tbuckley/cabot-search huggingface dataset:
Abstract 145: Unraveling SMARCB1 depletion in hiPSC-derived neural crest cells: Implications for ATRT cell of origin
Authors: Clark Wang, Frank Furnari
Journal: Cancer Research (2024)

Abstract Atypical teratoid rhabdoid tumors (ATRTs) are highly aggressive pediatric brain cancers that lack standardized treatment regimens and are associated with poor prognoses. Despite being driven by biallelic inactivation of a single gene, SMARCB1, ATRTs exhibit three epigenetic subgroups (SHH, TYR, and MYC), each with different clinical outcomes. Like many pediatric brain tumors, ATRTs share the fundamental underlying mechanism of stalled differentiation, suggesting that it may arise from neural progenitor cells that fail to terminally differentiate. However, unlike other brain tumors, ATRTs share molecular similarities with malignancies found outside of the CNS, especially in the kidney and soft tissues. This unique feature implies a putative cell of origin that is not restricted to the CNS: neural crest cells, a transient embryonic cell population that emerges from the neuroectoderm but then migrates throughout the embryo during development. To study SMARCB1 loss in a genetically defined neural progenitor cellular context with isogenic controls, the Furnari lab engineered a doxycycline inducible SMARCB1 knockdown system into human induced pluripotent stem cells (hiPSCs). After simultaneous SMARCB1 knockdown with directed neural differentiation, the resulting SMARCB1-depleted neural progenitor cells exhibited transcriptomic profiles that were similar to ATRTs, particularly to the SHH subgroup. Building upon these findings, the engineered hiPSCs were differentiated into neural crest cells using a modified version of a published protocol. Via RT-qPCR, these hiPSC-derived neural crest cells were confirmed to express typical neural crest marker genes and lose expression of SMARCB1 in the presence of doxycycline. Remarkably, ATP assays demonstrated that neural crest cells that were differentiated without SMARCB1 acquired enhanced proliferation in comparison to those differentiated with SMARCB1 intact. Further work aims to tease apart this proliferative phenotype in the neural crest cellular context via RNAseq, evaluate the impact of cell identity upon subgroup status, and to determine whether SMARCB1 depletion post-differentiation also enhances proliferation. Together, these findings feature the utility of hiPSC-derived models for investigating mechanisms underlying ATRTs to hopefully identify novel subgroup-specific targets. Citation Format: Clark Wang, Frank Furnari. Unraveling SMARCB1 depletion in hiPSC-derived neural crest cells: Implications for ATRT cell of origin [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 145.
Abstract 200: OA inhibits the development of breast cancer through K1108 acetylation of Zeb1
Authors: Min Guo, Yanjin Wang, Yi Shi, Shuang Yang
Journal: Cancer Research (2024)

Abstract Background:Olive oil has long been considered a healthier edible oil, rich in 75% oleic acid (OA) as its main component. OA is a monounsaturated fatty acid, and recent studies have shown that it is no longer limited to protecting cardiovascular and cerebrovascular systems, but can also reduce the risk of cancer. However, there is limited research on the specific mechanism. After fatty acid is ingested into the body, through fatty acids β-oxidation produces acetyl-CoA, which is a donor of protein acetylation. EMT is an important process to regulate tumor metastasis, and Zeb1 is one of the important EMT transcription factors. Therefore, we explored whether OA could inhibit the progress of breast cancer by affecting the acetylation modification of Zeb1. Methods: Western blotting, CCK8 assay, and Transwell were used to test the impact of gradient doses of OA on breast cancer cells. Immunoprecipitation and Immunoprecipitation mass spectrum were used to determine the acetylation modification sites of Zeb1. Coimmunoprecipitation, IF, and pull-down were used to test and verify the acetylase and deacetylase of Zeb1. Knockdown endogenous ZEB1 and then reconstructed stable cell lines of Zeb1 wild-type (Zeb1K1108WT), acetylation activated (Zeb1K1108Q), and inactivated mutants (Zeb1K1108R) by lentivirus. Detection of Zeb1 acetylation in patient tissue samples and mouse models under OA treatment using Zeb1-specific acetylation-modified antibodies. Results: OA inhibits the proliferation and migration of breast cancer cells in a concentration gradient-dependent manner, and inhibits the expression of Zeb1, N Cadherin, and upregulates E Cadherin. Among numerous fatty acids, only OA can promote the acetylation of Zeb1 by adjusting the ratio of acetyl-CoA and NAD+/NADH. K1108 is a biologically functional acetylation site of Zeb1, Zeb1K1108R exerts the cancer promoting function of Zeb1, while Zeb1K1108Q does not. OA can promote acetylation of Zeb1K1108WT, but cannot promote acetylation of Zeb1K1108R. Conclusions: OA inhibits the development of breast cancer through K1108 acetylation of Zeb1. These results suggest that breast cancer may be ameliorated through dietary interventions. Citation Format: Min Guo, Yanjin Wang, Yi Shi, Shuang Yang. OA inhibits the development of breast cancer through K1108 acetylation of Zeb1 [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 200.
Abstract 2001: Autocrine HGF maturation as a targetable regulatory step in cetuximab resistance in colorectal cancer
Authors: Vivian Truong Jones, Ramona Graves-Deal, Zheng Cao, Galina Bogatcheva, Marisol A. Ramirez, Sarah J. Harmych, James N. Higginbotham, Claudia C. Wahoski, Neeraj Joshi, Joseph T. Roland, Gregory D. Ayers, Qi Liu, Robert J. Coffey, James W. Janetka, Bhuminder Singh
Journal: Cancer Research (2024)

