bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1599: Metabolism as a key regulator of macrophage phenotype in pancreatic cancer
Authors: Anaraki Cecily , Halbrook Christopher 
Published: March 2024

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related deaths in the US, with a five-year survival rate of 12%. Barriers to treatment include the highly fibrotic tumor microenvironment (TME), the high interstitial pressure which acts to collapse the blood vessels, and the influx of immunosuppressive immune cells. Within this immune milieu, we find that the most abundant are tumor-associated macrophages (TAMs). These TAMs display a phenotype similar to anti-inflammatory (M2-like) macrophages. Despite TAMs exerting an immunosuppressive function within the TME, there is not a complete overlap with the characteristics associated with M2 macrophages. Interestingly, TAMs still display many markers associated with the pro-inflammatory (M1-like) macrophages. This dichotomy suggests there may be a level of plasticity within the macrophage compartment that can be exploited to lead to better tumor control. Previous studies have shown a connection between arginine metabolism and macrophage effector function along the M1/M2 axis. In macrophages, arginine can be broken down in two ways: via iNOS into nitric oxide, which aids in effector function, or via Arginase 1 (Arg1) into ornithine and later proline, which is an essential component of the extracellular matrix (ECM). This study seeks to elucidate how metabolic perturbations influence macrophage function and phenotype. Here we observed that changes in oxygen availability and glucose abundance shifted macrophage expression of iNOS and Arg1. In vivo we found that conditionally knocking out Arg1 in the myeloid compartment leads to lower fibrosis when inducing inflammation in the pancreas. Furthermore, macrophages polarized with PDAC cancer-conditioned media display a sharp increase in Arg1 expression as compared to unpolarized macrophages, as well as increased resistance to both glycolytic inhibitors and mitochondrial inhibitors. This preliminary data demonstrates an important link between macrophage metabolism and function in the context of pancreatic disease.
Citation Format: Cecily Anaraki, Christopher Halbrook. Metabolism as a key regulator of macrophage phenotype in pancreatic 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 1599.
Abstract 1669: KRAS G12X mutants display differential preferences in downstream effector binding
Authors: Ash Leonard J. , Bourdain Ottavia , Lam Dennis , Pallas Shlomo S. , Wolfe Andrew L. 
Published: March 2024

Abstract
KRAS is among the most frequently mutated oncogenic driver proteins in human cancers including lung, colorectal, and pancreatic cancers. Activating KRAS mutants cause increased cell proliferation through direct binding and overactivation of effector proteins. Effector activation preference is driver mutation specific, as KRAS G12D and G12C purportedly bind both RAF and PI3K, whereas G12R has been reported to bind RAF but not PI3K. The mechanisms of effector binding of G12S action are under-investigated. Furthermore, most KRAS mutations remain clinically untreatable, as clinically approved KRAS inhibitors (KRASi) are currently limited to specifically targeting G12C. While experimental non-G12C inhibitors are being developed, resistance mechanisms to non-G12C mutations—including G12D/R/S/V—remain relatively understudied.
We set out to characterize the binding efficiency of KRAS to RAF1 and the PI3K subunit p110α, and to understand how isoforms differ in inhibitor resistance strategies. Our findings suggest that significant variances in KRAS mutation-specific effector binding preference exist and are cell line dependent. We performed proximity ligation based immunofluorescence assays (PLA) on an isogenic panel of human colorectal SW48 KRAS cells with G12C/D/R/S/V or wildtype. SW48 cells with G12S significantly prefer the KRAS-RAF1 mode of binding over otherwise isogenic WT cells, and G12V homologs prefer PI3K. Our findings suggest that in this model, G12R cells have no specific preference of one binding mode over the other. We hypothesize that G12 chemistry drives effector binding preference and that G12X inhibitor resistant cell cultures will demonstrate variant mechanisms of resistance in line with their preferred binding partner. Ongoing studies will further characterize understudied RAS isoform biology and evaluate the links between isoform chemistry and mechanisms of inhibitor resistance. These studies will expand our mechanistic knowledge of the interplay between G12X chemistry and adaptive resistance in human cancer.
Citation Format: Leonard J. Ash, Ottavia Bourdain, Dennis Lam, Shlomo S. Pallas, Andrew L. Wolfe. KRAS G12X mutants display differential preferences in downstream effector binding [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 1669.
Abstract 1674: Inhibition of oncogenic nras signaling in acute myeloid leukemia cell lines through directed transcriptome alterations
Authors: Roberts Michael , Kovatsis Sophia , Harper Amelia , Cravinho Megan , Mangru Kishan , Bahadur Sher , Hesse Keagan , Meta Katy , Nguyen Cuong 
Published: March 2024

