bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6864: Tumor suppressor function of the ubiquitin ligase Siah1a in melanoma is mediated by myeloid derived suppressor cells
Authors: Scortegagna Marzia , Du Yuanning , Feng Yongmei , Ronai Ze'ev 
Published: March 2024

Abstract
Growing evidence supports the important role of myeloid-derived suppressor cells (MDSC) in melanoma progression and response to therapy. MDSC contributes to a pro-tumorigenic phenotype, yet the mechanistic basis for the immune suppressor properties acquired by MDSC remains largely unknown. Mammals have two homologous Siah genes, Siah1 (Siah1a and Siah1b in mice) and Siah2. In the context of melanoma, the ubiquitin ligases Siah1a and Siah2 have melanoma-intrinsic and -extrinsic (immune) functions. Correspondingly, ablation of Siah1a/2 in melanoma or its microenvironment attenuates melanoma development in a number of mouse melanoma models. Given that number of macrophage clusters infiltrated into melanoma when grown in Siah2 KO mice, we set to assess macrophage function in melanoma. Selective ablation of Siah1a or Siah2 in macrophages, using Lyz2Cre, revealed that Siah1a but not Siah2 elicits a tumor suppressor function in melanoma. Inoculation of mouse melanoma Yummer1.7 cells (Braf mutated and Pten deleted) in mice lacking Siah1a in macrophages, resulted in bigger melanoma tumors compared to melanoma grown in either WT or mice in which macrophages were ablated of Siah2. FACS analysis of melanoma tumors grown in mice harboring Siah1a mutant macrophages revealed a significant increase in MDSC, which coincided with a decrease in CD4+ and CD8+ cells, compared with WT mice. These observations suggest that a lack of Siah1a in macrophages leads to an expansion of MDSC that affects surrounding immune cells, including T cells. RNA-seq analysis of MDSC that were differentiated in vitro from bone marrow cells of WT or Siah1a ablated macrophage mice revealed increased expression of genes involved in proliferation and alternative macrophage activation in MDSC lacking Siah1a when compared to the WT genotype. Mapping mechanisms underlying Siah1a tumor suppressor function is expected to reveal novel regulatory cues in melanoma control by the MDSC population while mapping novel means for stratifications of melanoma to therapy, and possibly new means for therapy of this tumor type.
Citation Format: Marzia Scortegagna, Yuanning Du, Yongmei Feng, Ze'ev Ronai. Tumor suppressor function of the ubiquitin ligase Siah1a in melanoma is mediated by myeloid derived suppressor 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 6864.
Abstract 6904: Model-derived progression-free survival (mPFS): A better metric for patient-derived xenograft studies
Authors: Chen Andrew , Stoddard Madison , Yuan Lin , Van Egeren Debra , Chakravarty Arijit , Bottino Dean 
Published: March 2024

Abstract
Patient-derived xenografts (PDX) are a powerful assay system for translational prediction of therapeutic potential for experimental therapeutics. The primary readout from PDX models is tumor shrinkage, measured by the ratio of treated/control tumor volume. This readout corresponds loosely to the Objective Response Rate (ORR) metric used in clinical trials, in that it is a readout of drug effect on the sensitive subclones within a tumor. In prior work, we have shown that there is a paradoxical relationship between short-term tumor response and progression-free survival (PFS). While ORR is the primary measure utilized in the Phase II to III transition in clinical development, approval hinges on survival metrics, and the disconnect between ORR and PFS creates a potential risk of late-stage failures for experimental anticancer therapeutics. Thus, it is of interest to understand whether there are alternative approaches to analyzing PDX data that can enable the assessment of therapeutic potential in terms of a projected PFS. In this simulation study, we will examine the accuracy of progression-free survival (PFS) estimates obtained directly from observation during a PDX study and compare their accuracy with the accuracy of PFS estimates derived using a mathematical model-based approach that relies on a kinetic model of tumor subclone growth (model-based PFS, or mPFS) fitted directly to PDX tumor growth and rebound kinetics under treatment. We generated our test dataset using a mathematical model of tumor kinetic growth to simulate xenograft data using fitted parameters derived from literature, adding in experimental error consistent with prior experimental measurement-derived variability. We used the simulated raw data to calculate an observed PFS as well as mPFS derived from fitting the tumor clonal kinetic model to the raw data in a blinded fashion. Our results show that the empirical PFS from PDX models is subject to overestimation, as a function of the observation time interval. On the other hand, mPFS is significantly less biased and more accurate, but is subject to some logistical constraints on sampling. Our work demonstrates the practical translational utility of a novel analysis method (mPFS) in deriving estimates of progression-free survival from PDX model data.
Citation Format: Andrew Chen, Madison Stoddard, Lin Yuan, Debra Van Egeren, Arijit Chakravarty, Dean Bottino. Model-derived progression-free survival (mPFS): A better metric for patient-derived xenograft studies [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 6904.
Abstract 6935: Non-genetic routes of lung cancer evolution
Authors: Ciriello Giovanni , Tavernari Daniele , Varrone Marco 
Published: March 2024