Abstract Although amplifications and mutations in receptor tyrosine kinases (RTKs) act as bona fide oncogenes, in most cancers, RTKs maintain moderate expression and remain wild-type. Consequently, cognate ligands control many facets of tumorigenesis, including resistance to anti-RTK therapies. Herein, we show that the ligands for the RTKs MET and RON, HGF and HGFL, respectively, are synthesized as inactive precursors that are activated by cellular proteases. Our newly generated HGF/HGFL protease inhibitors could overcome both de novo and acquired cetuximab resistance in colorectal cancer (CRC). Conversely, HGF overexpression was necessary and sufficient to induce cetuximab resistance and loss of polarity. Moreover, HGF-induced cetuximab resistance could be overcome by the downstream MET inhibitor, crizotinib, and upstream protease inhibitors. Additionally, HAI-1, an endogenous inhibitor of HGF proteases, (i) was downregulated in CRC, (ii) exhibited increased genomic methylation that correlated with poor prognosis, (iii) HAI-1 expression correlated with cetuximab response in a panel of cancer cell lines, and (iv) exogenous addition of recombinant HAI-1 overcame cetuximab resistance in CC-HGF cells. Thus, we describe a targetable, autocrine HAI-1/Protease/HGF/MET axis in cetuximab resistance in CRC. Citation Format: Vivian Truong Jones, Ramona Graves-Deal, Zheng Cao, Galina Bogatcheva, Marisol A. Ramirez, Sarah J. Harmych, James N. Higginbotham, Claudia C. Wahoski, Neeraj Joshi, Joseph T. Roland, Gregory D. Ayers, Qi Liu, Robert J. Coffey, James W. Janetka, Bhuminder Singh. Autocrine HGF maturation as a targetable regulatory step in cetuximab resistance in colorectal 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 2001.
Abstract 4253: High expression of specific gene profiles in organoids from African American pancreatic cancer tumors
Authors: Beverly D. Lyn-Cook, Fatemeh Nouri Emamzaden, Beverly Word, George Hammons
Journal: Cancer Research (2024)