Abstract
Oncogenic mutations in genes involved in proliferative signaling are hallmarks of malignant transformation. The Ras family of signal transducing proteins are involved in the activation of several proliferative pathways and therefore are found to be oncogenically mutated in a variety of cancer types. The NRAS-directed pathways resulting in Erk1/2 activation are dysregulated in a significant percentage of acute myeloid leukemia (AML), metastatic melanoma, Hodgkin lymphoma, and thyroid cancers. The consequence of oncogenic NRAS signaling is the establishment of a transcriptome commanding constitutive proliferation and survival. It has long been known that phorbol ester treatment of AML cell lines, resulting in activation of protein kinase C (PKC), causes phenotypic changes that include cell cycle arrest, myeloid differentiation, and apoptosis. The paradox is that numerous studies identify PKC as an activator of RAS/ERK signaling. Here we show that phorbol ester treatment of NRAS-driven AML cell lines results in the transcriptional upregulation of genes encoding negative regulators of RAS signaling including DUSP1,2,4,5,6, SPRY2, SPRED1, RASA1, PEA15, RPS6KA1, and RASSF5. Additionally, phorbol ester treatment eventually results to ERK1/2 inactivation through dephosphorylation. Several of these negative regulators, when overexpressed in AML cell lines, dampen proliferation, and induce senescence. We propose that the induction of RAS negative regulators alters the AML transcriptome to a non-proliferative state in part through the transcriptional regulation of genes such as CDKN1A, CDKN2B, ZFP36L1, and MYC. As gene therapy strategies develop, designed to provide negative regulators of proliferative signaling pathways that are repressed in the malignant cell, we imagine the RAS/ERK pathway as a target for transcriptome reprogramming.
Citation Format: Michael Roberts, Sophia Kovatsis, Amelia Harper, Megan Cravinho, Kishan Mangru, Sher Bahadur, Keagan Hesse, Katy Meta, Cuong Nguyen. Inhibition of oncogenic nras signaling in acute myeloid leukemia cell lines through directed transcriptome alterations [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 1674.
Abstract 1675: Investigating the role of SRC-family kinases in MPNST tumorigenesis
Authors: Zereg Elamine , Voisin Laure , Grenier Karl , Courcelles Mathieu , Jung Sungmi , Thibault Pierre , Meloche Sylvain 
Published: March 2024

