tbuckley/cabot-search huggingface dataset:
Distinct clusters of bacterial and fungal microbiota in end-stage liver cirrhosis correlate with antibiotic treatment, intestinal barrier impairment, and systemic inflammation
Authors: Laura Buttler, David A. Velázquez-Ramírez, Anja Tiede, Anna M. Conradi, Sabrina Woltemate, Robert Geffers, Birgit Bremer, Vera Spielmann, Julia Kahlhöfer, Anke R.M Kraft, Dirk Schlüter, Heiner Wedemeyer, Markus Cornberg, Christine Falk, Marius Vital, Benjamin Maasoumy
Journal: Gut Microbes (2025)

Decompensated liver cirrhosis (dLC) is associated with intestinal dysbiosis, however, underlying reasons and clinical consequences remain largely unexplored. We investigated bacterial and fungal microbiota, their relation with gut barrier integrity, inflammation, and cirrhosis-specific complications in dLC-patients. Competing-risk analyses were performed to investigate clinical outcomes within 90 days. Samples were prospectively collected from 95 dLC-patients between 2017 and 2022. Quantitative metagenomic analyses clustered patients into three groups (G1-G3) showing distinct microbial patterns. G1 (n = 39) displayed lowest diversity and highest Enterococcus abundance, G2 (n = 24) was dominated by Bifidobacteria, G3 (n = 29) was most diverse and clustered most closely with healthy controls (HC). Of note, bacterial concentrations were significantly lower in cirrhosis compared with HC, especially for G1 that also showed the lowest capacity to produce short chain fatty acids and secondary bile acids. Consequently, fungal overgrowth, dominated by Candida spp. (51.63%), was observed in G1. Moreover, G1-patients most frequently received antibiotics (n = 33; 86.8%), had highest plasma-levels of Zonulin (p = 0.044) and a proinflammatory cytokine profile along with numerically higher incidences of subsequent infections (p = 0.09). In conclusion, distinct bacterial clusters were observed at qualitative and quantitative levels and correlated with fungal abundances. Antibiotic treatment significantly contributed to dysbiosis, which translated into intestinal barrier impairment and systemic inflammation.
Abstract 6265: Cross-tissue atlas of human disease identifies tumor-specific components in tumor microenvironment
Authors: Seongryong Kim, Sungmin Cheong, Suho Lee, Yeju Kim, Jong-Eun Park
Journal: Cancer Research (2025)

Abstract Human diseases affect various cell types within the local niche, but the multicellular responses of human diseases have not been collectively assessed across organs. Here, we categorize multicellular responses of human diseases based on a remapped human cell atlas, incorporating 12 million single-cell transcriptome profiles acquired from an automated data collection pipeline. Additional curation expands the collection up to 46 million cells, covering 160 disease conditions across 49 distinct organ identities. From the re-aligned atlas of single-cell transcriptome data, we constructed a hierarchical cell classification framework comprising 32 major cell types and 165 cell subtype annotations. Systematic profiling of disease and organ association patterns of cellular subtype reveals archetypes of human diseases repeatedly found across organs, including a multicellular phenotype highly specific to the tumor microenvironment. The universal cell atlas could serve as a reference for unbiased deconvolution of spatial transcriptome datasets, revealing spatial distribution patterns associated with immunotherapy responses. Collectively, our study provides foundational resources for cross-tissue cell type annotation, presents a comprehensive multicellular overview of disease-associated responses across human tissues, and highlights multicellular responses in tumor microenvironments. Citation Format: Seongryong Kim, Sungmin Cheong, Suho Lee, Yeju Kim, Jong-Eun Park. Cross-tissue atlas of human disease identifies tumor-specific components in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6265.
