bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5432: Validation of spatial gene expression patterns predicted by deep convolutional neural networks from breast cancer histopathology images
Authors: Ton Kathy , Wang Yinxi , Pan Liuliu , Kartasalo Kimmo , Acs Balazs , Weitz Philippe , Zhang Liang , Liang Yan , Hartman Johan , Volkonen Masi , Larsson Christer , Ruusuvuori Pekka , Beechem Joseph , Rantalainen Mattias 
Published: April 2023

Abstract
Molecular profiling is central in cancer precision medicine but remains costly and is only based on tumor average profiles. Morphologic patterns observable in histopathology sections from tumors are determined by the underlying molecular phenotype and therefore have the potential to be exploited for the prediction of molecular phenotypes. Transcriptome-wide expression morphology (EMO) analysis with deep convolutional neural networks (CNN) enables the prediction of mRNA expression and proliferation markers from routine histopathology whole slide images in breast cancer. The NanoString GeoMx® Digital Spatial Profiler (DSP) platform has capabilities of associating crucial spatial information with intratumor variabilities of gene expression, serving as an ideal tool to characterize and validate the prediction of intratumor heterogeneity. The GeoMx platform also provides functionalities of overlaying and aligning hematoxylin and eosin (H&E) whole slide scans on serial tissue sections with morphology marker staining to facilitate region of interest (ROI) selection to match relevant image tiles from the model input, which is a key step to ensure accuracy for the evaluation of the model predictions. The GeoMx RNA Immune Pathways Panel contains 84 gene targets including key genes involved in immune pathways and tumorigenesis and was used to validate the prediction of mRNA expression output from deep CNN models.
Citation Format: Kathy Ton, Yinxi Wang, Liuliu Pan, Kimmo Kartasalo, Balazs Acs, Philippe Weitz, Liang Zhang, Yan Liang, Johan Hartman, Masi Volkonen, Christer Larsson, Pekka Ruusuvuori, Joseph Beechem, Mattias Rantalainen. Validation of spatial gene expression patterns predicted by deep convolutional neural networks from breast cancer histopathology images. [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 5432.
Abstract 5494: Preclinical combination of ONC201 with radiotherapy and Temozolomide in a GBM mouse orthotopic model results in reduced tumor burden and prolonged survival
Authors: Zhou Lanlan , Wu Laura Jinxuan , Zhang Jun , George Andrew , Hahn Marina , Zhang Leiqing , Seyhan Attila A. , El-Deiry Wafik S. 
Published: April 2023

Abstract
Glioblastoma (GBM) is the most common and lethal primary malignancy of the central nervous system. It is estimated that more than 13,000 new cases of GBM will be diagnosed this year in the United States. Despite multidisciplinary treatments such as surgery, chemotherapy, and radiotherapy, the five-year survival rate for GBM patients is only 6.8 percent and has shown no notable improvement in the last three decades. There have only been five drugs and one device ever approved by the FDA for the treatment of GBM since it was first identified in the scientific literature in the 1920’s. Our in vitro studies suggested that first-in-class small-molecule imipridone TIC10/ONC201 can inactivate ERK/AKT, induce the integrated stress response (ISR), upregulate pro-apoptotic TRAIL receptor DR5, deplete cancer stem cells, and induce mitochondrial dysfunction, growth arrest or cell death in GBM cells. Knockdown of ClpP protects GBM cells from ONC201 but not TMZ. ONC201 crosses the blood-brain barrier and has induced durable tumor regressions in adult and pediatric H3K27M-mutant diffuse midline glioma patients. We hypothesized that ONC201 may synergize with radiotherapy and temozolomide in GBM. GBM mouse orthotopic models were established through intracranial injection of luciferase expressing U251 GBM cells with a KOPF model 940 small animal stereotaxic frame and a Stoelting Quintessential Stereotaxic Injector. Tumor formation and growth was confirmed with bioluminescence imaging. Randomized treatment group mice received weekly treatment of ONC201 (100 mg/kg p.o.) and/or radiotherapy (2 Gy local irradiation) and/or TMZ (20 mg/kg i.p.) for four weeks for long term survival and tumor monitoring or one week for short term biomarker studies. We observed that the triple combination of ONC201, radiotherapy and TMZ significantly prolongs survival and reduces tumor burden compared to single treatment and dual combinations. Short term biomarker studies demonstrated that triple combination treatment decreases tumor cell proliferation, induces more apoptosis and inhibits ClpX to unleash mitochondrial ClpP. Our data support further development of the triple combination regimen of ONC201, TMZ and radiation therapy for GBM first-line treatment.