Abstract
Purpose: Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, is the leading cause of mortality in patients with neurofibromatosis type 1. Over the past two decades, significant advancement has been made in understanding the pathogenesis of MPNST. Still, this progress has not improved overall survival of patients. Therefore, ongoing efforts to identify alterations contributing to the transformation, progression, and metastasis of MPNST are essential for pinpointing targetable oncogenic signaling pathways for this cancer. Previous studies have revealed an increase in YAP/TAZ activity through both LATS1/2-dependent and LATS1/2-independent mechanisms, suggesting that YAP/TAZ hyperactivity may act as a convergence point for MPNST pathogenesis. YES and SRC, two members of the SRC-family kinases (SFKs), were shown to phosphorylate LATS1/2 and YAP/TAZ, and stimulate the transcriptional activity of YAP/TAZ by promoting their nuclear accumulation in hepatocellular carcinoma and colorectal cancer cells. Thus, we have investigated whether YES and SRC are involved in the pathogenesis of MPNSTs.
Experimental Design: To assess whether the SFK-YAP/TAZ signaling axis is implicated in the development of MPNST, we have used genetic and pharmacological approaches to investigate the roles of YES and SRC in the proliferation of a subset of human MPNST cell lines, and in the growth of xenografted MPNST tumors in ectopic and orthotopic mouse models. We also performed a phosphoproteome and a transcriptome analysis of YES and SRC-depleted MPNST cells to assess their oncogenic signaling network. Lastly, we evaluated the clinical significance of phospho-SFK and YAP in human MPNST TMAs.
Results: Our findings reveal that YES and SRC activity play an essential and redundant role in sustaining the proliferation of human MPNST cell lines. Further, the simultaneous depletion of both kinases impedes tumor growth in xenograft MPNST mouse models. Transcriptomic analyses identified YAP and TAZ as potential effectors of SFKs, as well as other family of transcription factors. Finally, TMA data suggested a correlation between the expressions of YAP, YAP/TAZ, and phospho-SFK and the progression of MPNST.
Citation Format: Elamine Zereg, Laure Voisin, Karl Grenier, Mathieu Courcelles, Sungmi Jung, Pierre Thibault, Sylvain Meloche. Investigating the role of SRC-family kinases in MPNST tumorigenesis [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 1675.
Abstract 1678: Docetaxel induces Rac1 and Cdc42 Rho GTPase activation in prostate cancer cells
Authors: González Andrea Paola López , González Jessica Colón , Fuentes María C. Santa María , Dharmawardhane Surangani , Osterman Carlos J. Diaz 
Published: March 2024

Abstract
Prostate cancer (PCa) is a major health burden that affects the quality of life of men worldwide. In the United States, PCa is the second leading cause of mortality among cancers that affect men. Treatment of advanced PCa aims to suppress androgen signaling and proliferation in cancer cells using anti-androgens and chemotherapy. However, the development of drug resistance is a major limitation to curing advanced prostate cancer and strategies to block mechanisms of therapy resistance would enhance treatment efficacy and potentially improve patient prognosis. Cdc42 and Rac1, members of the family of Rho GTPases, have been associated with the progression of different types of hormone-associated cancer, such as breast, ovary, and prostate, among others. The current study was designed to evaluate the role of Cdc42 and Rac1 in chemoresistant prostate cancer cells, including under castration-resistant and androgen-independent conditions. We did not observe significant differences in active (Rac-GTP) or total Rac1 levels in chemoresistant compared to parental PC3 or DU145 cells; similar findings were observed for Ccd42. Treatment of drug-naïve cells with a sublethal dose of docetaxel (10uM) induced gradual increases in Rac1-GTP up to 30 minutes in 22rv1, 60 minutes in LNCaP and DU145, and 24 hours in PC3 cells. Cdc42-GTP levels also increased with subacute docetaxel treatment up to 24 hours in 22rv1 and DU145. Chemoresistant 22rv1, PC3, and DU145 exhibited similar sensitivity to Rac1 and Ccd42 inhibitors including MB1-167, MBQ-168, EHop-097, with an IC50 of about 1uM for each compound and line. Ongoing studies are evaluating the role of these Rho-GTPases in 3-dimensional growth and survival.
Citation Format: Andrea Paola López González, Jessica Colón González, María C. Santa María Fuentes, Surangani Dharmawardhane, Carlos J. Diaz Osterman. Docetaxel induces Rac1 and Cdc42 Rho GTPase activation in prostate 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 1678.
Abstract 1679: Understanding the mechanism of Daple-PDGFRB gene fusion in leukemia
Authors: Ibarra Arnel Cardona , Ly Vivian , Ear Jason 
Published: March 2024

