bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B008: UBXN2A targets Rictor-mTORC2 signaling pathway to inhibit colorectal cancer metastasis
Authors: Rezvani Khosrow S. 
Published: December 2022

Abstract
The mTORC2 pathway plays a critical role in promoting tumor progression in human colorectal cancer (CRC). The regulatory mechanisms for this signaling pathway are only partially understood in CRC. We previously identified UBXN2A as a novel tumor suppressor protein in CRCs and hypothesized that UBXN2A suppresses the mTORC2 pathway, thereby inhibiting CRC growth and metastasis. We first used murine models to show that haploinsufficiency of UBXN2A significantly increases colon tumorigenesis. Induction of UBXN2A reduces AKT phosphorylation downstream of the mTORC2 pathway, which is essential for a plethora of cellular processes, including cell migration. Meanwhile, mTORC1 activities remain unchanged in the presence of UBXN2A. Mechanistic studies revealed that UBXN2A targets Rictor protein, a key component of the mTORC2 complex, for 26S proteasomal degradation. A set of genetic and pharmacological studies showed that UBXN2A regulates cell proliferation, apoptosis, migration, and colon cancer stem cells (CSCs) in CRC. CRC patients with a high level of UBXN2A have significantly better survival, and high-grade CRC tissues exhibit decreased UBXN2A protein expression. UBXN2A induction in tumor organoids suppresses the mTORC2 pathway. These findings provide new insights into the functions of a ubiquitin-like protein by inhibiting a dominant oncogenic pathway in CRC.
Citation Format: Khosrow S. Rezvani. UBXN2A targets Rictor-mTORC2 signaling pathway to inhibit colorectal cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B008.
Abstract B031: The effects of tissue processing and microfluidic factors on single-cell RNA-sequencing data quality in colorectal tissues
Authors: Arceneaux Deronisha L. , Chen Zhengyi , Simmons Joey , Chen Bob , Heiser Cody , Xu Yanwen 
Published: December 2022

Abstract
Our HTAN (Human Tumor Atlas Network) study presented in Chen et al. documented single-cell RNA-sequencing (scRNA-seq) data on 128 human colonic specimens for mapping out distinct paths for polyp to cancer transformations. What we have not detailed is our optimizations on the droplet-based scRNA-seq approach that generate high quality data from challenging tissues such as the colonic epithelium. In this work, we provide a systematic dissection of tissue processing and microfluidic encapsulation factors that affect data quality generated on colonic epithelial cells using an open droplet-based scRNA-seq platform (inDrops). We optimized our process based on these factors to significantly decrease dying cell bodies and ambient RNA from being co-encapsulated with true cells, which led to the development of the current scRNA-seq protocol used for human specimens. We have also developed pre-filtering data metrics to score data quality stemming from degree of ambient contamination. We envision that these experimental optimizations reduce the amount of introduced artifacts, leading to more rigorous biological interpretations.
Citation Format: Deronisha L. Arceneaux, Zhengyi Chen, Joey Simmons, Bob Chen, Cody Heiser, Yanwen Xu. The effects of tissue processing and microfluidic factors on single-cell RNA-sequencing data quality in colorectal tissues [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B031.
Abstract IA010: Patient derived organoids in precision oncology
Authors: Valeri Nicola 
Published: December 2022

Abstract
Limits in the predictive power of molecular profiling and shortcomings of some pre-clinical models used in drug development represent important obstacles hampering the success of personalized medicine and drug discovery. LGR5+ stem cells can be isolated from a number of organs and propagated as epithelial organoids in vitro. Mouse and human organoids have been used to study the physiology and neoplastic transformation of the liver, pancreas, bowel and prostate among other organs. During my talk, I will highlight opportunities, limitations and potential clinical applications of patient-derived organoids in personalized oncology, emphasizing strengths and hurdles in the use of the organoid technology in forward and reverse translational cancer research. In particular, I will stress the importance of patient-derived organoids as pre-clinical tools to define mechanisms of drug resistance and to design novel drug combinations.
Citation Format: Nicola Valeri. Patient derived organoids in precision oncology [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA010.
Abstract IA014: Synthetic essentiality identifies TDO2 as a key target in APC-deficient CRC
Authors: Lee Rumi , Li Jiexi , Li Jun , Wu Chang-Jiun , Jiang Shan , Hsu Wen-Hao , Chakravarti Deepavali , Chen Peiwen , LaBella Kyle A. , Li Jing , Spring Denise J. , Zhao Di , Wang Y. Alan , DePinho Ronald A. 
Published: December 2022