Citation Format: Lanlan Zhou, Laura Jinxuan Wu, Jun Zhang, Andrew George, Marina Hahn, Leiqing Zhang, Attila A. Seyhan, Wafik S. El-Deiry. Preclinical combination of ONC201 with radiotherapy and Temozolomide in a GBM mouse orthotopic model results in reduced tumor burden and prolonged survival. [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 5494.
Abstract 5630: Robust spatial biomarker discovery through multi-platform multiplex image analysis of breast cancer clinical cohorts
Authors: Eng Jennifer R. , Bucher Elmar , Hu Zhi , Sanders Melinda , Chakravarthy Bapsi , Pietenpol Jennifer , Sears Rosalie C. , Gibbs Summer , Gray Joe W. , Chin Koei 
Published: April 2023

Abstract
Spatial profiling of tissues promises to elucidate tumor-microenvironment interactions and enable development of spatial biomarkers to predict response to immunotherapy and other therapeutics. However, spatial biomarker discovery is often limited to small patient cohorts and single technologies, limiting statistical power and increasing the likelihood of technical artifacts. We utilized cyclic immunofluorescence, (CyCIF), to profile patient tissues from 102 breast cancer patients, 63 with clinical follow up. We then developed methods for comparative analysis of data from three disparate imaging technologies including our CyCIF images, as well as publicly available imaging mass cytometry and multiplex ion-beam imaging breast cancer data sets. We demonstrate similar single-cell phenotyping results across breast cancer patient cohorts imaged with the three methods, and furthermore, show agreement in the prognostic value of cellular and spatial biomarkers across platforms. We identified T cell infiltration as independently associated with longer survival in high-proliferation breast cancer, which was enriched for activated and spatially clustered T cells. A comparison of six spatial analysis methods revealed robust spatial biomarkers, including tumor-macrophage and tumor-fibroblast proximity associated with poor prognosis in estrogen receptor positive and triple negative tumors, respectively. Our methods enable assembly of larger clinical cohorts from diverse platforms to aid in predictive and prognostic spatial biomarker identification and validation.
Citation Format: Jennifer R. Eng, Elmar Bucher, Zhi Hu, Melinda Sanders, Bapsi Chakravarthy, Jennifer Pietenpol, Rosalie C. Sears, Summer Gibbs, Joe W. Gray, Koei Chin. Robust spatial biomarker discovery through multi-platform multiplex image analysis of breast cancer clinical cohorts. [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 5630.