Abstract
Gene fusion between the scaffolding protein Daple and cell-surface receptor PDGFRB have been identified in several patients with leukemia. Patients with Daple-PDGFRB gene fusion are responsive to tyrosine kinase inhibitors, suggesting that the kinase domain on the receptor is active. How the Daple-PDGFRB gene fusion is activated and affects leukemia cells is poorly understood. It is hypothesized that the PDGFRB kinase domains found in gene fusion remain constitutively active, leading to hyperactivation of cell-signaling downstream of receptor tyrosine kinases (RTKs). To test this, identified Daple-PDGFRB mutants found in patients were ectopically expressed in cells and kinase activation were determined using a phospho-specific antibody. We demonstrated that indeed, the kinase domain on the gene fusion were active, and partake in rampant cell signaling. Because drug resistance is common in cancers such as leukemia, the implications from this work may uncover additional methods of therapeutic interventions for patients harboring these types of mutations.
Citation Format: Arnel Cardona Ibarra, Vivian Ly, Jason Ear. Understanding the mechanism of Daple-PDGFRB gene fusion in leukemia [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 1679.
Abstract 1729: SUV420H1 depletion reveals therapeutic potential in HPV-negative head and neck squamous cell carcinoma
Authors: Moshiri Arfa , Kim Sohyoung , Luff Marie , Saloura Vassiliki 
Published: March 2024

Abstract
Human Papilloma Virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) poses a significant clinical challenge with limited treatment options. SUV420H1, which encodes for a protein lysine methyltransferase (PMT) that methylates H4K20 (H4K20me3), is recurrently amplified in ~5% of HPV-negative HNSCC tumors and is the second most frequently amplified PMT in this disease, suggesting an oncogenic function in this subset of HPV-negative HNSCC patients. Gene set enrichment analysis using the TCGA database of HPV-negative HNSCC tumors revealed that SUV420H1 overexpressing tumors showed enrichment in the mitotic spindle related pathways, and repression of immune-related pathways. To assess whether SUV420H1 depletion affects the proliferation of HPV-negative HSNCC cells, CCK8 and colony formation assays were pursued after siRNA-mediated knockdown of SUV420H1 in five SUV420H1-overexpressing HPV-negative HNSCC cell lines and revealed a significant reduction in cell proliferation and colony forming capacity. SUV420H1 CRISPR knockout (KO) HPV-negative HNSCC human and mouse cell lines were generated. Proliferation and colony formation assays with the SUV420H1 KO cell lines are ongoing to validate the aforementioned phenotypes. To identify oncogenic mechanism of SUV420H1, genome-wide mapping of H4K20me3 after siRNA-mediated depletion or enzymatic inhibition of SUV420H1 (A-196) was pursued using CUT&RUN assays combined with RNA-seq in a SUV420H1 amplified cell line (SCC-151), and analysis is ongoing. Preliminary RNA-seq analysis revealed upregulation of a number of type I IFN response genes after siRNA-mediated knockdown of SUV420H1. In vivo mouse experiments using SUV420H1 KO mouse cell lines are planned in a syngeneic HPV-negative HNSCC flank mouse model (MOC1) with or without anti-PD-1 treatment with the goal to assess whether SUV420H1 depletion affects tumor growth and/or sensitizes cancer cells to anti-PD-1 therapy. These data provide preliminary support for the function of SUV420H1 as an oncogene in HPV-negative HNSCC.
Citation Format: Arfa Moshiri, Sohyoung Kim, Marie Luff, Vassiliki Saloura. SUV420H1 depletion reveals therapeutic potential in HPV-negative head and neck squamous cell carcinoma [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 1729.
Abstract 1740: Histone proteomic profiling of EMT-transformed MCF10A breast cells demonstrates a loss in novel histone arginine methylation sites via dual p53 and PTEN deletion
Authors: McGuinness Charlotte B. , Wilson Megan A. , Leonard Margaret V. , Ouzounova Maria , Korkaya Hasan , Shull Austin Y. 
Published: March 2024

