bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2397: An advanced approach technique for tracking point between immune check point inhibitor and cancer cell mechanism in immune response motility by infiltration a breast cancer cell
Authors: Kim Hyunseok , Ahn Soyeon , Kwon Hyungjin , Chen Hsuan-Ju , Park Inwon , Kim Pilhan , Kubra Akyildiz 
Published: April 2023

Abstract
In Breast Cancer, Tumor-infiltrating lymphocyte (TIL) motility has been reported that it is reflecting tumor microenvironment response by adoptive cell therapy (ACT). ACT is well-known to be best applied for suppressing cancer cell growth with immune response and it also was well-known the immunotherapy. However, ACT response tracking by general analysis method included immunohistochemistry and flow cytometry was provided limited information for cancer therapy in recent years. Therefore, by assessing relationship immunotherapy marker, PD-L1, known as immune check point inhibitor and TIL using intravital microscopy in breast cancer model, we also imaged whether TIL response was related to immunotherapy following dependent on time point in a various breast cancer cell implanted mouse model such as 4T1 (mouse breast cancer cell), MDA-MB-231 (human triple negative breast cancer cell) and MCF7 (human breast cancer cell). These images result in PD-L1 expression was decreased in cancer cell implanted until 10days, whereas TIL expression increased in a various breast cancer cell when it is measuring displacement length, track mean velocity and confinement ratio called tumor microenvironment. These results indicated that we can imaged immune response related to TIL response in breast cancer cell line by intravital microscopy instead of general microscopy. It means that intravital microscope was an advanced approach technique to understand cancer mechanism accompanied by the immune response and established the method of high-resolution intravital cellular visualization compared to a general histopathological method for evaluating immune response in cancer tissue
Citation Format: Hyunseok Kim, Soyeon Ahn, Hyungjin Kwon, Hsuan-Ju Chen, Inwon Park, Pilhan Kim, Akyildiz Kubra. An advanced approach technique for tracking point between immune check point inhibitor and cancer cell mechanism in immune response motility by infiltration a breast cancer cell [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 2397.
Abstract 240: Comprehensive analytical solution to measure HRD genomic scars from SNP arrays, pan-cancer NGS panels, and optical genome mapping (OGM)
Authors: Saul Daniel , Roytman Megan , Wasnikar Viren , Burnside Rachel , Hastie Alex , Chaubey Alka 
Published: April 2023

Abstract
Homologous recombination deficiency (HRD) status has been shown to be an effective pharmacogenetic biomarker for determining the efficacy of PARP inhibitor therapy across various tumor types. A functional assessment of the genomic instability associated with HRD is critical as more than half of HRD positive tumors do not have a known causative mutation. Genomic instability is commonly achieved through assessment of three characteristic genomic scars: Loss of heterozygosity (LOH), Telomeric Allelic Imbalance (TAI), & Large-Scale State Transitions (LST) but is challenging due to the need for robust detection of copy number and allelic events genome-wide. As the technology commonly used to analyze tumors varies, we sought to compare the concordance of commonly used platforms to measure genomic instability.
Bionano VIA™ software provides a standardized analytical measurement of the genomic scars across technologies, including SNP arrays, pan-cancer gene panels, and optical genome mapping (OGM). The software is uniquely capable to profile solid tumors from pan-cancer sequencing panels, such as the Illumina TruSight Oncology 500 (TSO500) panel, by employing a dynamic binning approach of sequencing data to detect copy number variant (CNV) and LOH events. OGM can detect additional classes of structural rearrangements missed by other technologies to provide new insights into genomic instability. In this study, tumor samples were run on multiple technologies and analyzed in VIA to provide a measurement of the genomic scars. A comparative analysis of each technology’s performance to detect genomic instability through a standardized analytical approach will be described to provide insight into the most effective technologies to assess HRD.
Citation Format: Daniel Saul, Megan Roytman, Viren Wasnikar, Rachel Burnside, Alex Hastie, Alka Chaubey. Comprehensive analytical solution to measure HRD genomic scars from SNP arrays, pan-cancer NGS panels, and optical genome mapping (OGM) [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 240.
Abstract 2495: Investigating pancreatic cancer-derived extracellular vesicle signaling in the tumor microenvironment
Authors: Finan Jennifer M. , Saugstad Julie , Brody Jonathan 
Published: April 2023