Abstract
Cancer cell plasticity underlies the progression of several solid tumors. In lung adenocarcinoma, morphological changes characterizing the transition from indolent to aggressive disease exhibit profound epigenetic and transcriptional reprogramming1. However, the extent, features, and drivers of cancer cell plasticity in the progression of human lung adenocarcinoma is still largely unexplored. Here, we assembled and analyzed a meta-cohort of 119 human lung tumors analyzed by single-cell RNA-sequencing, for a total of ~730,000 cells. Cancer cell heterogeneity was the result of differential activation of 17 transcriptional programs associated with common cancer phenotypes, such as proliferation, cell migration, and response to hypoxia, as well as alveolar lineage identity (AT2). In particular, AT2-specific expression of MHC-II was down-regulated with the progression of the disease and markedly reduced in KEAP1 and/or STK11 mutated samples, providing a rationale for the association between these mutations and immunotherapy resistance. Co-activation of transcriptional programs clustered tumor cells in 4 major cell states, which emerged with the progression of the disease. To explore spatial distribution of different cancer cell states, we generated and analyzed multiple spatial transcriptomics and proteomics lung adenocarcinoma cohorts. To this purpose we developed a new algorithm called CellCharter2. CellCharter identified distinct cancer-enriched niches within individual samples, corresponding to the cancer cell states that we discovered in the scRNA-seq cohort and exhibited specific interactions with the tumor microenvironment (TME). In particular, we identified a cancer cell state characterized by response-to-hypoxia and migratory phenotypes, which spatially segregated from highly proliferative cancer cell niches and formed specific interactions with tumor associated neutrophils. This cell state was enriched in advanced primary samples, it uniquely characterized metastatic samples, and was an independent marker of poor prognosis across multiple independent datasets. Overall, our work uncovered cell plasticity trajectories associated with the progression of lung adenocarcinoma and shed new light into the tumor-TME interactions at their origin. 1 Tavernari et al., Cancer Discovery, 20212 Varrone et al, Nat. Genetics, (in press)
Citation Format: Giovanni Ciriello, Daniele Tavernari, Marco Varrone. Non-genetic routes of lung cancer evolution [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 6935.
Abstract 6953: Wnt2b deficiency exacerbates colitis and leads to increased tumorigenesis in mice
Authors: Oliveira Luiz Fernando Silva , O'Connell Amy E. 
Published: March 2024

Abstract
Colitis-associated cancer (CAC) is considered the most severe complication of inflammatory bowel disease (IBD). It has been demonstrated that WNT2B deficiency leads to severe intestinal impairment in humans and predisposes to colitis in mice. Evaluating a human cohort from The Cancer Genome Atlas (TCGA), we observed that low expression of WNT2B is associated with poor prognosis of patients with colon cancer. However, the functional roles of WNT2B in CAC development remain unclear, and we hypothesized that WNT2B is involved in the resistance to CAC development during long-term colitis. Thus, we model CAC development using Wnt2b deficient mice subjected to mutagenesis induction with 10 mg/kg Azoxymethane (AOM) and a long-term colitis protocol with three cycles of 2.5% Dextran Sodium Sulfate in the drinking water for three days, followed by a recovery period with autoclaved water. We observed that Wnt2b KO mice had increased susceptibility to colitis and more significant body weight changes than WT mice, especially in the first and second recovery cycles of colitis recovery. The maximum weight loss and disease activity index (DAI) were significantly higher in KO than in WT mice. Interestingly, Wnt2b KO mice developed more tumors, which were more extensive than those observed in WT. Moreover, the histopathological analysis showed that Wnt2b KO had the highest score for ulceration, aberrant crypt foci, and immune cell infiltration. Our data suggest a protective role for WNT2B, conferring resistance to tumor development during colitis. Furthermore, our data provides new insights into the functional roles of Wnt ligands in colon cancer. A better understanding of the factors involved in CAC etiology is critical for improving diagnosis and developing new targeted therapies. We believe WNT2B may emerge as one of these factors and offer novel targets for improved colorectal cancer management.
Citation Format: Luiz Fernando Silva Oliveira, Amy E. O'Connell. Wnt2b deficiency exacerbates colitis and leads to increased tumorigenesis in mice [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 6953.
Abstract 6954: Glycine decarboxylase regulates renal carcinoma progression and DNA damage response via interferon stimulated gene factor 3-mediated pathway
Authors: Kim Jin Young , Kim Byung Hoon , Choe Misun , Pham Thi Tuyet Mai , Kim Mikyung , Seo Ji Hae , Shin So Jin 
Published: March 2024