Abstract Pancreatic cancer remains one of the leading causes of cancer-related deaths in the United States with limited therapies for advanced stages of this disease. African Americans have the highest morbidity and mortality rates of pancreatic cancer compared to other racial groups. Many factors are known to contribute to this disparity such as, socioeconomic and lifestyle factors. One of the major factors contributing to this disparity is the lack of African Americans with pancreatic cancer in clinical trials or genomic databases. In order to gain insight into the biology or genetic differences that may exist in signals driving the aggressiveness of this cancer in this population more studies are needed. Innovative in vitro models are needed to investigate possible differences in molecular changes that may exist in African Americans. Studies have shown that organoids developed from metastatic and primary tumors can give sights into genetic and epigenetic changes detected in several type of cancers. Using a Human Pancreatic Adenocarcinoma TagMan Array 96 (Applied Biosystems), which contained 76 genes known to be expressed in pancreatic cancer, pancreatic organoids from African American metastatic tumors revealed high expression levels of specific genes. Usually K-ras is highly expressed in pancreatic tumors but it was not significantly expressed in the organoids from African Americans metastatic tumors. However, preliminary results from organoids, compared to pancreatic cancer cell line spheroids, showed significantly increased gene expression of HSP90AA1 (13-fold), MMP1(36-fold), BRACA2 (20-fold), MDM2 (19-fold), RB1 (14-fold), Rel (12-fold), STAT1 (15-fold), STAT5B (5-fold), and TGFBR1 (1- fold). High expression of HSP90AA1 is related to poor prognosis, constitutively expression of STAT5B confers gemcitabine chemoresistance and promote invasiveness, and mutations in BRCA2 can increase pancreatic cancer risk. Further studies are being done to validate these findings in African American pancreatic tumors and to ascertain their relevance to the metastatic progression phenotype. Citation Format: Beverly D. Lyn-Cook, Fatemeh Nouri Emamzaden, Beverly Word, George Hammons. High expression of specific gene profiles in organoids from African American pancreatic cancer tumors [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 4253.
Abstract 2341: Morph: A feature extraction toolset for spatial transcriptomics
Authors: André Luiz N. Targino da Costa, Jingxian Liu, Chia-Kuei Mo, Erik Storrs, Austin N. Southard-Smith, Reyka G. Jayasinghe, Julia T. Wang, Michael D. Iglesia, Michael Wendl, Siqi Chen, Andrew Houston, Alla Karpova, Yize Li, Li Ding
Journal: Cancer Research (2024)

Abstract Accurately defining spatial characteristics of tumors has been a challenge in cancer research. Specifically, there is still a lack of spatial transcriptomic (ST) bioinformatic methods that infer tumor boundaries, a necessity for tumor microenvironment (TME) analyses, that are fully automated and handle non-rectangular grids (like the one found in Visium). Here we introduce Morph, a toolset that not only addresses these limitations, but also accurately extracts tumor regions, layers surrounding them, and distances related to such regions. Morph was tested on a dataset composed of 117 ST slides across 6 different cancer types, including primary and metastatic tumors. More broadly, Morph is a computationally efficient tool based on mathematical morphology that is designed to work without any approximations on ST slides (that can be composed of spots in a hexagonal lattice) of any resolution. The toolset accepts a variety of input types, such as tumor purity and manual annotation, and can perform a diverse set of morphological operations, such as erosion, dilation, opening and closing, using a number of structuring elements with different shapes and sizes, such as a hexagon of side 1. Moreover, Morph runs quickly (seconds per sample). Its main focus is to unveil the aforementioned features of any spatially distinct tumor region (here defined as microregion) for various downstream analyses, such as spatially-varying copy number variations, cell-type distribution, and tumor-microenvironment interaction. Overall, we developed a spatial transcriptomics toolset that is not limited to any specific technology platform, and that can accurately extract ST features facilitating the discovery of spatial transcriptomic and interaction patterns. Citation Format: André Luiz N. Targino da Costa, Jingxian Liu, Chia-Kuei Mo, Erik Storrs, Austin N. Southard-Smith, Reyka G. Jayasinghe, Julia T. Wang, Michael D. Iglesia, Michael Wendl, Siqi Chen, Andrew Houston, Alla Karpova, Yize Li, Li Ding. Morph: A feature extraction toolset for spatial transcriptomics [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 2341.
Abstract 3549: PMed-TRIAL PDX database: Integrated multidimensional information to facilitate new drug development
Authors: Xinlei Chen, Youbin Guo, Loc Van, Josh Caggiula, Xiaorong Gu, Danyi Wen
Journal: Cancer Research (2024)