Abstract
In many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), the secretion of extracellular vesicles (EVs) has been shown to support tumor progression, chemotherapeutic resistance, and metastasis. Importantly, PDAC tumors are composed of up to 80% non-tumor cells and an extracellular matrix, yet no studies have been performed to determine whether PDAC EVs are imported preferentially by specific non-tumor cell types. To improve our understanding of this signaling, we aim to define the recipient cells of PDAC EVs and evaluate the functional importance of this internalization. Utilizing an in vitro live imaging system, we found that cancer-associated fibroblasts (CAFs) import more PDAC EVs than normal pancreas epithelial, endothelial, or PDAC cells, suggesting PDAC EV trafficking may be preferential to CAFs. We have generated human PDAC and mouse KrasG12D Trp53R172H driven (KPC) PDAC cell lines to express an extracellular particle reporter labeling the inner leaflet of cell membranes with GFP-nLuc. We are currently using this model to characterize recipient cells of the GFP-nLuc-positive EVs in an immunocompetent orthotopic PDAC mouse model. We developed flow cytometry and immunofluorescence panels to assess PDAC EV import by CAFs, endothelial cells, macrophages, B cells, and T cells in developed tumors. Utilizing immunofluorescence staining for a panel of phenotypic markers, we will assess the functional importance of EV internalization. Future studies will begin to determine how EV mRNA cargoes are important for recipient cell phenotypic and functional changes. This study is the first to ascertain the fate of PDAC EVs within the tumor microenvironment in a physiologically relevant model.
Citation Format: Jennifer M. Finan, Julie Saugstad, Jonathan Brody. Investigating pancreatic cancer-derived extracellular vesicle signaling in the tumor microenvironment [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 2495.
Abstract 2518: Heterogeneity of cytokine secretion in single senescent fibroblasts is impacted by ONC201 and ABT-263
Authors: Zhou Lanlan , Zhang Shengliang , Huntington Kelsey E. , Carneiro Benedito A. , El-Deiry Wafik S. 
Published: April 2023

Abstract
Cellular senescence and the associated secretory phenotype (SASP) promote cancer. During the process of aging, cellular and molecular changes that occur in non-cancerous cells can alter responses to cancer therapy and immune response in the tumor microenvironment (TME). Targeting senescent cancer-associated fibroblasts (CAFs) by means of removal, modulation of the SASP, or through cellular reprogramming represent therapeutic avenues for treating cancer. Heterogeneity of CAFs is emerging as an important area of investigation in cancer therapy. To better elucidate the interplay between cancer cells, immune cells, and senescent fibroblasts from different tissues and determine their impact on tumor growth and response to cancer therapy, we investigated the heterogeneity of cytokine secretion in senescent fibroblasts by a single cell cytokine assay. Control and treated proliferating and senescent fibroblasts were loaded onto IsoPlexis IsoCode chips coated with multiplexed antibodies which allows detection of 32 cytokines at a single-cell level for frequency and intensity. The Polyfunctional Strength Index (PSI) showed that stimulatory and chemo-attractant cytokines were dominant in the senescent fibroblasts. The Polyfunctional heat map showed that there are subpopulations of cells which have polyfunctional cytokine secretion (&gt;2 different cytokines) in live senescent IMR90 cells. Treatment with ONC201 reduced cytokine polyfunctionality in live senescent IMR90 cells. Although ABT-263 (small molecule inhibitor of Bcl-2, Bcl-XL) did not show a significant reduction of polyfunctionality in live senescent IMR90, the frequency showed that ABT-263 reduced the secretion frequency of live senescent IMR90 cells except for GM-CSF. Combining ONC201 and ABT-263 diminished polyfunctionality and secretion frequency of senescent IMR90 cells except for MIF which was detected in 1.5% of the cells. Single cell cytokine profiling of live cells in the complex tumor microenvironment is providing insights into tumor progression, therapy resistance, and the effects of senolytic drugs and drug combinations.
Citation Format: Lanlan Zhou, Shengliang Zhang, Kelsey E. Huntington, Benedito A. Carneiro, Wafik S. El-Deiry. Heterogeneity of cytokine secretion in single senescent fibroblasts is impacted by ONC201 and ABT-263 [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 2518.
Abstract 2584: Overcoming cetuximab resistance in colorectal cancer through inhibition of HGF processing
Authors: Jones Vivian Truong , Graves-Deal Ramona , Bogatcheva Galina , Cao Zheng , Higginbotham James , Harmych Sarah , Ayers Gregory , Ramirez Marisol , Liu Qi , Janetka James , Singh Bhuminder 
Published: April 2023