Abstract
Glycine decarboxylase (GLDC) is a mitochondrial enzyme of glycine cleavage system which catalyzes glycine to donate for one-carbon metabolism. It is implicated as a tumor suppressor in hepatocellular carcinoma but as an oncogene in lung cancer. Although GLDC expression in the kidney is second highest next to the liver, the role of GLDC in the kidney remains unclear. Thus, this study was designed to determine the role of GLDC in renal carcinoma. We found markedly increased expressions of GLDC in patients with renal cell carcinoma (RCC) classified as poor-risk group based on the Memorial Sloan Kettering Cancer Center prognostic model. In vitro studies revealed that cellular proliferation, colony formation was decreased in GLDC-deficient renal carcinoma cells. Additionally in vivo xenograft studies with GLDC-deficient and -overexpressing cells also revealed that tumor sizes were noticeably decreased in GLDC-deficient cell-injected mice while those were increased in GLDC-overexpressing cell-injected mice. Mechanistically, we found GLDC regulates renal carcinoma progression via interferon (IFN) stimulated gene factor 3 (ISGF3)-mediated pathway. Expressions of IRF9 and STAT2 were increased in GLDC-deficient cells while those were decreased in GLDC-overexpressing cells. Upon inducing expression of ISGF3 subunits, GLDC deletion elevated DNA damage, mitotic catastrophe, mitochondrial deficiency induced by chemotherapy. Finally, GLDC knockdown diminished pyrimidine synthesis to impair renal cancer progression. In summary, our finding reveals that GLDC regulates renal carcinoma progression and DNA damage response via ISFG3-medated pathway and lays a scientific foundation that could support a therapeutic strategy that targets GLDC for the treatment of renal carcinoma.
Citation Format: Jin Young Kim, Byung Hoon Kim, Misun Choe, Thi Tuyet Mai Pham, Mikyung Kim, Ji Hae Seo, So Jin Shin. Glycine decarboxylase regulates renal carcinoma progression and DNA damage response via interferon stimulated gene factor 3-mediated pathway [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 6954.
Abstract 696: Proton radiation and Seco-Duocarmycin SA: A synergistic strategy unveiling new frontiers in glioblastoma multiforme therapy
Authors: Morcos Ann , Bertucci Antonella , Fuller Ryan Nicholaus , Wall Nathan Robert , Vazquez Marcelo Eduardo 
Published: March 2024

Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive brain cancers with a 6.9% five-year survival rate. More effective therapies are needed as standard treatments, which include surgery, radiation, and chemotherapy are inefficient due to radio-chemo-resistance and relapse. The goal of this project is to investigate the efficacy of seco-duocarmycin SA (sDSA) as an anticancer drug, alone and the potential synergy of combining proton radiation and sDSA in human GBM cell lines. Proton therapy offers numerous advantages in treating cancers because of its superior dose distribution and biological effects. sDSA is an exceptionally potent agent that selectively alkylates DNA at the N3 position of adenine, making it of great interest as a therapeutic drug. We hypothesize that by pairing sDSA with proton radiation, a more dynamic effect will result, which will amplify their collective power, unleashing an enhanced cytotoxicity against human GBM cells. GBM cell lines (T98G and LN18) were exposed to graded doses and concentrations of protons and sDSA respectively in order to evaluate cellular changes in proliferation, survival, cell cycle, apoptosis/necrosis induction, and DNA damage. Results show that proton radiation and sDSA when used alone induce a dose-dependent decrease of cell proliferation, an increase in foci formation, and an increase in G2/M phase arrest in LN18 and T98G cells. The data also illustrates that the combination of proton radiation and sDSA synergistically enhances these effects. The utilization of proton radiation in conjunction with sDSA against GBM represents an innovative and previously unexplored approach. Currently, the cellular mechanisms of sDSA cytotoxicity are not well understood or studied, and even less is known regarding the effects when combined with proton radiation. This study serves as a vital cornerstone in unraveling the biological response of GBM cells when confronted with proton radiation and sDSA, paving the way for the future development of a more precise and potent combination therapy.
Citation Format: Ann Morcos, Antonella Bertucci, Ryan Nicholaus Fuller, Nathan Robert Wall, Marcelo Eduardo Vazquez. Proton radiation and Seco-Duocarmycin SA: A synergistic strategy unveiling new frontiers in glioblastoma multiforme therapy [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 696.
Abstract 7021: Selecting your epigenomic assay: Comparing ChIP-seq, CUT&RUN, and CUT&Tag
Authors: Guo Angela H. , Comeau Christopher R. , Chen Fang 
Published: March 2024

