tbuckley/cabot-search huggingface dataset:
Abstract LB340: Analyzing both germline and somatic variants using Variant WorkBench in the Kids First Data Resource Portal: Children’s Brain Tumor Network as an example
Authors: Yiran Guo, Jared Rozowsky, Jean-Philippe Thibert, Qi Li, Jeremy Costanza, Michele Mattioni, Eric Wenger, David Higgins, Yuankun Zhu, Allison Heath, Vincent Ferretti, Adam Resnick
Journal: Cancer Research (2025)

Abstract Aiming at facilitating researchers to uncover new insights into the biology of childhood cancers and structural birth defects, the Gabriella Miller Kids First Pediatric Research Program (Kids First) is initiated. The Kids First Data Resource Center (KFDRC) developed the Kids First Data Resource Portal (KFDRP; https://portal.kidsfirstdrc.org/), a centralized data platform for both Kids First and collaborative cohorts. On behalf of KFDRC, we present as part of KFDRP the upgraded Variant WorkBench (VWB) with more data incorporated, on a more efficient platform, in a more streamlined data flow design, and capable of analyzing both germline and somatic genomic variants. First, the current collection of Kids First data include reharmonized genomics data of over 922,000 files in more than 35,400 participants from 35 studies. We also provide updated variant/gene annotation databases from more than 50 public resources (e.g. gnomAD, ClinVar, HPO etc.). Second, VWB is running on Velsera’s Cavatica Data Studio platform with a new Spark version 3.5.1 plus Python 3.11, achieving a ∼10 fold acceleration in terms of executing PySpark codes when compared to previous versions. Third, we redesigned the data flow from KFDRP to VWB, where portal users can now import Kids First data with which they have dbGaP approval directly to a Cavatica project and start analyzing in VWB. As an example, we show how to use VWB to identify deleterious variants within the same genes in both germline and somatic genomes of the same participant from the Children’s Brain Tumor Network, the largest Kid First cohort so far. In conclusion, the upgraded Variant WorkBench enables accelerated exploration of pediatric disease genomics under the Kids First program. Citation Format: Yiran Guo, Jared Rozowsky, Jean-Philippe Thibert, Qi Li, Jeremy Costanza, Michele Mattioni, Eric Wenger, David Higgins, Yuankun Zhu, Allison Heath, Vincent Ferretti, Adam Resnick. Analyzing both germline and somatic variants using Variant WorkBench in the Kids First Data Resource Portal: Children’s Brain Tumor Network as an example [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB340.
Abstract SY22-03: Multifaceted mitochondria in the regulation of chromosome inheritance
Authors: Maria J. Rodriguez Colman
Journal: Cancer Research (2025)

Abstract Mitosis, the shortest and most dynamic phase of the cell cycle, entails a complex sequence of events that result in the equal distribution of genetic material to two daughter cells. It has been proposed that mitochondrial respiration increases during mitosis to ensure sufficient ATP for this highly energy-demanding process. However, beyond bioenergetics, how concomitant metabolic changes influence mitotic progression and DNA inheritance remains unclear. To visualize these metabolic changes, we introduce fluorescent-based, genetically encoded reporters into cell lines and human tumor organoids, targeting different cellular compartments to track metabolic and redox dynamics during mitosis with high temporal and subcellular resolution. We observe an increase in ATP production in mitochondria and, notably, an increase in the NAD+/NADH ratio in mitotic chromatin upon nuclear envelope breakdown. Strikingly, disrupting this redox change at mitotic entry alters the epigenetic landscape, leading to a hyperacetylated chromatin state that affects chromatin compaction and Aurora B activity. Importantly, this series of events, initiated by metabolic perturbation, induces mitotic errors that result in genetically distinct daughter cells. Altogether, these findings uncover a novel role for mitochondria in regulating genetic inheritance through NAD(H) redox control, a mechanism with the potential to underlie genomic instability in cancer, where lactate accumulation due to the Warburg effect perturbs redox homeostasis. Citation Format: Maria J. Rodriguez Colman. Multifaceted mitochondria in the regulation of chromosome inheritance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY22-03.
Abstract SY23-01: Diffuse midline gliomas: From cell cycle to therapeutic opportunities
Authors: Anastasia E. Hains, Joana G. Marques, Kashish Chetal, Tsunetoshi Nakatani, Andreas Ettinger, Carlos A. O Biagi, Adriana Gonzalez-Sandoval, Renjitha Pillai, Alberto Gatto, Maria-Elena Torres-Padilla, Ruslan I. Sadreyev, Mariella G. Filbin, Capucine Van Rechem
Journal: Cancer Research (2025)