Abstract
Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR) and can prolong survival in metastatic colorectal cancer (CRC) patients. However, therapeutic resistance can limit its efficiency and use. Our lab has previously identified that the activation of receptor tyrosine kinases (RTKs) MET and RON contributed to cetuximab resistance. In the absence of activating mutations of MET and RON, the activity of these RTKs depends on the availability of their ligands, hepatocyte growth factor (HGF) and hepatocyte growth factor-like (HGFL), respectively. To become biologically active, the inactive precursors of HGF and HGFL must be processed by serine proteases (HGFA, matriptase, and hepsin). A survey of TCGA datasets indicated that MET and HGF were overexpressed in several CRC CMS subtypes. However, we did not observe any significant overexpression of the serine proteases. Hepatocyte growth factor activator inhibitor type 1 and 2 (HAI-1/2) are two Kunitz-type serine protease inhibitors that displayed reduced expression in TCGA datasets. The addition of recombinant human HGF conferred cetuximab resistance to cetuximab-sensitive cells and cetuximab-sensitive cells engineered to overexpress HGF also exhibited cetuximab-resistant phenotype. Cetuximab resistance induced by HGF addition or overexpression could be overcome by downstream inhibition with crizotinib, a multi-targeted RTK inhibitor. ZFH7116 is a small molecule inhibitor of the serine proteases that mimics HAI-1 activity. ZFH7116 suppressed HGF cleavage and maturation in our cetuximab-resistant SC cells. We observed cooperative effect of ZFH7116 with cetuximab to reduce SC cell growth in 3D collagen cultures. We are currently testing if upstream inhibition with recombinant human HAI-1 addition can suppress HGF cleavage and overcome cetuximab resistance induced by HGF overexpression. Collectively, our findings suggest that inhibiting HGF cleavage and processing may be a unique strategy for overcoming EGFR-targeted therapy resistance in colorectal cancer.
Citation Format: Vivian Truong Jones, Ramona Graves-Deal, Galina Bogatcheva, Zheng Cao, James Higginbotham, Sarah Harmych, Gregory Ayers, Marisol Ramirez, Qi Liu, James Janetka, Bhuminder Singh. Overcoming cetuximab resistance in colorectal cancer through inhibition of HGF processing [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 2584.
Abstract 2585: Mutant p53 gains oncogenic functions through a cytosolic DNA response
Authors: Zhao Mei , Wang Tianxiao , Gleber-Netto Frederico O. , Chen Zhen , McGrail Daniel J. , Gomez Javier A. , Ju Wutong , Gadhikar Mayur A. , Ma Wencai , Shen Li , Tang Ximing , Pathak Sen , Raso Maria G. , Burks Jared , Lin Shiaw-Yih , Wang Jing , Multani Asha S. , Pickering Curtis R. , Chen Junjie , Myers Jeffrey N. , Zhou Ge 
Published: April 2023