Abstract 5834: The pro-tumoral function of cancer-associated mesothelial cells
Authors: Chauvin Maeva 
Published: April 2023

Abstract
Cancer-associated mesothelial cells have emerged as significant contributors to the tumor microenvironment, influencing tumor growth and immune evasion. Mesothelial cells are the first point of contact with ovarian cancer cells during peritoneal spread. Peritoneal mesothelial cells also play an essential role in immune surveillance. However, the mechanism by which cancer and mesothelial cells within the tumor microenvironment coordinate growth and immune evasion remains poorly understood. To study the role of mesothelial cells in the tumor microenvironment, we have recently generated novel syngeneic mouse models of high-grade serous ovarian cancer, which were derived from Fallopian tube epithelium, and bear human-relevant mutational genotypes. Analysis of one such model (CCNE1 amplified) using single-cell transcriptomics in omental metastases revealed specific expression of the anti-Mullerian hormone type II receptor (Amhr2) in cancer-associated mesothelial cells, whereas normal omental mesothelium does not express Amhr2. Co-culture of cancer cells with normal omental mesothelial cells induces AMHR2 expression along with a pro-tumorigenic cancer-associated mesothelial cell phenotype. Overexpression of AMHR2 in a human immortalized mesothelial cell line significantly modulated the expression of genes involved in immune response pathways, remodeling of extra-cellular matrix, and secretion of growth factors by RNAseq and qPCR. Furthermore, we showed that anti-Mullerian hormone (AMH) (the ligand of AMHR2), is secreted by ovarian cancer cells and further downregulates the chemoattractant cytokines secreted by CAMCs, thus promoting immunosuppression within the tumor. Finally, implantation of ovarian cancer cells in syngeneic Amhr2-/- hosts results in tumors that grow significantly slower than those implanted in wild-type hosts. Together these data suggest AMHR2 is a specific marker of CAMCs, whose expression is necessary for the reprogramming of mesothelial cells into CAMCs. The AMH-AMHR2 axis mediates paracrine signaling between cancer cells and CAMCs within the tumor microenvironment to promote tumor growth and immune evasion. These results suggest that AMHR2 could be a highly specific target to enhance immunotherapies in ovarian cancer.
Citation Format: Maeva Chauvin. The pro-tumoral function of cancer-associated mesothelial 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 5834.
Abstract 5843: miR-224 activates cancer-associated fibroblasts to promote cancer cell invasion in lung tumor microenvironment
Authors: Oh Seonyeong , Cheon Inyoung , Ahn Young-Ho 
Published: April 2023

Abstract
Cancer-associated fibroblasts (CAFs) promote EMT (epithelial-mesenchymal transition), invasion, and metastasis of cancer cells in the tumor microenvironment. To identify microRNAs (miRNAs) associated with the reprogramming of normal lung fibroblasts (LFs) into CAFs, global miRNA expression was profiled in LFs and CAFs through Nanostring nCounter. miR-224 was one of the increased miRNAs in CAFs, and its expression was higher in tumors than in normal tissues in dbDEMC and TCGA_lung adenocarcinoma data. miR-224 levels were then checked by qRT-PCR in paraffine-embedded tumor samples from patients with lung adenocarcinoma. Kaplan-Meier survival analysis showed that high miR-224 expression was related to poor survival. These data show that lung cancer progression is promoted by miR-224. To discover the roles of increased miR-224 in CAFs, miR-224 was overexpressed by lentiviral infection in LFs. LF_miR-224 overexpression enhanced the expression of CAF activation markers including Fap, S100a4, and Vim. In spheroid invasion assay using co-culture of LFs and cancer cells, as an experimental model of the tumor microenvironment, LF_miR-224 promoted invasion of lung cancer cells compared with control LFs. In transwell migration assay, LF_miR-224 stimulated migration of lung cancer cells more than control LFs. Collectively, these results indicate that CAFs reprogrammed by miR-224 promote the migration and invasion of lung cancer cells.
Citation Format: Seonyeong Oh, Inyoung Cheon, Young-Ho Ahn. miR-224 activates cancer-associated fibroblasts to promote cancer cell invasion in lung 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 5843.
Abstract 5862: ABCB5 knockdown suppresses tumor-intrinsic expression of immune checkpoint regulators PD-1 and PD-L1 in hepatocellular carcinoma (HCC)
Authors: Yeung Chun Philip , Wilson Brian J. , Sasamoto Yuzuru , Waaga-Gasser Ana Maria , Karpova Svetlana , Guo Qin , Frank Natasha Y. , Frank Markus H. 
