revealed high expression levels of specific genes. Usually K-ras is highly expressed in pancreatic tumors but it was not significantly expressed in the organoids from African Americans metastatic tumors. However, preliminary results from organoids, compared to pancreatic cancer cell line spheroids, showed significantly increased gene expression of HSP90AA1 (13-fold), MMP1(36-fold), BRACA2 (20-fold), MDM2 (19-fold), RB1 (14-fold), Rel (12-fold), STAT1 (15-fold), STAT5B (5-fold), and TGFBR1 (1- fold). High expression of HSP90AA1 is related to poor prognosis, constitutively expression of STAT5B confers gemcitabine chemoresistance and promote invasiveness, and mutations in BRCA2 can increase pancreatic cancer risk. Further studies are being done to validate these findings in African American pancreatic tumors and to ascertain their relevance to the metastatic progression phenotype.
Citation Format: Beverly D. Lyn-Cook, Fatemeh Nouri Emamzaden, Beverly Word, George Hammons. High expression of specific gene profiles in organoids from African American pancreatic cancer tumors [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 4253.
Abstract 4265: ZEB1-regulated hyaluronan network in the lung tumor microenvironment
Authors: Lee Sieun , Park Jihye , Kim Eun Ju , Cho Seongran , Park Sungsoo , Kurie Jonathan M , Ahn Young-Ho 
Published: March 2024

Abstract
In the tumor microenvironment, hyaluronan surrounds neighboring cells as one of the major components of the extracellular matrix and stimulates the epithelial-mesenchymal transition (EMT) of various epithelial cancer cells. However, the mechanism of how the hyaluronic network is formed by cancer cells and regulates cancer progression and metastasis has not been known in detail. Therefore, we investigated the role of the hyaluronan network built-up by cancer cells in regulating cancer progression and metastasis in the tumor microenvironment. Our study demonstrated that ZEB1, an EMT-inducing transcription factor, reconstructs the hyaluronan network to induce the expression of ITIH2, a hyaluronan-binding protein, and hyaluronic acid synthase-2 (HAS2), ZEB1 was also shown to control the isoform switching of CD44, a hyaluronan receptor. ITIH2 knockdown and HAS inhibition reduced the formation of hyaluronan cables and inhibited cancer cell migration and invasion. In addition, the treatment of a specific ITIH2 inhibitor identified through deep learning-based screening suppressed the formation of hyaluronan cables, cell migration, and metastasis. These findings suggest that targeting the hyaluronan network could be a novel strategy for suppressing lung cancer progression and metastasis in the tumor microenvironment.
Citation Format: Sieun Lee, Jihye Park, Eun Ju Kim, Seongran Cho, Sungsoo Park, Jonathan M Kurie, Young-Ho Ahn. ZEB1-regulated hyaluronan network in the lung tumor microenvironment [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 4265.
Abstract 4267: Inflammation mediated expression of integrin αvβ3 potentiates KRAS driven PDAC oncogenesis
Authors: Shepard Ryan M. , Campos Alejandro D. , Ortega Zachary M. , Wettersten Hiromi I. , Von Schalscha Tami , Weis Sara M. , Cheresh David A. 
Published: March 2024

Abstract
Understanding how pancreatic epithelial cells respond to inflammation and why some become tumorigenic and aggressive could identify new methods of early detection and novel therapeutic targets to control disease progression. Here, we leveraged an in vivo model in which mice with pancreas-specific expression of mutant Kras progress from pre-malignant intraepithelial neoplasias (PanINs) to pancreatic ductal adenocarcinoma (PDAC) following caerulein-induced chronic pancreatitis. During the transition from PanINs to PDAC, we observe two classes of neoplastic lesions: classically-described PanIN tubular structures that are highly organized and previously uncharacterized atypical highly disorganized lesions that are marked by robust integrin αvβ3 expression, observations which are consistent with human pancreatitis and PDAC. In vitro, we report that immune-, stroma-, and tumor cell-derived inflammatory cytokines induce β3 expression in a STAT3-dependent manner leading to increased integrin αvβ3. Considering that we previously established αvβ3 as a driver of cancer cell stress tolerance, drug resistance, and a stem-like phenotype, the acquisition of αvβ3 during chronic inflammation may promote tumorigenesis. Indeed, using the spontaneous tumor mouse model and xenograft models of human PDAC, we find that cells with an inability to upregulate β3 during tumor initiation fail to form tumors. These findings implicate integrin αvβ3 as a critical driver of inflammation-mediated pancreatic tumorigenesis.
Citation Format: Ryan M. Shepard, Alejandro D. Campos, Zachary M. Ortega, Hiromi I. Wettersten, Tami Von Schalscha, Sara M. Weis, David A. Cheresh. Inflammation mediated expression of integrin αvβ3 potentiates KRAS driven PDAC oncogenesis [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 4267.
Abstract 4309: Establishment of intratumor heterogeneity using patient derived lung cancer cells
Authors: Funazo Tomoko , Ozasa Hiroaki , Tsuji Takahiro , Shima Yusuke , Suminaga Keiichiro , Hashimoto Kentaro , Yoshida Hiroshi , Ogimoto Tatsuya , Hosoya Kazutaka , Ajimizu Hitomi , Nomizo Takashi , Yoshida Hironori , Hirai Toyohiro 
Published: March 2024

