Author: Pullara, Filippo ; Yang, Michael ; Yanagawa, Fumiki ; Yan, Raymond ; Quinn, Shannon ; Tosun, Arif Burak ; Fearey, Brenna ; Falkenstein, Brian ; Yoshioka, Junya ; Joshi, Gaurav ; Sciascia, Nicholas ; Chennubhotla, S. Chakra

AbstractBackground:Colorectal cancer is the second most fatal cancer worldwide, accounting for 9% of all reported cancer deaths, and is the number one cause of death among people under the age of 50. Rapid technical advances in the field of spatial biology are allowing us to gain new insight into colorectal cancer biology and patient heterogeneity, which can help to guide the development of immunotherapies. Using a combination of modalities such as sequential multiplex immunofluorescence (mIF) and spatial transcriptomics (STx) on a colon cancer sample we determined the spatial distribution, phenotype, function, and a cytokine and chemokine profile within the colon cancer tissue.Experimental Procedure:5 um FFPE sections were prepared from a colon cancer sample exhibiting moderate to poorly differentiated adenocarcinoma of T3, N0 staging. mIF was performed using Lunaphore COMET with a 20-antibody panel, followed by H&E staining and imaging. An adjacent section was used for STx with the 10x Genomics Visium CytAssist platform. Data was analyzed with Lunaphore Horizon®, 10x Genomics Loupe Browser software and PredxBio SpaceIQ™ unbiased cell typing, microdomain discovery and network biology platform that co-analyzes mIF and STx datasets.Results:The tumor showed an aberrant growth pattern and a highly proliferated crypt region. Three distinct microdomains in the tumor tissue were discovered: one with high levels of PD-L1+ cells, a second with high levels of NK cells and a third with low levels of infiltrating cells in the lumen and crypt. There was significant presence of VISTA+ and IDO1+ cells throughout the lumen. These cells interacted with CD4+ and CD8+ cells which were found to be present in both lumen and crypt regions. PD-L1 was prominent in the cells found in both lumen and crypt. Finally, NK cells were abundant throughout the lumen and in regions adjacent to the crypt.Conclusions:Using multimodal spatial imaging and spatial co-analysis of mIF and STx data, we were able to elucidate relationships between different cell types in a complex tumor tissue and assign context to their activities. Despite high levels of NK cells, indicative of a possible active anti-tumor immune response, the tumor has developed an immune evasion mechanism due to the presence of cells expressing high levels of the anti-tumor immune response markers such as PD-L1, IDO1, and VISTA. Based on these results, therapies targeting more than one immune checkpoint protein may yield improved response due to an abundance of the existing NK cells. The transcriptomic profiling reveals a complex relationship between various cytokines secreted by different cell populations which alter the landscape of the tumor microenvironment, facilitating the emergence of an immunosuppressive phenotype.Citation Format:Gaurav Joshi, Nicholas Sciascia, Michael Yang, Brian Falkenstein, Raymond Yan, Shannon Quinn, Brenna Fearey, Junya Yoshioka, Arif Burak Tosun, S. Chakra Chennubhotla, Filippo Pullara, Fumiki Yanagawa. Multimodal spatial analysis of colon cancer tissue reveals emergence of an immunosuppressive tumor maintenance mechanism [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 5317.

21 Apr 2025·Cancer Research

Abstract 2485: A Bayesian framework for unraveling disease biology from spatially resolved single-cell omics datasets by combining unbiased approaches with biological priors for cell-based microdomain discovery

Author: Falkenstein, Brian ; Tosun, Akif Burak ; Pullara, Filippo ; Yan, Raymond ; Chennubhotla, S. Chakra ; Kulasinghe, Arutha ; Quinn, Shannon