Abstract
Loss of adenomatous polyposis coli (APC) is considered a critical initiating event in colorectal cancer (CRC), where it occurs in 90% of sporadic CRCs. APC deficiency results in activation of WNT; however, major hurdles persist to therapeutic intervention of this pathway. Here, the synthetic essentiality framework was used to discover other potential druggable vulnerabilities for APC-deficient cancers. Through this approach, tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient CRC. Upregulation of TDO2 activates the Kyn-AhR pathway, increasing glycolysis. Subsequent cancer cell growth and CXCL5 secretion leads to macrophage recruitment into the tumor microenvironment. APC-deficient CRC models were found to be susceptible to both TDO2 depletion and pharmacologic inhibition. Overall, this study identifies the TCF4-TDO2-AhR-CXCL5 axis as a critical pathway in the maintenance of APC-deficient CRC, informing potential genotype-specific therapeutic targets and the use of TDO2 inhibitors to combat this disease.
Citation Format: Rumi Lee, Jiexi Li, Jun Li, Chang-Jiun Wu, Shan Jiang, Wen-Hao Hsu, Deepavali Chakravarti, Peiwen Chen, Kyle A. LaBella, Jing Li, Denise J. Spring, Di Zhao, Y. Alan Wang, Ronald A. DePinho. Synthetic essentiality identifies TDO2 as a key target in APC-deficient CRC [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA014.
Abstract IA028: Circulating tumor DNA in the management for colorectal cancer: Are we there yet?
Authors: Morris Van Karlyle 
Published: December 2022

Abstract
Assessment of circulating tumor DNA represents a highly specific and highly sensitive "liquid biopsy" methodology to detect the presence (or absence) of microscopic disease for patients with colorectal cancer. With performance of available circulating tumor DNA assays rapidly evolving, the clinical and scientific applications subsequently continue to expand. Data generated by circulating tumor DNA/liquid biopsies has translated into the clinical management of colorectal cancer as a prognostic biomarker forecasting disease recurrence after resection and also for quantitative and qualitative characterization of treatment response in patients with metastatic colorectal cancer. To date, evidence of utility of circulating tumor DNA as a predictive biomarker for systemic treatment remains missing and illustrates a critical gap in knowledge. To address this unmet need, currently assessment of patients' blood specimens can provide critical cancer-specific insight into the dynamics not only of the colorectal cancer genome but also of the epigenome and transcriptome. Clinical trials are evaluating circulating tumor DNA as a novel approach to identifying micrometastatic colorectal cancer as a biologically distinct pathology that differs from larger, clinically detectable disease, with the intention for development of unique, targeted approaches which may ultimately improve outcomes for patients with colorectal cancer.
Citation Format: Van Karlyle Morris. Circulating tumor DNA in the management for colorectal cancer: Are we there yet? [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA028.
Epigenetic Rewiring UnderliesSMARCA4-Dependent Maintenance of Progenitor State in PediatricH3K27MDiffuse Midline Glioma
Authors: Beytagh Mary Clare , Weiss William A. 
Published: December 2022