Abstract
Metastatic potential of basal-like breast cancers typically is initiated by genetic alterations that lead to a process known as epithelial-mesenchymal transition (EMT). However, much is currently not understood regarding the role of epigenetic modifications that lead to invasive characteristics and EMT phenotype of metastatic breast cancers. Based on the previous notion connecting epigenetic changes to breast cancer metastasis, we performed DIA-based mass spectrometry of isolated histones from an isogenic panel of MCF10A breast cell lines where the tumor suppressor genes TP53 and PTEN were silenced and induced EMT. With this approach, we determined which histone modifications were differentially enriched in the non-EMT and EMT-induced MCF10A cell lines. From approximately 72 histone modifications identified and annotated from our mass spectrometry results, we were able to identify 5 histone events that were differentially enriched in our MCF10A cell line panel. Two events of note were histone H3 lysine-14 acetylation (H3K14ac) significantly increasing and histone H4 arginine 55 dimethylation (H4R55me2) significantly decreasing in our EMT-transformed MCF10A p53-/PTEN- cell lines when compared to the parental, non-tumorigenic MCF10A cell line, showing these events are differentially affected during the EMT process in breast cancer cells. Furthermore, significant arginine demethylation of H4R55me2 & H3.1R83me in the EMT-transformed MCF10A p53-/PTEN- cell lines corresponded with JMJD6, an established histone arginine demethylase, being overexpressed in basal-like breast cancer cell lines as well as basal-like breast cancer patients from The Cancer Genome Atlas (TCGA) and METABRIC datasets. Based on histone proteomic profiling of our isogenic cell line model, the loss of specific histone arginine methylation events corresponding with JMJD6 overexpression could highlight the potential for a targetable epigenetic mechanism in breast cancer metastasis.
Citation Format: Charlotte B. McGuinness, Megan A. Wilson, Margaret V. Leonard, Maria Ouzounova, Hasan Korkaya, Austin Y. Shull. Histone proteomic profiling of EMT-transformed MCF10A breast cells demonstrates a loss in novel histone arginine methylation sites via dual p53 and PTEN deletion [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 1740.
Abstract 1760: Mutational landscape of the canine acute myeloid leukemia exome
Authors: Harris Robert , Conaway Evan , Avery Anne 
Published: March 2024

Abstract
Over 21,000 newly diagnosed cases of human acute myeloid leukemia (hAML) and 10,000 hAML-related deaths are reported in the United States every year. hAML is considered a highly diverse aggressive hematopoietic malignancy, with over 16 recurrent gene rearrangements, 60 recurrent point mutations, and hundreds of rarely mutated genes. There are large ongoing multi-institutional studies devoted to advancing medical management for hAML by providing targeted therapeutics to patients based on their molecular characteristics. A preclinical spontaneous large animal model for testing novel therapies could accelerate the development of better treatments in people. Dogs spontaneously develop AML with similar clinical features and outcomes. As such, the dog may be a useful pre-clinical model, but little is known about the molecular landscape and/or drivers of canine AML (cAML). The goal of this work was to identify somatic mutation candidates in cAML and determine the overlapping features with hAML. We utilized whole exome sequencing at 300x coverage to identify candidate mutations in 51 cAML samples. Somatic variant calling was performed per the GATK best practice recommendations using Mutect2 and a reference panel of normals (n=77) and a variant call file of canine germline variants. We focused our analysis on novel variants predicted to have a moderate to high impact and that occurred in genes implicated in cancer. At least one variant was identified in genes involved in the RTK/RAS pathway (e.g. NRAS, KRAS, PTPN11, FLT3, KIT) in over 75% of cAML samples, a trend that is also found in people. Additionally, recurrent point mutations were predicted in NRAS and KRAS, and some of which, such as the codon changes G13R and Q61R/H in NRAS, were noted to be shared between hAML and cAML. Mutations in DNMT3A were uncommon (n=3/44) and NPM1 mutations were not identified in our cohort, both of which are common hAML-associated genes. However, mutations in other epigenetic modifiers, such as KDM5C and KDM6A, occurred at a high frequency. This data provides insight into the candidate mutations potentially driving cAML pathogenesis and highlights the overlapping molecular features with hAML.
Citation Format: Robert Harris, Evan Conaway, Anne Avery. Mutational landscape of the canine acute myeloid leukemia exome [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 1760.