Abstract 5746: Development of Pt-HDACi complexes to enhance potency and selectivity for advanced cancer therapy
Authors: Rabeya Bosri, Jayden Stahl, Nghia Tran, Chao Feng, Liang Xue, Qinliang Zhao
Journal: Cancer Research (2025)

Abstract Combining standard chemotherapy drugs with low doses of histone deacetylase inhibitors (HDACis) has emerged as a promising approach to enhance cancer treatment efficacy. Incorporation of HDACi onto the platinum (Pt) core as a non-leaving group may improve the potency and selectivity of the Pt anticancer drugs and maintain the synergistic effect. In the newly synthesized inhibitors, the linker domain was modified by including heterocyclic rings or amine groups. One or two amine groups were installed onto the aromatic ring in the protein recognition domain to build monodentate or bidental coordination sites to incorporate Pt. Four HDACi derivatives (L19, L20, L21, L22) were successfully synthesized and fully characterized. Pt-HDACi complexes were obtained by reacting K2PtCl4 with bidentate L19 and L20, and K[PtCl3(2-picoline)] with monodentate L21 and L22. Intermediates and final compounds were analyzed using mass spectrometry and NMR spectroscopy. The purity was confirmed by melting point measurement, analytical HPLC, and/or elemental analysis. Different bioassays, such as enzyme inhibition, cell viability studies with cell lines K562, HCT-116, and A549, and DNA binding assay, have been applied to evaluate their efficacy. All four derivatives and Pt-HDACi conjugates have shown promising enzyme inhibition and potent bioactivities. Particularly, L19 and L21 with a heterocyclic ring in the linker showed the highest potency, with IC50 values significantly lower than the FDA-approved Vorinostat and Panobinostat. Molecular docking studies further supported these findings by revealing stronger binding affinity towards the HDAC enzymes, demonstrating similar trend in inhibition and potency toward cancer treatment. Citation Format: Rabeya Bosri, Jayden Stahl, Nghia Tran, Chao Feng, Liang Xue, Qinliang Zhao. Development of Pt-HDACi complexes to enhance potency and selectivity for advanced cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5746.
Abstract 6579: Elucidating glioblastoma-derived extracellular vesicle cargo using TurboID: Implications for tumor microenvironment adaptation
Authors: Marissa Russo, Emily Norton-Ramos, Maria Jose Ulloa Navas, Alfredo Quinones-Hinojosa, Hugo Guerrero-Cazares
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM), the most aggressive primary brain tumor in adults, presents significant challenges due to its universal recurrence and limited survival rates, exacerbated when proximal to the lateral ventricles (LV). The subpopulation of brain tumor-initiating cells (BTICs) plays a pivotal role in tumor initiation and invasiveness, interacting with the microenvironment, particularly the cellular components in the subventricular zone (SVZ). Some mechanisms of intercellular communication present in the SVZ include paracrine, autocrine, direct cell contact, gap junctions, nanotubes, and more recently extracellular vesicles (EVs). EVs are membrane-bound particles released by cells that are central to intercellular communication. They have the ability to carry bioactive proteins, RNA, and other molecules that influence recipient cell behavior.This study investigates the role of EVs in GBM's communication with non-cancer cells. Our findings indicate that BTIC-derived EVs promote migration and proliferation (*p &amp;lt; 0.02, ****p &amp;lt;0.001) in neural progenitor cells (NPCs) in vitro, highlighting the EVs' role in altering the microenvironment. To identify the protein cargo contained in GBM-derived EVs, we utilized the innovative proximity-labeling system TurboID. We successfully induced TurboID expression in primary-cultured human BTICs from GBM patients, enabling the unbiased biotinylation of proteins in EVs. We isolated biotinylated proteins from BTIC lysates and BTIC-EVs, preserving the integrity of EVs, and conducted proteomic analysis via mass spectrometry. Our method marks the first implementation of TurboID for unbiased global labeling of EV protein cargo in primary GBM cells. This approach facilitates the investigation of EV-mediated communication and potential therapeutic targets, contributing to the understanding of GBM's complex interactions with the brain's microenvironment and the identification of biomarkers for improved diagnosis and treatment response. Citation Format: Marissa Russo, Emily Norton-Ramos, Maria Jose Ulloa Navas, Alfredo Quinones-Hinojosa, Hugo Guerrero-Cazares. Elucidating glioblastoma-derived extracellular vesicle cargo using TurboID: Implications for tumor microenvironment adaptation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6579.