Abstract
TP53 mutations are the most common cancer driver mutations among all cancers. Although some TP53 mutations lead to a loss of function of wild-type p53, many other TP53 mutations confer gain-of-function (GOF) activities, which promote cancer cell metastasis and pro-tumorigenic inflammation. Despite that many functional models of GOF mutant p53 (mutp53) have been proposed previously, the mechanisms involved in mutp53 GOF still remain largely elusive. Here we show that by directly targeting minichromosome maintenance complex component 5 (MCM5), a component of the hexametric DNA helicase MCM2-7 complex, GOF mutp53 predisposes cancer cells to replication stress and chromosomal instability, which leads to a tumor cell-autonomous and stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Furthermore, our results demonstrate that GOF mutp53-activated tumor cell-intrinsic STING-NC-NF-κB signaling not only stimulates tumor cell metastasis, but also promotes tumor immune resistance through fostering an immunosuppressive tumor microenvironment. Therefore, our findings that mutp53 exerts its GOF role through pro-tumorigenic MCM5-CIN-STING-NC-NF-κB signaling highlight the importance of TP53 and its inactivation in cancer genome evolution of genomic instability that drives tumor development and progression.
Citation Format: Mei Zhao, Tianxiao Wang, Frederico O. Gleber-Netto, Zhen Chen, Daniel J. McGrail, Javier A. Gomez, Wutong Ju, Mayur A. Gadhikar, Wencai Ma, Li Shen, Ximing Tang, Sen Pathak, Maria G. Raso, Jared Burks, Shiaw-Yih Lin, Jing Wang, Asha S. Multani, Curtis R. Pickering, Junjie Chen, Jeffrey N. Myers, Ge Zhou. Mutant p53 gains oncogenic functions through a cytosolic DNA response [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 2585.
Abstract 2593: A MYCN-independent mechanism mediating secretome reprogramming and metastasis in MYCN-amplified neuroblastoma
Authors: Zhang Hai-Feng , Delaidelli Alberto , Javed Sumreen , Turgu Busra , Hughes Christopher S. , Yang Xiaqiu , Lizardo Michael , Martinez Daniel , Maris John M. , Bosse Kristopher R. , Williams Karla C. , Sorensen Poul H. 
Published: April 2023

Abstract
MYCN amplification (MNA) is a defining feature of high-risk neuroblastoma (NB) that predicts poor prognosis. However, whether genes within or in close proximity to the MYCN amplicon also contribute to aggressiveness in MNA+ NB remains poorly understood. Here we identify that GREB1, a transcription factor encoding gene neighboring the MYCN locus, is frequently co-expressed with MYCN, and promotes gene expression independently of MYCN in MNA+ NB. We found that GREB1, as a crucial estrogen receptor (ER) regulatory factor, is highly expressed in MNA+ NB comparable to ER+ breast cancer. Among GREB1-regulated genes altered in MNA+ NB, we uncover that Myosin 1B (MYO1B) promotes aggressive features in MNA+ NB, including invasive capacity in vitro, as well as extravasation and distant metastasis in vivo. Global secretome and proteome profiling uncover MYO1B as a major regulator of secretome reprogramming in MNA+ NB cells. Moreover, we identify the cytokine MIF as an important pro-invasive and pro-metastatic mediator of MYO1B activity. Together, we have identified a putative GREB1-MYO1B-MIF axis as an unconventional mechanism that promotes the aggressiveness of MNA+ NB, and independently of MYCN. Furthermore, we found that MYO1B is also upregulated in association with other oncoproteins during cellular transformation, and is dramatically increased in multiple human cancer types, suggesting a crucial role of MYO1B in cancers in addition to MNA+ NB.
Citation Format: Hai-Feng Zhang, Alberto Delaidelli, Sumreen Javed, Busra Turgu, Christopher S. Hughes, Xiaqiu Yang, Michael Lizardo, Daniel Martinez, John M. Maris, Kristopher R. Bosse, Karla C. Williams, Poul H. Sorensen. A MYCN-independent mechanism mediating secretome reprogramming and metastasis in MYCN-amplified neuroblastoma [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 2593.
Abstract 2594: Alcohol drinking inhibits NOTCH-PAX9 signaling in esophageal squamous epithelial cells
Authors: Xiong Zhaohui , Shi Menghan , Ren Shuang , Chen Hao , Li Jing , Huang Caizhi , Li Yahui , Han Yuning , Li Yong , Sun Zheng , Chen Xiaoxin 
Published: April 2023