Abstract PDX models play a crucial role in pre-clinical research for new drugs. In recent years, research based on PDX models has entered the 'Big Data Era.' On the one hand, there are numerous factors influencing drug responses, such as cancer types, genetic backgrounds, clinical treatment histories, and more. Therefore, selecting the appropriate PDX models for drug efficacy testing based on relevant information has become increasingly important. On the other hand, conducting in-depth genomics and transcriptomics analyses on PDX models allows us to gain a deeper understanding of the mechanisms of drug efficacy and drug sensitivity. After years of effort, LIDE have successfully built and maintained over 1800 PDX models from 40 different cancer types. And in this year (2023), we launched LIDE’s PMed-TRIAL PDX database website. As a comprehensive database of PDX models, it includes fundamental PDX clinical information, medication history, growth curves, and standard of care (SOC) data. It also contains whole exome sequencing data and RNA-seq data. Cancer is a complex and heterogeneous disease characterized by tumor heterogeneity, encompassing both inter-tumor diversity (between patients) and intra-tumor variability (within a single patient), thereby complicating drug responsiveness. PDX models preserve heterogeneity of individual patients, and a robust PDX cohort is essential for accurately representing inter-tumor heterogeneity. LIDE’s PDX cohorts effectively capture representative molecular subtypes across various major cancer types, highlighting their potential as a valuable resource for pre-clinical trials. LIDE’s PMed-TRIAL PDX database comes with a concise and efficient web user interface. Users can search and filter models using keywords, such as drug names, gene symbols, and other information. The website can now be accessed via the following URL (https://pmed.lidebiotech.com:8000/). Citation Format: Xinlei Chen, Youbin Guo, Loc Van, Josh Caggiula, Xiaorong Gu, Danyi Wen. PMed-TRIAL PDX database: Integrated multidimensional information to facilitate new drug development [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 3549.
Abstract 5119: Exploring the relationship between metabolism and the epigenome in <i>MYCN</i>-amplified neuroblastoma
Authors: Krista M. Dalton, Timothy L. Lochmann, Colin Coon, Marissa L. Calbert, Mikhail Dozmorov, Lisa Shock, Jennifer Koblinski, Anthony C. Faber
Journal: Cancer Research (2024)

Abstract Background: Neuroblastoma (NB) is the most common cancer of infancy and is responsible for the most cancer-related deaths in children under the age of five. The transcription factor MYCN is the most studied oncogene in NB and automatically confers high-risk. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis. NB has also been demonstrated to be a highly methylated cancer, with DNA methyltransferases (DNMTs) largely responsible for these modifications. Epigenetics and metabolism are closely connected, with oncogene-driven metabolic rewiring modifying the epigenetic landscape through increases of metabolites that are critical for the activities of epigenetic enzymes, and conversely the enhanced epigenetic activity further regulating the activity of metabolic enzymes. Aims: As metabolism is believed to be a key regulator of the epigenome, the objective of this proposal is to understand the connection between MYCN-DNMT1-driven epigenetic alterations and dysregulated metabolism in MYCN-amplified NB. Methods: RNA-seq and mass spectrometry analyses were performed to explore the MYCN-driven metabolome in NB and changes that occur with DNMT1 inhibition. The efficacy of DNMT1 inhibition in MYCN-amplified NB was tested in vivo. Results: Our data demonstrate that sensitivity to DNMT1 inhibition is linked to MYCN status in NB. We found that MYCN indeed dysregulates metabolism in NB, and DNMT1 inhibition led to a global decrease in oxidative phosphorylation and exacerbated mitochondrial dysfunction in MYCN-amplified NB. Expression of MYCN was linked to an increase in methionine and subsequently SAM, the universal methyl donor, further supporting reliance on DNMT1. Most importantly, we have found that treatment with DNMT1 inhibitors in vivo inhibited tumor growth, even after treatment had stopped. Conclusion: We have found a correlation between MYCN and metabolism that supports DNMT1 activity. This relationship allows for a potential treatment for a high-risk disease in which there is few clinically actionable targets. Citation Format: Krista M. Dalton, Timothy L. Lochmann, Colin Coon, Marissa L. Calbert, Mikhail Dozmorov, Lisa Shock, Jennifer Koblinski, Anthony C. Faber. Exploring the relationship between metabolism and the epigenome in MYCN-amplified neuroblastoma [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 5119.
Abstract 4341: Non canonical mitochondrial hotspot mutations in cancer
Authors: Sonia Boscenco, Jaqueline Tait-Mulder, Minsoo Kim, Cerise Tang, Mark Zucker, Tricia Park, Wei Wei, Patrick F. Chinnery, Payam A. Gammage, Ed Reznik
Journal: Cancer Research (2024)