Abstract 6464: Spatial mapping of the tumor microenvironment for combination therapy design
Authors: Arindam Bose, Susan Keezer, Emily Quann Alonzo, Sophie Struble, Jeremy Fisher, Matthew Norton, Richard A. Heil-Chapdelaine, Natasha F. Diaz Granados, Vasundhara Agrawal
Journal: Cancer Research (2025)

Abstract Cancer immunotherapy is a promising treatment for many forms of cancer, however only a small subset of patients benefit, and relapse/recurrence frequently occurs due to various resistance mechanisms. To overcome this challenge combinatorial therapeutic strategies are needed targeting multiple steps of the cancer-immunity cycle to achieve long-term efficacy in a large population of cancer patients. It is now known that DNA damage activates the innate immune response and improves immune checkpoint blockade (ICB) efficacy. Combination immunotherapy can target several immunosuppressive elements in the tumor microenvironment and activate multiple steps of the cancer-immunity cycle. For developing an effective combination treatment strategy, including ICB with various other therapeutic modalities, we need to first understand the diverse expression pattern of various factors within tumor immune microenvironment. Multiplex immunofluorescence (mIF) is an important tool for profiling protein expression patterns in tumor tissues. This can provide a framework to understand the sensitivity to a particular combination of therapies and identify potential predictive biomarkers. Here we show spatial proteomics profiling of a diverse range of biomarkers in human colon adenocarcinoma tissue. Our findings demonstrate that spatial proteomics can be tailored to precision oncology using artificial intelligence to predict a patient’s response to combination treatment strategies. The Cell DIVE Multiplex Imaging Solution in combination with AI-based image processing software, AIVIA delivers a comprehensive solution for exploring immune landscape of tumor tissue. The broad portfolio of robust IHC- validated antibodies from Cell Signaling Technology (CST) enables the detection of key proteins in the tumor microenvironment (TME). Here, we demonstrate multiplexed Cell DIVE imaging using a novel CST panel to probe human colon adenocarcinoma. The availability of cell type specific biomarkers, combined with the ability to interrogate using multiplexed tissue imaging, provides unprecedented and novel insights and spatial resolution of diverse cell populations in the TME. Citation Format: Arindam Bose, Susan Keezer, Emily Quann Alonzo, Sophie Struble, Jeremy Fisher, Matthew Norton, Richard A. Heil-Chapdelaine, Natasha F. Diaz Granados, Vasundhara Agrawal. Spatial mapping of the tumor microenvironment for combination therapy design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6464.
Abstract 6161: Exploring BRG399, a novel microtubule-binding agent, as an inducer of immunogenic cell death in cancer therapy
Authors: Kaila M. Bennett, Jacob P. Matson, Sylwia Stopka, Juan J. Aristizabal-Henao, Archna Ravi, Andressa L. Mota, Dinesh Chimmanamada, Vivek K. Vishnudas, Stephane Gesta, Maria-D Nastke
Journal: Cancer Research (2025)

Abstract Cancer therapy is transforming from traditional chemotherapeutic agents (CTAs) to innovative immunotherapies. Despite this shift, chemotherapy remains clinically stable, as CTAs are thought to convert the tumor microenvironment (TME) from immunosuppressive to immune-active by inducing immunogenic cell death (ICD) in tumor cells which leads to stimulation of immune cells. This ICD induction is thought to be crucial for enhancing the efficacy of immunotherapies. Thus, using CTAs as ICD agents—alone or in combination with immunotherapies—may offer significant anti-cancer benefits and new treatment avenues. This study investigates the potential of BRG399, a novel microtubule-binding agent, as an immunogenic cell death (ICD) inducer utilizing preclinical in vitro and in vivo models. Treatment of cancer cell lines with BRG399 showed a dose-dependent increase in surface calreticulin and