Abstract The fatal Diffuse Midline Gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3. K27M impairs normal development by stalling of differentiation. As replication timing influences gene expression, cell fate, and cellular response to therapeutics, we undertook a multi-omics approach (Repli-seq, cell cycle RNA-seq, single cell RNA-seq) in DMG cells (H3.1K27M and H3.3K27M subgroups) and tumors in comparison to normal brain to gain an appreciation for targetable pathways in DMG. DMG cells presented differential replication timing in each subgroup, which, in turn, correlated with significant differential gene expression including the cholesterol biosynthesis pathway. Consistent with these findings, DMG tumors presented high replication stress and cholesterol biosynthesis pathway signatures. Moreover, DMG cells were specifically vulnerable to an inhibitor of the cholesterol pathway and to a replication stress therapy, singly and in combination. In conclusion, this combinatorial genomics approach revealed insights into therapeutic opportunities for this incurable disease. Citation Format: Anastasia E. Hains, Joana G. Marques, Kashish Chetal, Tsunetoshi Nakatani, Andreas Ettinger, Carlos A. O Biagi, Adriana Gonzalez-Sandoval, Renjitha Pillai, Alberto Gatto, Maria-Elena Torres-Padilla, Ruslan I. Sadreyev, Mariella G. Filbin, Capucine Van Rechem. Diffuse midline gliomas: From cell cycle to therapeutic opportunities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY23-01.
Abstract SY20-01: Programming the lymphatic state to maintain immune surveillance and limit regional metastasis
Authors: Amanda W. Lund
Journal: Cancer Research (2025)

Abstract Lymphatic vessels play a crucial role in activating anti-tumor immune surveillance but also contribute to metastasis and systemic tumor progression. Whether there are distinct lymphatic phenotypes that switch between immunity and metastasis remains unclear. Here we reveal that cytotoxic immunity normalizes lymphatic function and uncouples immune and metastatic potential. We find that in mice and humans, intratumoral lymphatic vessel density negatively correlates with productive cytotoxic immune responses and identify IFNg as an intrinsic inhibitor of lymphangiogenesis. Specific deletion of the Ifngr1 in lymphatic endothelial cells (LECs) greatly expanded the intratumoral lymphatic network and drove the emergence of a tip-like endothelial state, promoting lymph node metastasis but not dendritic cell migration. IFNg inhibits oxidative phosphorylation, which is required for proliferation and acquisition of the pathologic transcriptional state. Our data indicate that IFNg induces a phenotypic switch in tumor-associated lymphatic vessels to reinforce canonical immune surveillance and block metastasis. Citation Format: Amanda W. Lund. Programming the lymphatic state to maintain immune surveillance and limit regional metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY20-01.
Abstract SY21-02: Inflammatory drivers of the obesity-cancer connection
Authors: Jeffrey C. Rathmell, Jackie E. Bader
Journal: Cancer Research (2025)