Published: April 2023

Abstract
ATP-binding cassette member B5 (ABCB5) identifies cancer-initiating cells (CICs) in multiple malignancies, including malignant melanoma, colorectal cancer, glioblastoma, and hepatocellular carcinoma (HCC). In human melanoma, ABCB5-positive CIC subpopulations have been shown to preferentially express the immune checkpoint molecules PD-1 and PD-L1, and tumor-intrinsic PD-1 receptor functions have been found to promote tumor growth, even in mice lacking adaptive immunity. In HCC, where ABCB5 mediates CIC chemoresistance, PD-1 expression has also recently been identified. However, whether ABCB5 regulates tumor-intrinsic PD-1 expression in HCC or other malignancies is currently unknown. Here, we employed RNA interference in Hep G2 HCC cells with high endogenous ABCB5 expression to study the potential role of ABCB5 in regulating PD-1 expression, utilizing the ABCB5 shRNA target sequence GCTGGAAAGATAGCAACTGAA for ABCB5 knockdown (KD) as described previously. Endogenous ABCB5 levels in ABCB5-KD cells were successfully reduced by 92.8% compared to controls. Investigation of the effects of ABCB5-KD on tumor-intrinsic immune checkpoint molecule expression and on expression of the HCC-CIC marker GRN revealed that ABCB5-KD significantly reduced PD-1 expression by 98.0%, and PD-L1 expression by 62.8% compared to controls. Expression of GRN was also significantly reduced in ABCB5-KD cells by 78.8% compared to controls, suggesting ABCB5 KD-dependent loss of CIC phenotype. Injection of ABCB5-KD cells in NSG mice showed 32.3% reduction in tumor size at endpoint (6 weeks) compared to controls (728.7 ± 199.3mm3 vs 1076.0 ± 450.9 mm3, mean ± SD; p&lt;0.005, repeated measures ANOVA) and 8.53% reduction in tumor weight at endpoint (0.47 ± 0.21g vs 0.51 ± 0.21g, mean ± SD). These results provide initial evidence in an HCC cell line model system that ABCB5 functionally regulates tumor-intrinsic PD-1 and PD-L1 expression. They therefore suggest that ABCB5 blockade represents a novel therapeutic strategy for targeted inhibition of pro-tumorigenic tumor-intrinsic PD-1/PD-L1 expression, with important additional implications for immune checkpoint-targeted cancer immunotherapy.
Citation Format: Chun Philip Yeung, Brian J. Wilson, Yuzuru Sasamoto, Ana Maria Waaga-Gasser, Svetlana Karpova, Qin Guo, Natasha Y. Frank, Markus H. Frank. ABCB5 knockdown suppresses tumor-intrinsic expression of immune checkpoint regulators PD-1 and PD-L1 in hepatocellular carcinoma (HCC) [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 5862.
Abstract 5884: Targeting T regulatory cells to intercept progression from preinvasive to invasive lung adenocarcinoma using a novel KRAS-driven murine model
Authors: Martin Mitchell , Crowley Michael J. , Markowitz Geoffrey , Borczuk Alain , Zhang Chen , Yoffe Liron , Singh Arshdeep , Altorki Nasser K. , Mittal Vivek 
Published: April 2023

Abstract
Non-small cell lung cancer is the leading cause of cancer-related death in the US and worldwide, with a 5-year survival of ~18-20%. Understanding of the biology of early lung cancer is necessary to intercept early steps of progression. Indeed, increased utility of low-dose CT guided lung cancer screens in populations at risk have begun to detect early premalignant disease; however, little is known about the underlying biology that drives progression of preinvasive lesions to invasive adenocarcinoma. Moreover, there exists a lack of reliable animal models to assess interception strategies to target disease progression. We have developed and characterized a lung cancer cell-of-origin-specific KRAS-driven mouse model which accurately mirrors progression of human precursor lesions to invasive disease. Transcriptional analysis of preinvasive and invasive stages identified cellular and molecular alternations observed in human lesions, including upregulation of cell proliferation, extracellular matrix remodeling, and an increasingly complex immune microenvironment. Interrogation with immunofluorescence microscopy and Hyperion mass cytometry imaging showed marked reprogramming of the immune microenvironment including increased T cell infiltration and abundance of T regulatory cells (Tregs). Surprisingly, depletion of T cells impaired progression of preinvasive lesions, implicating the critical immunosuppressive roles of Tregs. Spatial transcriptomics (10X Genomics Visium) revealed unique spatial transcriptional changes in the progression from preinvasive to invasive stage disease, including specific ligand-receptor interactions highly expressed in Tregs. Genetic and pharmacological approaches using FoxP3-DTR-GFP mice and low dose cyclophosphamide have begun to define the functional role of Tregs in early premalignant disease.