Abstract
For many years, chromatin immunoprecipitation (ChIP) was the standard assay for studying epigenetic mechanisms. However, two new versatile techniques have recently been developed that are faster, experimentally easier, and more cost-effective than ChIP. Cleavage Under Targets & Release Using Nuclease (CUT&RUN) and Cleavage Under Targets & Tagmentation (CUT&Tag) can be used for understanding protein-DNA interactions within the natural chromatin context of the cell. Both CUT&RUN and CUT&Tag can be combined with Next Generation Sequencing (NGS) to analyze the function of histone modifications and the binding of transcription factors, DNA replication factors, or DNA repair proteins across the genome.
CUT&RUN and CUT&Tag are rapid, robust, and true low cell number methods for the detection of protein-DNA interactions. Unlike ChIP, both assays are free of formaldehyde cross-linking, chromatin fragmentation, and immunoprecipitation. When compared to ChIP, CUT&RUN and CUT&Tag require fewer starting cells (as low as 5,000 – 20,000), are shorter assays (one day from cells to DNA), and generate lower background signal (requiring fewer sequencing reads). At Cell Signaling Technology (CST), we have developed ChIP-seq, CUT&RUN, and CUT&Tag assay kits and validated a broad set of antibodies against histone modifications, transcription factors, and cofactors that are compatible with these kits. This poster will discuss the fundamentals of all three assays and highlight important factors to consider when selecting an assay for your experiment.
Through our antibody validation efforts, we have also generated a unique and extensive archive of ChIP-seq, CUT&RUN, and CUT&Tag NGS data using recombinant, monoclonal antibodies. This allows for the controlled comparison of these three commonly used chromatin profiling techniques. In this poster, I will highlight the similarities and differences between these assays when mapping a variety of histone modifications, transcription factors, and cofactor binding events across multiple sample types.
Citation Format: Angela H. Guo, Christopher R. Comeau, Fang Chen. Selecting your epigenomic assay: Comparing ChIP-seq, CUT&RUN, and CUT&Tag [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 7021.
Abstract 7111: Homoharringtonine is effective in treating acute lymphoblastic leukaemia via WEE1 downregulation and inducing DNA damage
Authors: Sin Chun-fung , Yuen Kei-ching , Jiao Anan , Li Bai-lin , Yu Hau-wai 
Published: March 2024

Abstract
Acute lymphoblastic leukaemia (ALL) is an aggressive haematolymphoid malignancy that originated from clonal mutations in lymphoid precursors. The prognosis is poor in adult patients and relapse/refractory disease is not uncommon which carries dismal prognosis. There is an urgent need to develop novel therapeutics. Homoharringtonine (HHT) is a plant alkaloid which can bind to ribosomal A-site and thus inhibit protein synthesis. It was used to treat acute myeloid leukaemia in China during 1980s. Herein, we conducted a study to explore the therapeutic efficacy and mechanism of action in ALL. T-ALL (DND-41, PEER) and B-ALL (PALL-2, SUP-B15) cell lines were treated with HHT for 24 and 72 hours. Cell viability was reduced at a time and dose-dependent manner in all cell lines we tested, with increased in percentage of apoptosis. Western blot showed upregulation of p53, with PARP and caspase 3 cleavages upon treating with HHT for 24 hours. Moreover, we observed WEE1 downregulation which allowed cell cycle progression through G2/M with damaged DNA. Comet assay showed evidence of DNA damage. Proteomics study by label-free protein quantitation showed downregulation of proteins involving in homologous recombination-mediated DNA repairing machinery, including BRCA1 and RAD51. The findings not only showed therapeutic efficacy of HHT in ALL, but also demonstrated the first evidence of DNA damage induced by HHT which might account for its therapeutic effects. Further studies will be conducted for delineating the mechanisms of DNA damage and its relationship with therapeutic efficacy.
Citation Format: Chun-fung Sin, Kei-ching Yuen, Anan Jiao, Bai-lin Li, Hau-wai Yu. Homoharringtonine is effective in treating acute lymphoblastic leukaemia via WEE1 downregulation and inducing DNA damage [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 7111.