Summary:Epigenetic reprogramming drives tumorigenesis in pediatric H3K27M diffuse midline glioma (DMG) by altering the canonical functions of chromatin remodeling complexes. These studies (i) identified BRG1 (encoded by SMARCA4), the catalytic subunit of the mammalian SWI/SNF (BAF) chromatin remodeling complex, as a novel dependency in pediatric H3K27M glioma; (ii) investigated the molecular mechanisms underlying the maintenance of the progenitor state; and (iii) demonstrated efficacy for BRG1 inhibitors.The authors identified the BRG1 ATPase as a dependency in pediatric H3K27M-mutant DMG. SOX10 recruits BRG1 to regulatory elements to drive progression. Pharmacologically targeting BRG1 reduced tumor volume and improved survival in vivo. Inhibiting BRG1 ATPase represents a potential therapeutic strategy for pediatric H3K27M DMG.See related article by Panditharatna et al., p. 2880 (5)See related article by Mo et al., p. 2906 (4) .
Cancer in 2022
Authors:   The AACR Cancer Progress Report 2022 Steering Committee
Published: December 2022

Summary:
Excerpts from the 12th edition of the annual AACR Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/) to U.S. Congress and the public highlight how medical research continues to extend and improve lives by accelerating advances in cancer prevention, detection, diagnosis, and treatment. Current challenges are described, and a call to action is issued.
Highlights of FDA Oncology Approvals in 2022: Tissue-Agnostic Indications, Dosage Optimization, and Diversity in Drug Development
Authors: Duke Elizabeth S. , J. Fusco Michael , DeMoss Patrick , Dilawari Asma , Pamuk Gulsum E. , Boehmer Jessica , Mixter Bronwyn , Goldberg Kirsten B. , Kluetz Paul , Pazdur Richard 
Published: December 2022

Summary:
In 2022, cancer drug development continued to progress rapidly despite the lingering COVID-19 pandemic. Highlights of U.S. drug approvals for oncology indications this year include ongoing development in rare diseases and molecular subgroups, improved dosage optimization, and updated data for drugs granted accelerated approval, with confirmatory studies demonstrating verification of clinical benefit in some instances, as well as indication withdrawal when clinical benefit was not verified.
Abstract A27: TRIM29-mediated immune evasion in bladder cancer invasive progression
Authors: Kelleher Alan , Wang Yin , Broses Luke , Lei Yu Leo , Palmbos Phillip 
Published: December 2022

Abstract
Background: Progression from noninvasive to muscle-invasive and then metastatic bladder cancer causes &gt;17,000 deaths each year in the United States. Unfortunately, the molecular drivers of progression remain poorly understood and no strategies to prevent progression exist. We have identified an E3 ubiquitin ligase, TRIM29, which is highly expressed in 70% of muscle invasive bladder cancers (MIBC). Global overexpression of TRIM29 in a genetically engineered mouse model (GEMM) is sufficient to induce urothelial cancer initiation and invasive progression. TRIM29 has also been shown to bind and ubiquitinate STING (Stimulator of Interferon Genes), a regulator of anti-tumor cytokine production. However, the role of TRIM29-mediated suppression of STING and innate immune responses in invasive progression was not previously understood. Hypothesis: Given the importance of Trim29 in invasive progression demonstrated in our GEMM, we hypothesized TRIM29-mediated degradation of STING creates an immune-privileged niche required for muscle invasion. Methods: To determine the requirement for Trim29-mediated immune suppression and bladder cancer invasive progression, we generated a urothelial specific tamoxifen inducible Trim29 knockout (KO) GEMM. To induce bladder tumorigenesis, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), a urothelial specific chemical carcinogen with similarities to tobacco, was delivered to mice via drinking water. Results: As expected, BBN promoted development of muscle-invasive urothelial tumors in 50% of mice after 24 weeks. Tamoxifen-induced Trim29 KO completely blocked progression to muscle-invasion, although these mice did demonstrate development of low grade, non-muscle invasive tumors. BBN upregulated Trim29 expression in the urothelium, but only modestly increased Sting and infiltrating macrophage and T cells. In contrast, Trim29 KO mice, which did not develop invasive tumors, harbored substantially elevated Sting levels in the urothelium and substantially increased macrophage and T cell infiltration in the bladder and tumor. In vitro, TRIM29 promoted STING ubiquitination and TRIM29 knockdown increased STING protein levels in bladder cancer cell lines. TRIM29 KO in these cells also resulted in increased expression of innate immune cytokines. Conclusion: These results suggest that TRIM29-mediated downregulation of STING in the bladder results in decreased immune surveillance in the tumor microenvironment, contributing to the development of an immune privileged niche required for MIBC progression.
Citation Format: Alan Kelleher, Yin Wang, Luke Broses, Yu Leo Lei, Phillip Palmbos. TRIM29-mediated immune evasion in bladder cancer invasive progression [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A27.
Abstract B22: B7-H3 promotes progression of prostate cancer harboring PTEN and TP53 defects
Authors: Shi Wei , Zhao Di 
Published: December 2022