Abstract Obesity is the second leading modifiable risk factor for many cancers, behind only smoking. It can, however, also provide a benefit and increase responses and outcomes to checkpoint immune therapies. To understand this paradox and improve cancer immunotherapy, we examined the tumor immune microenvironment of lean and obese animals and human subjects. Interestingly, we found that the immune suppressive receptor PD-1 was upregulated on tumor associated macrophage with obesity. PD-1 directly suppressed macrophage metabolism and ability to phagocytose targets and stimulate T cells. Blockade or genetic deletion of PD-1, however, released macrophages from this suppression and allowed robust anti-tumor activity. These data define a mechanism of the obesity-cancer paradox and point to obesity-induced inflammation as a modifier of tumor associated macrophages that could be exploited to broadly improve immune therapy outcomes. Citation Format: Jeffrey C. Rathmell, Jackie E. Bader. Inflammatory drivers of the obesity-cancer connection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY21-02.
Abstract LB313: Inflammatory cytokines and extracellular matrix remodeling genes are epigenetically regulated in neoplastic HK-2 cells transformed by chronic exposure to arsenic
Authors: Priti Roy, Kamaleshwar Prasad Singh
Journal: Cancer Research (2025)

Abstract Arsenic is an environmental carcinogen. Epidemiological studies suggest that chronic exposure to lower levels of arsenic is associated with kidney cancer in human population. Increased proliferation, cellular remodeling by epithelial-mesenchymal transition and stemness contribute to neoplastic transformation of cells. Additionally, the aberrant expression of Inflammatory cytokines and extracellular matrix (ECM) related genes are known to mediate these changes. However, the underlying mechanism for altered expression of these genes is not fully understood. Overwhelming evidence suggest that epigenetic dysregulation leads to cancer development. Therefore, the objective of this was to investigate if arsenic induces the epigenetic dysregulation of cytokines and ECM related genes during malignant transformation. Using HK-2 kidney epithelial cells malignantly transformed by chronic arsenic exposure, gene expressions were analyzed by qRT-PCR. The result of this study revealed aberrant expression of genes for inflammatory cytokines and ECM in these cells. DNA demethylating agent 5 Aza 2-deoxycytidine and histone deacetylase inhibitor Trichostatin A restored the expression of cytokines and ECM related genes. Changes in the levels of modified histone H3 with gene activating and repressing marks were observed. To further evaluate the role of histone modifications in gene regulation, ChIP-qRT-PCR was performed to determine the binding of Histone H3 with gene activating and repressive marks to the promoter regions of inflammatory cytokines and ECM related genes. The result revealed several fold changes in H3K9ac and H3K9me2-bound promoter DNA in arsenic exposed cells as compared to control cells. This suggests aberrant expression of genes is regulated by these histone marks. In summary, the findings of this study suggest epigenetic regulation of inflammatory cytokines and ECM related genes expression by changes in histone marks during arsenic induced neoplastic transformation of HK-2 cells. Citation Format: Priti Roy, Kamaleshwar Prasad Singh. Inflammatory cytokines and extracellular matrix remodeling genes are epigenetically regulated in neoplastic HK-2 cells transformed by chronic exposure to arsenic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB313.
Abstract SY04-02: Clinical applications of cancer digital twins
Authors: Jasmin Fisher
Journal: Cancer Research (2025)

Abstract Digital twins for cancer tumors are emerging as a transformative tool in oncology to enable a more personalized and dynamic approach to cancer treatment. In this talk, I will showcase a growing library of mechanistic, data-driven computational models, focused on the signaling pathways within tumor cells and their microenvironment for various types of cancer (namely triple-negative breast cancer, non-small cell lung cancer, melanoma and glioblastoma). These computational models are mechanistically interpretable, enabling us to understand and anticipate emergent resistance mechanisms and to design patient-specific treatment strategies that counteract the forces of clonal selection driving treatment relapse, to improve outcomes for patients with hard-to-treat cancers. Citation Format: Jasmin Fisher. Clinical applications of cancer digital twins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY04-02.
Abstract LB443: Unlocking cell cycle dynamics: Gene regulation of CRISPR-Cas9 and siRNA phenotypes using cell painting
Authors: Alexander Schreiner, Angelika Foitzik, Josien Levenga, Karin Boettcher, Barbara Sonnenberg, Žaklina Strezoska, Joe Trask
Journal: Cancer Research (2025)