secreted HSP70, measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. The enhancement of both ICD markers was comparable to that observed with established ICD agents. To explore the potential of BRG399 to exert influence on immune-regulated anti-tumor effects, in vivo studies in immune-competent syngeneic models were conducted with measurable endpoints of tumor growth inhibition and TME composition by flow cytometry and TIMS TOF spatial omics. BRG399 displayed anti-tumor activity while largely preserving tumor-associated immune cells and notably modifying the immune cell landscape within the tumor. Our findings suggest that BRG399 acts as an ICD agent, effectively modulating both tumor and immune cells within the TME and highlighting its potential for future combination therapies with immunotherapeutics. Further in vivo studies are currently being conducted to comprehensively elucidate the immune-mediated effects of BRG399 aiming to clarify its role in enhancing anti-tumor responses ultimately contributing to the development of more effective cancer therapies. Citation Format: Kaila M. Bennett, Jacob P. Matson, Sylwia Stopka, Juan J. Aristizabal-Henao, Archna Ravi, Andressa L. Mota, Dinesh Chimmanamada, Vivek K. Vishnudas, Stephane Gesta, Maria-D Nastke. Exploring BRG399, a novel microtubule-binding agent, as an inducer of immunogenic cell death in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6161.
Abstract 5606: The novel brain-penetrant paradox breaker BRAF inhibitor RG6344 manifests exceptional activity in BRAF mutant colorectal cancers
Authors: Florian Renner, Jan Eckmann, Cornelia Handl, Nicole Kratochwil, Jürgen Wichmann, Gabriel Schnetzler, Nino Keshelava, Héctor G. Palmer, Jordi Martinez-Quintanilla, Irene Chicote, Jordi Vergés, Piergiorgio Pettazzoni
Journal: Cancer Research (2025)

Abstract Despite the approval of the combination Encorafenib/Cetuximab in metastatic colorectal cancers (CRC) harboring BRAF V600E mutations, the therapeutic benefits offered by this regimen remains limited and short lived. We developed a next generation brain permeable, paradox breaker BRAFi (RG6344, previously identified as Compound Ia in Wichmann et al., Clin Cancer Res 2022) currently undergoing clinical testing (ISRCTN13713551). Here we present its preclinical activity for BRAF mutated CRC. RG6344 proves paradox breaking properties by not triggering MAPK over-activation in BRAF WT contexts at all levels. For in vivo testing regimens covering IC80 (60 mg/kg) and IC95 (140 mg/kg) p-ERK inhibition were used. RG6344 was highly tolerated in all studies as a single agent and in all combination regimens tested clearly highlighting that the lack of paradoxical MAPK activation allows superior target inhibition in vivo. In BRAFi naïve xenograft models (LS411N, HT29) RG6344 as monotherapy outperformed Encorafenib/Cetuximab at all doses tested indicating higher activity of this agent even at doses targeting only IC80 p-ERK inhibition, the same BRAF inhibition levels reached by Encorafenib in CRC approved clinical regimens. RG6344 activity was further strengthened in combination with cetuximab and demonstrated long-lasting responses in PDX models derived from patients that progressed to Encorafenib/Cetuximab therapy supporting the use of RG6344 even in BRAFi experienced patients. Additional combination studies of RG6344 with FOLFOX in BRAFi naive models resulted in tumor regression and dramatic superiority compared to the same combination with Encorafenib. These data collectively provide strong preclinical translational evidence for the potentially transformative activity of RG6344 in BRAF mutated CRC. Citation Format: Florian Renner, Jan Eckmann, Cornelia Handl, Nicole Kratochwil, Jürgen Wichmann, Gabriel Schnetzler, Nino Keshelava, Héctor G. Palmer, Jordi Martinez-Quintanilla, Irene Chicote, Jordi Vergés, Piergiorgio Pettazzoni. The novel brain-penetrant paradox breaker BRAF inhibitor RG6344 manifests exceptional activity in BRAF mutant colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5606.