Abstract
Prostate cancer is the most diagnosed cancer in men worldwide and the leading cause of cancer death in men worldwide. Genetic inactivation of PTEN and TP53 are common in advanced prostate cancers. Checkpoint immunotherapy has yielded meaningful responses across many cancers but shown minimal activity in advanced prostate cancer. Prior studies showed that overexpression of immune checkpoint B7-H3 (CD276) correlates with the increased risks of clinical recurrence, disease spread, and poor outcomes in various cancer types, including prostate cancer. However, the roles of B7-H3 in prostate cancer development and its tumor microenvironment remain unclear, partially due to the lack of tissue-specific deletion mouse models. This gap in knowledge hinders the application of immunotherapy targeting B7-H3 in prostate cancers. To identify PTEN- and p53-associated immune checkpoints, we performed multi-omics analyses of expression patterns of 51 checkpoint molecules in human prostate cancer samples. Then, we generated a novel generated genetically engineered mouse model to elucidate the role of B7-H3 in tumor development and progression of PTEN/p53-deficient prostate cancer. We also performed unbiased immunoprofling using Mass Cytometry (CyTOF) and Immunofluorescence to visualize B7-H3's impact on immune components in prostate tumors. Our multi-omics analyses in human samples revealed that B7-H3 is one of the most significantly overexpressed immune checkpoints in prostate tumors containing PTEN and TP53 genetic inactivation. Mechanistically, we found that the PTEN-AKT pathway co-operates with the p53 pathway in modulating B7-H3 expression in cancer cells. In Pten/Trp53 genetically engineered mouse (GEM) models, prostate-specific deletion of Cd276 resulted in markedly delayed tumor progression. Cd276 deletion also reversed the immunosuppression characterized by increased tumor-infiltrating lymphocytes. Our studies also provided mechanistic insights into potential combinatorial strategies for immunotherapy targeting B7-H3 in advanced prostate cancer harboring PTEN and TP53 defects.
Citation Format: Wei Shi, Di Zhao. B7-H3 promotes progression of prostate cancer harboring PTEN and TP53 defects [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B22.
Abstract B25: Novel regulation and function of Dishevelled 2 in the tumor microenvironment
Authors: Boligala Geetha P , Martinez-Marin Dalia , Melkus Michael W , Rahman Rakhshanda Layeequr , Pruitt Kevin 
Published: December 2022