This study demonstrates critical roles of immunosuppressive Tregs in driving progression of preinvasive to invasive lung cancer, and advocates for Treg targeting as a potent immunoprevention approach for patients at risk of developing lung cancer.
Citation Format: Mitchell Martin, Michael J. Crowley, Geoffrey Markowitz, Alain Borczuk, Chen Zhang, Liron Yoffe, Arshdeep Singh, Nasser K. Altorki, Vivek Mittal. Targeting T regulatory cells to intercept progression from preinvasive to invasive lung adenocarcinoma using a novel KRAS-driven murine model [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 5884.
Abstract 5898: Gut microbiota-derived metabolism of 5-fluorouracil affects drug efficacy
Authors: Chrysostomou Despoina , David Mark , Alexander James L. , Marchesi Julian R. , Kinross James M. 
Published: April 2023

Abstract
Introduction: Fluoropyrimidines are drugs currently used as a first-line treatment for colorectal cancer (CRC)1. The impact of gut bacteria on 5-Fluorouracil (5FU) activity remains relatively unknown. The objective of this analysis was to delineate potential bacteria-drug interactions that modify 5FU.
Methods: Tumor and tumor-adjacent healthy tissue samples from 130 colorectal adenocarcinoma patients, 55% males and 45% females, median age of 71 years old (36-91 age range), were extracted following surgical resection of the tumor. TNM classification varied across the cohort (15% pT1, 43% pT2, 35% pT3, 4% pT4). 16s rRNA gene amplicon sequencing was performed to map the microbiome composition of tumor and paired normal mucosa. 20 bacterial from the genera whose abundance changed significantly between tumor and healthy tissue were incubated with 5FU to assess drug-bacteria interactions. Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) was employed to identify changes in drug concentration (Wilcoxon spare rank test) as well as products of bacteria-driven drug metabolism. A metabolic activity-based assay was used to assess viability of a colorectal adenocarcinoma cell line (HCA46) following co-incubation with microbe-driven drug metabolites, aiming to determine significant effects on 5FU efficacy, assessed by 2-way ANOVA.
Results: Escherichia coli BW25113, Bifidobacterium longum, Citrobacter freundii and Enterococcus faecalis significantly modify 5FU in vitro, allowing us to conclude that bacteria can metabolise the drug (q &lt; 0.001). Ruminococcus gnavus does not have the ability to metabolise the drug as no significant change in 5FU concentration was observed. Incubation of microbe-derived drug metabolites with HCA46 resulted in significant decrease in cell viability compared to incubation with 5FU only, indicating that bacteria-5FU interactions result in increase of drug efficacy (Figure 2).
Conclusion: This is the first report of 5FU metabolism by Escherichia coli BW25113, Bifidobacterium longum, Citrobacter freundii and Enterococcus faecalis in vitro. This study provides an insight into the potential of large and small intestinal bacteria in chemically modifying chemotherapeutic agents and therefore modulating their activity.
1. Mahipal A, Grothey A. Role of biologics in first-line treatment of colorectal cancer. J Oncol Pract. 2016.
Citation Format: Despoina Chrysostomou, Mark David, James L. Alexander, Julian R. Marchesi, James M. Kinross. Gut microbiota-derived metabolism of 5-fluorouracil affects drug efficacy [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 5898.