Abstract 7503: Detection of genomic alterations in lenvatinib-resistant liver cancer cell lines
Authors: JungHyun Kim, Ji Young Kim, Gamin Han, BoYoon Kim, Hoon Kim, Yeup Yoon, Wonseok Kang
Journal: Cancer Research (2025)

Abstract Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the sixth most prevalent tumor worldwide and the fourth leading cause of cancer-related deaths. Lenvatinib, a multi-targeted tyrosine kinase inhibitor (TKI), is a first-line therapy for HCC patients who are ineligible for immunotherapy. However, like other targeted therapies, its efficacy is often compromised by the development of resistance. Understanding the molecular alterations driving this resistance is critical to improving therapeutic outcomes in HCC. In this study, lenvatinib-resistant human HCC cell lines were established by exposing parental sensitive cells to increasing concentrations of lenvatinib. Resistant Hep3B and Huh7 cell lines were successfully developed, exhibiting higher lenvatinib-specific IC50 values compared to their sensitive counterparts. To investigate the mechanisms underlying drug resistance, whole-genome sequencing (WGS, average depth: 30X) was performed, identifying resistance-specific genomic alterations, including copy number variations (CNVs), mutations, and structural variations (SVs). Emerging evidence suggests that chromosomal instability (CIN) plays a critical role in resistance evolution through structural rearrangements and focal amplifications. To reconstruct these amplified regions, we utilized AmpliconArchitect, followed by classification into chromosomal amplification (ChrAmp) and extrachromosomal DNA (ecDNA) using AmpliconClassifier. The number of focal amplifications increased from 4 to 7 in resistant Hep3B cells and from 14 to 18 in resistant Huh7 cells. Notably, newly identified oncogenes were detected within these amplicons, including ZIC2 in Hep3B and EGFR in Huh7. Despite the emergence of new amplicon profiles in resistant cells, most retained their original classifications as ecDNAs or ChrAmps, suggesting that clones carrying these amplicons exhibit an intrinsic resistance phenotype. Ongoing studies involving single-clone isolation and further genomic characterization aim to refine and expand these findings. In conclusion, we successfully established lenvatinib-resistant HCC cell lines and characterized their resistance-specific genomic alterations. Our results highlight the role of CIN in driving resistance under the selective pressure of targeted therapies, offering potential insights for improving therapeutic strategies in HCC. Citation Format: JungHyun Kim, Ji Young Kim, Gamin Han, BoYoon Kim, Hoon Kim, Yeup Yoon, Wonseok Kang. Detection of genomic alterations in lenvatinib-resistant liver cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7503.
Abstract 6797: Mechanisms of nuclear MCL1 mediated chemoresistance
Authors: Kylin A. Emhoff, Jesse A. Coker, Jan J. Melenhorst
Journal: Cancer Research (2025)

Abstract The upregulation of anti-apoptotic BCL2 family members is a major mechanism of chemoresistance in many solid cancers. MCL1 (myeloid cell leukemia 1), an anti-apoptotic member of BCL2 family, is overexpressed in many solid tumors and associates with poor prognosis and therapeutic failure. In addition to its anti-apoptotic functions, MCL1 reportedly has non-apoptotic, nuclear functions that play a role in DNA damage response, cell cycle, and chemoresistance. However, the nuclear functions of MCL1 remain sparse and unelucidated. Our lab has investigated the nuclear interactome of MCL1 in solid cancer cells by implementing a proximity biotinylation approach. As a result, we have identified many novel MCL1 interactors in the nucleus, adding to MCL1’s repertoire of interactors. We are currently investigating whether our newly defined nuclear interactors of MCL1 play a role in MCL1-mediated chemoresistance. Overall, we are hoping to further elucidate the role of MCL1 in the nucleus in mediating chemoresistance. Citation Format: Kylin A. Emhoff, Jesse A. Coker, Jan J. Melenhorst. Mechanisms of nuclear MCL1 mediated chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6797.