Abstract
Overcoming cancer treatment resistance is a problem that must be solved to improve the prognosis of cancer patients. In recent years, genome analysis has revealed the existence of multiple subgroups with different properties within a single tumor, and intratumor heterogeneity is a cause of treatment resistance. It has also been reported that. However, the mechanism of intratumor heterogeneity remains unclear. Previous research on intratumor heterogeneity has mainly focused on analyzing patient cancer cells, classifying subgroups, and estimating characteristic factors. This method has two drawbacks. One is limitations in including all subgroups as research subjects, and other is lack of verification of whether characteristic factors are actually involved in intratumor heterogeneity in patients. Therefore, it is necessary to use a model of "early intratumor heterogeneity" in which monoclonal cells are divided into subgroups with different properties, and to verify the discovered factors using patient-derived cancer cell lines. In alectinib-resistant cell line (H2228-AR1S) created from monoclonal ALK-positive lung cancer cell line (H2228) by exposing to alectinib in vitro, existence of two fractions with different appearances. Using flow cytometry, it was revealed that H2228-AR1S bimodally expresses EpCAM, and the EpCAM-low fraction has high migration ability. In EpCAM-low fraction, epithelial markers were decreased, and mesenchymal markers were increased using immunoblotting. It suggests that EpCAM low subpopulation has undergone epithelial-mesenchymal transition (EMT). Additionally, we established a BRAF-positive lung cancer cell line (KTOR83) collected with consent from patients attending Kyoto University Hospital. Cells after in vitro dabrafenib exposure to KTOR83 showed bimodal EpCAM expression, and the EpCAM-low fraction has high migration ability. We established an intratumor heterogeneous model using commercially available cells and a patient-derived lung cancer cell line. Furthermore, we will explore factors common to the two models and examine factors involved in intratumor heterogeneity.
Citation Format: Tomoko Funazo, Hiroaki Ozasa, Takahiro Tsuji, Yusuke Shima, Keiichiro Suminaga, Kentaro Hashimoto, Hiroshi Yoshida, Tatsuya Ogimoto, Kazutaka Hosoya, Hitomi Ajimizu, Takashi Nomizo, Hironori Yoshida, Toyohiro Hirai. Establishment of intratumor heterogeneity using patient derived lung 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 4309.
Abstract 4312: KRAS oncogenic activation in Gramd2
+ AT1 cells form lung adenocarcinoma with distinct transcriptomic and tumor microenvironment signatures
Authors: Yang Minxiao , Castillo Jonathan , Gonzalez Edgar , Yan Chunli , Torres Evanthia Roussos , Borok Zea , Marconett Crystal 
Published: March 2024

Abstract
Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology recognizes alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains relatively unknown. Here, we examined transformation via activation of the oncogenic KRASG12D mutation in a Gram-domain containing 2 (Gramd2)+ AT1 cell lineage tracing model system, which resulted in multifocal LUAD, primarily of papillary histology. Spatial transcriptomic sequencing revealed significant differences of transcriptomic signatures and signaling activities between Gramd2+ AT1 cell-derived and Sftpc+ AT2 cell-derived LUAD. Single-cell RNA sequencing of macrodissected LUAD lesions demonstrated heterogeneous cell composition of the tumor microenvironment (TME), with Gramd2+ AT1 cell-derived LUAD fostering a proinflammatory, immunoreactive TME and Sftpc+ AT2-derived LUAD presenting with an immunosuppressive TME. Collectively, our study suggests that cell of origin for LUAD is associated with histologic subtype, transcriptomic aberrations, and immune cell composition within LUAD that may influence response to therapy.
Citation Format: Minxiao Yang, Jonathan Castillo, Edgar Gonzalez, Chunli Yan, Evanthia Roussos Torres, Zea Borok, Crystal Marconett. KRAS oncogenic activation in Gramd2 + AT1 cells form lung adenocarcinoma with distinct transcriptomic and tumor microenvironment signatures [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 4312.
Abstract 4317: The role of autophagy in triple negative breast cancer
Authors: Gamal Sameh , El-Nikhely Nefertiti A. , Nematallah Hesham , Saeed Hesham M. 
Published: March 2024

Abstract
Breast cancer (BC) remains a global health concern, being the most common cancer amongst women in the world, and the second-leading cause of cancer related death. Triple-negative breast cancer (TNBC) represents a challenging frontier in oncology, characterized by its aggressiveness and its unique molecular profile devoid of the known receptors. Its elusiveness lies in the inherent heterogeneity within its subtypes, contributing to diverse clinical behaviours and treatment responses. TNBC has also shown elevated basal autophagy level as a pro-survival mechanism to make up for the increased nutrients demand mandated by the high K-RAS signalling. To tackle such tumour, we chose an autophagy blocker in addition to multi-kinase inhibitor. The combination index calculated for the proposed drugs has shown promising results in reduction of cell viability more than each drug separately. Selectivity index proved the safety of our doses on normal fibroblast cells in contrast to two breast cancer cell lines (MDA-MB 231 & MCF7). To further complement the findings, cell cycle arrest was witnessed at S phase which lead to apoptosis seen by flowcytometry and other expression analysis studies. Finally, Imaging studies and expression analysis on protein level have documented the apoptotic effects rendered by autophagy inhibition.Research endeavours continue to unravel the intricate landscape of TNBC, seeking novel avenues for targeted treatments, immunotherapies, and personalized medicine, aiming to transform the paradigm of care for those affected by this enigmatic form of breast cancer. As evident from the results, our combination has also managed to reduce the cells migration effectively which reflects that it can be initiated with aggressive metastatic tumours like TNBC.
Citation Format: Sameh Gamal, Nefertiti A. El-Nikhely, Hesham Nematallah, Hesham M. Saeed. The role of autophagy in triple negative breast 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 4317.