Abstract The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 15,619 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT - RNR1) and large (16S, MT - RNR2) RNA subunits of the mitoribosome. In total, we identified 70 recurrent, hotspot mutations affecting either subunit of the mitoribosome. Compared to non-hotspot positions, rRNA hotspots preferentially affect positions participating in Watson-Crick base pairing, and tend to arise at positions under strong purifying selection in the germline. Consistent with their putative selection, hotspot rRNA alleles arose at higher heteroplasmy than silent mutations under neutral selection. Transcriptional and metabolomic profiling of the m.1227G&amp;gt;A MT - RNR1 hotspot revealed a heteroplasmic dosage-dependent shift in energy generation towards glycolysis. Mutations disrupting the mitoribosome therefore represent a novel class of functional mutations under positive selection in cancer genomes. Citation Format: Sonia Boscenco, Jaqueline Tait-Mulder, Minsoo Kim, Cerise Tang, Mark Zucker, Tricia Park, Wei Wei, Patrick F. Chinnery, Payam A. Gammage, Ed Reznik. Non canonical mitochondrial hotspot mutations in 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 4341.
Abstract 2695: A higher percentage of M2 macrophages in non-tumor part predict the tumor recurrence in patients with hepatocellular carcinoma after surgical resection
Authors: Po-Ting Lin, Wei-Ting Ku, Tsung-Han Wu, Cheng-Heng Wu, Chan-Keng Yang, Wei Teng, Yung-Chang Lin, Chun-Yen Lin
Journal: Cancer Research (2024)

Abstract The primary hurdle in improving outcomes for hepatocellular carcinoma (HCC) patients after curative treatment is the high early recurrence rate. The existing literature indicates the presence of type 2 macrophages (M2), renowned for their immunosuppressive capabilities, has been implicated in creating a microenvironment conducive to tumor growth and recurrence. However, the intricate interplay involving M2 macrophages and the recurrence of HCC is underexplored. Therefore, we conducted an analysis involving HCC patients who underwent hepatectomy at our hospital between 2013 and 2017. We collected samples from both the tumor and non-tumor regions and subjected them to bulk RNA sequencing for comprehensive molecular profiling. The proportion of immune cells was calculated by CIBERSORTx.In our study, we enrolled fifty patients, with sixty percent presenting with cirrhosis and seventy-three percent having viral hepatitis. Twenty-three patients experienced tumor recurrence, with a median time to recurrence of 12.6 months. First, we found no correlation between five TIMR subtypes defined by TIMELASER (Xue R, Nature, 2022) and recurrence. However, as for the proportions of immune cell, a significantly lower NK/Treg ratio (p= 0.0163) and high within the resected tumor section in recurrent group was found. On the other hand, the ratio of M2 macrophages to total macrophages (M2/M) was significantly higher within the non-tumor region in patients experiencing tumor recurrence after hepatectomy (p=0.0357). Furthermore, the expression of the ACGT2 gene in non-tumor part, which strongly correlates with Treg function, was significantly higher (p=0.0056) in recurrent group. In addition, the innate T cells score was increased in non-tumor pat in recurrent group but with borderline significance (p=0.0628). However, in multivariable analysis, only a higher M2/M ratio within the non-tumor region (HR 3.756, p=0.0072) were identified as independent risk factors for tumor recurrence. We also found that patients with a higher M2/M ratio had a lower percentage of cirrhotic patients (p=0.0049) and less association with TIME-IA (immune activation) subtype of HCC by TIMELASER classification (p=0.0030). In conclusion, a higher M2/M ratio within the non-tumor region predict the tumor recurrence in patients with hepatocellular carcinoma. Citation Format: Po-Ting Lin, Wei-Ting Ku, Tsung-Han Wu, Cheng-Heng Wu, Chan-Keng Yang, Wei Teng, Yung-Chang Lin, Chun-Yen Lin. A higher percentage of M2 macrophages in non-tumor part predict the tumor recurrence in patients with hepatocellular carcinoma after surgical resection [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 2695.