Abstract In cancer research, perturbing gene function is crucial for understanding disease mechanisms and developing treatments. Techniques such as RNA interference and CRISPR-knockout, -interference, or -activation are commonly used. In this recent study we compared the phenotypic effects of cellular morphology by knocking out or knocking down key cell cycle regulators, Aurora kinase B (AURKB), Geminin (GMNN), and Polo-like kinase 1 (PLK1), which are known key critical proteins involved in cell cycle regulation, and their dysfunction linked to cancer progression. In this in vitro osteosarcoma cell line (U 2-OS) model, we inhibited these proteins using CRISPR-Cas9 for gene knockout or siRNA for mRNA knockdown in a comparative study not previous reported. Employing Cell Painting methodology (6 fluorescent probes, high content screening (HCS) confocal imaging, and multivariant analysis) we imaged and profiled the morphological phenotypes following gene perturbations. Principal component analysis (PCA) analysis of hundreds of HCS image phenotypic feature measurements revealed significant morphological changes and reduced cell numbers from AURKB, GMNN, and PLK1 inhibition in U 2-OS cells caused significant phenotypic changes and reduced cell numbers suggesting alteration of cell cycle progression. Interestingly, in the GMNN inhibition, the siRNA-treated cells showed a higher percentage of large nuclei compared to small nuclei from CRISPR-treated cells. These findings suggest siRNA-mediated knockdown has a faster inhibitory effect on GMNN than CRISPR-treated conditions. This study demonstrates the complementary nature of CRISPR-Cas9 and siRNA gene modulation and underscores the importance of orthogonal validation for robust genetic studies with key cell cycle regulators. Citation Format: Alexander Schreiner, Angelika Foitzik, Josien Levenga, Karin Boettcher, Barbara Sonnenberg, Žaklina Strezoska, Joe Trask. Unlocking cell cycle dynamics: Gene regulation of CRISPR-Cas9 and siRNA phenotypes using cell painting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB443.
Abstract LB316: Enabling long-read mRNA-seq for oncology biomarker discovery using limited clinical sample inputs
Authors: Bryan Bell, Lisa Welter, Kazuo Tori, Jackson Peterson, Alan Du, Gilma Sevilla, Yana Ryan, Ploy Setthasap, Sherry Wei, Tomoya Uchiyama, Shiyi Yin, Mike Covington, Mohammad Fallahi, Saloni Pasta, Yue Yun, Andrew Farmer
Journal: Cancer Research (2025)

Abstract RNAs serve a central role in cellular biology by converting genomic information into effector molecules, either as mRNAs or directly functional RNAs. Measurement of RNA through RNA Sequencing has become an important method to understand biological processes. While it has been long appreciated that a vast diversity of RNA transcripts can be produced through alternative splicing, more recent work has defined a significant contribution of alternate and aberrant splicing to diseases like cancer, neurodegeneration, and autoimmunity. Thus, understanding the diversity of RNA transcripts is a key emerging topic in pathophysiology and biomarker discovery. Third-generation sequencing technologies provide the opportunity to sequence full-length cDNA without the need for fragmentation and hence provide a more complete picture of isoform structure and transcript abundance. However, a current limitation of long-read RNA sequencing (LR-RNA-seq) is the requirement for high input amounts of RNA that can be unachievable for some primary sample types, like RNA isolated from small amounts of tumor samples or sorted blood cancer cells. Here we describe a new LR-RNA-seq product enabling full-length RNA sequencing from single cells (∼10pg) up to 100 ng total RNA. With a 10ng total RNA input we demonstrate the ability to reliably sequence at an average length (N50) of 2kb and detection of full-length transcripts as long as 10kb. Performance at the single-cell level substantially outperforms existing single-cell LR-RNA-seq methods. Further, our data provides a more complete picture of isoform-specific changes compared to other commercially available technologies. With the ability to process up to 96 samples at a time, this technology will enable the processing of rare or valuable samples to uncover novel biomarkers beyond gene expression. Citation Format: Bryan Bell, Lisa Welter, Kazuo Tori, Jackson Peterson, Alan Du, Gilma Sevilla, Yana Ryan, Ploy Setthasap, Sherry Wei, Tomoya Uchiyama, Shiyi Yin, Mike Covington, Mohammad Fallahi, Saloni Pasta, Yue Yun, Andrew Farmer. Enabling long-read mRNA-seq for oncology biomarker discovery using limited clinical sample inputs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB316.
Abstract PL02-01: Overcoming the undruggable nature of the most common human oncogene, K-Ras
Authors: Kevan M. Shokat
Journal: Cancer Research (2025)