Abstract
Background: The Wnt/β-catenin pathway contributes to tumorigenesis and recently has been shown to modulate T cell infiltration into the tumor microenvironment (TME). Dishevelled paralogs (DVL1-3) are key mediators of β-catenin dependent and independent Wnt signaling. Though DVL proteins are significant drivers of oncogenic Wnt signaling, little is known about their post-translational regulation and its impacts on tumor immunity. We aimed to study novel DVL post translational modifications (PTMs) and their influence on transcription and epigenetic regulation of immune associated genes in breast cancer (BC). Previous DVL1/3 ChIP-seq analyses revealed that other DVL paralogs bind to genes in tumor cells that modulate immune cell function. We hypothesize that tumor-intrinsic DVL2 regulates the expression of immunomodulatory genes. We further hypothesize that our recently discovered DVL PTMs will impact DVL function and immune cell infiltration into the TME. Experimental design: The cancer genome atlas (TCGA) database was mined for DVL2 expression in BC patients. To determine DVL2 localization to promoters of immune associated genes across a panel of BC cells, DVL2 ChIP-PCR was performed. To determine whether DVL2 was a positive or negative regulator of these genes, RT-qPCR was performed in BC cells in which DVL2 was stably depleted via shRNA. Finally, to identify novel DVL2 post-translational modification, immunoprecipitation and LC-MS/MS were performed.Result: TCGA analyses suggested a significant positive correlation between high DVL2 expression and poor overall and metastasis free survival in BC patients. DVL2 ChIP-PCR analyses showed that DVL2 binds to genes involved in antigen presentation and TIL recruitment. Moreover, RT-qPCR analyses revealed that DVL2 regulates mRNA expression of genes that modulate immune cell function, and Wnt target genes that impact cell proliferation, angiogenesis, and invasion. Interestingly, we have identified novel DVL2 PTMs from proteomic analyses and investigated its impact on genes involved in BC tumor immunity.Summary: Our study examines the novel biology of DVL2 and shows its aberrant expression in BC. We also show for the first time that DVL2 binds to gene promoters and regulates the expression of targets that influence TIL recruitment to the tumor microenvironment. A deeper understanding of DVL2 biology in BC tumors may lead to the development of novel therapeutic strategies.
Citation Format: Geetha P Boligala, Dalia Martinez-Marin, Michael W Melkus, Rakhshanda Layeequr Rahman, Kevin Pruitt. Novel regulation and function of Dishevelled 2 in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B25.
Abstract B65: MetaTiME: meta-components of the tumor immune microenvironment
Authors: Zhang Yi , Xiang Guanjue , Jiang Yijia Alva , Lynch Allen , Zeng Zexian , Wang Chenfei , Zhang Wubing , Fan Jingyu , Kang Jiajinlong , Gu Shengqing , Wan Changxin , Zhang Boning , Liu Shirley , Brown Myles , Meyer Clifford 
Published: December 2022

Abstract
Recent advances in single-cell RNA sequencing have revealed heterogeneous cell types and gene expression states in the non-cancerous cells in tumors. The integration of multiple scRNA-seq datasets across tumors can reveal common cell types and states in the tumor microenvironment (TME). However, tumor scRNA analysis relies on clustering cells and annotating with markers from experts. Subsequent challenges include inconsistent cell type and state definition, different marker usage among studies, and that clustering doesn’t find continuous cell states. We developed a data-driven framework, MetaTiME, to overcome the limitations in resolution and consistency that result from manual labeling using known gene markers. Using millions of TME single cells, MetaTiME learns meta-components that encode independent components of gene expression observed across cancer types. The meta-components are biologically interpretable as cell types, cell states, and signaling activities. For example, the T cell co-signaling meta-component reflects co-expressed gene modules of multiple immune checkpoint blockade targets. Also, the tumor-infiltrating macrophage meta-components found macrophage states in different metabolism preferences, rather than the pro-inflammatory versus anti-inflammatory classifications. We also observed certain macrophage states associated with tumor prognosis and cancer immunotherapy response. By projecting onto the MetaTiME space, we provide a tool to annotate cell states and signature continuums for TME scRNA-seq data. Lastly, leveraging epigenetics data, MetaTiME reveals critical transcriptional regulators for the cell states. Overall, MetaTiME learns data-driven meta-components that depict cellular states and gene regulators for tumor immunity and cancer immunotherapy.
Citation Format: Yi Zhang, Guanjue Xiang, Yijia Alva Jiang, Allen Lynch, Zexian Zeng, Chenfei Wang, Wubing Zhang, Jingyu Fan, Jiajinlong Kang, Shengqing Gu, Changxin Wan, Boning Zhang, Shirley Liu, Myles Brown, Clifford Meyer. MetaTiME: meta-components of the tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B65.