Abstract
Alcohol drinking has been established as a major risk factor for esophageal diseases, such as gastroesophageal reflux disease (GERD) and esophageal squamous cell carcinoma (ESCC). Certain mechanisms of alcohol-induced esophageal injury are supported by experimental data, whereas most are speculative or extrapolated from studies on cancers of other organ sites. Our previous study showed that ethanol exposure inhibited PAX9 expression in human esophageal squamous epithelial cells in vitro and in vivo, and promoted ESCC. In this study, we aimed to investigate the molecular pathways through which alcohol drinking suppresses PAX9 in esophageal squamous epithelial cells. Gene microarray, qRT-PCR, ChIP-PCR, Western blotting, and immunostaining were used to identify and validate inhibition of NOTCH-PAX9 signaling in human esophageal squamous epithelial cells and mouse esophagus after ethanol exposure. Human tissue samples were analyzed to further validate NOTCH inhibition by alcohol drinking. We first demonstrated the inhibition of NOTCH by ethanol exposure in vitro. NOTCH regulated PAX9 expression in esophageal squamous epithelial cells in vitro and in vivo. RBPJ and NOTCH intracellular domain (NICD1) ChIP-PCR confirmed Pax9 as a direct downstream target of NOTCH signaling in mouse esophagus. NOTCH inhibition by alcohol drinking was further validated in mouse esophagus and human tissue samples. In conclusion, ethanol exposure inhibited NOTCH signaling and thus suppressed PAX9 expression in esophageal squamous epithelial cells in vitro and in vivo. Our data
support a novel mechanism of alcohol-induced esophageal injury through the inhibition of NOTCH-PAX9 signaling. As a result, chemical NOTCH activators may be used to prevent or treat alcohol-associated esophageal diseases such as GERD and ESCC.
Citation Format: Zhaohui Xiong, Menghan Shi, Shuang Ren, Hao Chen, Jing Li, Caizhi Huang, Yahui Li, Yuning Han, Yong Li, Zheng Sun, Xiaoxin Chen. Alcohol drinking inhibits NOTCH-PAX9 signaling in esophageal squamous epithelial 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 2594.
Abstract 2629: Single and combined inhibition of PAK and Hippo pathway in NF2-deficient schwannoma
Authors: Benton Dorothy , Chernoff Jonathan 
Published: April 2023

Abstract
Neurofibromatosis 2 (NF2) Syndrome is a rare, but devastating genetic condition that leads to non-cancerous tumors of the nervous system. NF2 patients are likely to develop Schwannomas on the eighth cranial nerve that lead to progressive deafness and spinal cord compression as well as meningiomas and peripheral nerve tumors. Effective treatment for these patients is lacking, with risky surgery being the most reliable approach and pharmacotherapies having inadequate results. The hallmark mutation of this condition is inactivation of NF2, which codes for the protein Merlin. Merlin plays several roles in the cell, two of the most consequential being inhibition of PAK1 and activation of the Hippo tumor suppressor pathway. However, drugs targeting these pathways have not yet been investigated in NF2-deficient Schwannoma. In this study, we explored the use of YAP-TEAD inhibitors as well as the combination of Hippo family and Group I PAK inhibition in NF2-deficient Schwannoma cells. We used several Schwannoma cells lines of human, mouse, and rat origin as well as a human Schwann cell line with NF2 knocked out via CRISPR compared to its wild-type control line. We investigated the role of YAP, the main effector of the Hippo pathway, and PAK1/2 in NF2 Schwannoma cells via genetic and pharmacologic inhibition. We also combined YAP-TEAD inhibitors with several PAK family inhibitors to induce a synergistic reduction in cell viability and proliferation as well as an increase in apoptosis. We found that genetic inhibition of both YAP and Group I PAK proteins led to partial reduction in Schwannoma growth. Using several YAP-TEAD binding inhibitors (TED-347, NSC682769, IK-930), Group I PAK inhibitors (FRAX-1036, G555) and PAK1-specific inhibitor (NVS-1-PAK1) we found that YAP-TEAD binding inhibition combined with Group I PAK inhibition has the greatest reduction on Schwannoma cell viability, proliferation, and increase in cell death. Taken together, our findings indicate that both the Hippo pathway and PAK proteins may be viable targets for Schwannoma therapies. Furthermore, combining the two may lead to a synergistic effect and further prevent growth of NF2-deficient Schwannomas.
Citation Format: Dorothy Benton, Jonathan Chernoff. Single and combined inhibition of PAK and Hippo pathway in NF2-deficient schwannoma [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 2629.