Abstract Somatic mutations in the small GTPase K-Ras are responsible for approximately 30% of human cancers and are generally associated with poor response to standard therapies. The mutations in K-Ras were identified in the early 1980’s but it took almost four decades for the first drugs targeting the protein to be approved. The long delay was a result of the apparent lack of a drug binding pocket on K-Ras despite detailed structural and biochemical characterization of the protein, leading to it being referred to as “undruggable.” This view changed when a chemical strategy based on targeting the K-Ras (G12C) mutant common in lung cancer was successful in identifying a druggable pocket in 2013. This finding led eight years later to the approval of two new medicines for patients with K-Ras (G12C) lung cancer, sotorasib and adagrasib. One current challenge in K-Ras drug development is development of agents to inhibit the more frequent K-Ras (G12D) and K-Ras (G12V) versions found in colon and pancreatic cancer. The other challenge is drug resistance which is faced by all targeted cancer therapies including the new K-Ras (G12C) directed drugs. In this lecture I will provide a perspective on challenges and opportunities of newly developed K-Ras targeting drugs. Citation Format: Kevan M. Shokat. Overcoming the undruggable nature of the most common human oncogene, K-Ras [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr PL02-01.
Abstract LB472: Role of <i>PLCG2</i> in colorectal cancer development and progression
Authors: Onur Mert Batmaz, Xiaodong Wang, Patricia Raude, Vera Leidig, Dominik Saul, Robyn L. Kosinsky
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) has the fourth highest incident with the third highest mortality rate among all cancer types with global five-year survival rate of 65%. Although, due to advances in non-invasive imaging technologies, CRC can be detected at early stages, the number of incidents increase yearly. Therefore, uncovering new mechanism underlying CRC development and progression is crucial to provide improvement in making diagnostic and prognostic outcome assessment in the clinical field. For these reasons, we determined CRC tumor cell expression profiles in several publicly available scRNA-seq data sets. Interestingly, we found that although PLCG2 expression largely downregulated in most epithelial cells, some cells retained their expression. These PLCG2-High (PLCG2-H) cells found to be enriched in their proliferative and metastatic capabilities compared to PLCG2-Low (PLCG2-L) tumor epithelial cells. We tested our observations from scRNA-seq datasets in vitro by inducing suppression and over-expression of PLCG2 in human CRC cell lines. Our functional assays as well as RNA-seq analyses have shown that suppression of PLCG2 decreased migratory capacity of CRC cells, whereas over-expression of PLCG2 increased it. Finally, we try to verify our observations in ovo using chorioallantoic membrane (CAM) model. These findings suggest that retained PLCG2 levels could enable CRC cells to become more metastatic, and have the potential to be used as a biomarker to make improved prognostic outcome assessment for CRC patients. Citation Format: Onur Mert Batmaz, Xiaodong Wang, Patricia Raude, Vera Leidig, Dominik Saul, Robyn L. Kosinsky. Role of PLCG2 in colorectal cancer development and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB472.