AbstractBackground:The emergence of single-cell spatial omics platforms generating high-plex proteomic and transcriptomic measurements sets the foundation for accurate downstream biologically interpretable analyses. This includes biased and unbiased approaches for cell typing, cell-cell interactions and the discovery of microdomains, complex multicellular microenvironments, underlying disease progression.Problem:There is a lack of a computational framework for optimizing unbiased approaches with biological priors for unraveling a deeper understanding of disease mechanisms. This requires innovative integrational methods that assign confidence and robustness to data-driven biological hypotheses, e.g., presence of transition cells and other rare cell types, emergent microdomains and spatially modulated network biology.Solution:We present a Bayesian computational approach, SpaceIQ™, that not only elucidates potential novel hypotheses driving disease mechanisms, but also cross-references existing working hypotheses from alternative methods. SpaceIQ is agnostic to imaging platforms with the ability to ingest any combinatorial forms of spatial data (e.g., transmitted light, proteomics and transcriptomics).Results:To illustrate our approach, we compare the results from SpaceIQ to the interpretative analyses presented in He et al. Nat Biotech 2022, a publicly available 960-plex RNA data from CosMx platform on NSCLC samples. We aim to provide additional mechanistic insights underlying Stage II/III progression that can augment the biological annotations reported. We have identified 16 unbiased cell types with probabilistic representation of a priori phenotypes annotated as myeloid, lymphocytes, endothelial, epithelial/tumor, and fibroblast. IFI27, SOX4, MALAT1, TYK2, CD74, HLADRB1, and COL3A1 were among the highly-expressed discriminatory genes among cell types. 28 significant spatial interactions (p<0.1) were found resulting in 7 microdomains. Comparison of microdomains to niche neighborhoods defined in He et al. shows that macrophages in the stroma and TLS play a role in tumor progression. Ligand-Receptor analysis on microdomains identified IL-2 signaling, GPCR ligand binding, TNF activity, and TGF regulation to be significant cell-cell communication channels in NSCLC progression (p<1e-04).Conclusions:We proposed a Bayesian integration framework to further the biological interpretations of the spatially-resolved high-plex single-cell CosMx dataset on NSCLC patients presented in He et al. We’ve found unbiased cell types linked to known cell phenotypes in addition to potentially novel gene signatures. These unbiased cell types formulate microdomains with identified key signaling events that are associated with cancer progression.Citation Format:Brian Falkenstein, Raymond Yan, Shannon Quinn, Akif Burak Tosun, S. Chakra Chennubhotla, Arutha Kulasinghe, Filippo Pullara. A Bayesian framework for unraveling disease biology from spatially resolved single-cell omics datasets by combining unbiased approaches with biological priors for cell-based microdomain discovery [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 2485.

01 Sep 2024·Redox Biology

NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease

Article

Author: Hu, Xiaoping ; Di Maio, Roberto ; Forsmann, Madison C ; Pullara, Filippo ; Ayoob, Joseph C ; Greenamyre, J Timothy ; Furbee, Emily ; Castro, Sandra L ; General, Ignacio J

Ca²⁺/calmodulin-dependent protein kinase II α (CaMKIIα) signaling in the brain plays a critical role in regulating neuronal Ca²⁺ homeostasis. Its dysfunctional activity is associated with various neurological and neurodegenerative disorders, including Parkinson's disease (PD). Using computational modeling analysis, we predicted that, two essential cysteine residues contained in CaMKIIα, Cys30 and Cys289, may undergo redox modifications impacting the proper functioning of the CaMKIIα docking site for Ca²⁺/CaM, thus impeding the formation of the CaMKIIα:Ca²⁺/CaM complex, essential for a proper modulation of CaMKIIα kinase activity. Our subsequent in vitro investigations confirmed the computational predictions, specifically implicating Cys30 and Cys289 residues in impairing CaMKIIα:Ca²⁺/CaM interaction. We observed CaMKIIα:Ca²⁺/CaM complex disruption in dopamine (DA) nigrostriatal neurons of post-mortem Parkinson's disease (PD) patients' specimens, addressing the high relevance of this event in the disease. CaMKIIα:Ca²⁺/CaM complex disruption was also observed in both in vitro and in vivo rotenone models of PD, where this phenomenon was associated with CaMKIIα kinase hyperactivity. Moreover, we observed that, NADPH oxidase 2 (NOX2), a major enzymatic generator of superoxide anion (O₂^●-) and hydrogen peroxide (H₂O₂) in the brain with implications in PD pathogenesis, is responsible for CaMKIIα:Ca²⁺/CaM complex disruption associated to a stable Ca²⁺CAM-independent CaMKIIα kinase activity and intracellular Ca²⁺ accumulation. The present study highlights the importance of oxidative stress, in disturbing the delicate balance of CaMKIIα signaling in calcium dysregulation, offering novel insights into PD pathogenesis.

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28 Apr 2025

·www.prnewswire.com

PredxBio and Hamamatsu Photonics Announce Strategic Partnership to Deliver Next-Generation Spatial Biology Solutions for Cancer Research and Therapeutic Development

PITTSBURGH and BRIDGEWATER, N.J., April 28, 2025 /PRNewswire/ -- PredxBio, a pioneer in AI-powered spatial biomarker discovery, today announced a strategic collaboration with Hamamatsu Photonics K.K., a global leader in imaging technologies. The partnership unites Hamamatsu's advanced MoxiePlex™ multiplex immunofluorescence imaging system with PredxBio's SpaceIQ™ spatial analytics platform to deliver an integrated workflow tailored to basic and translational research tailored to immuno-oncology. Launched in late 2024, Hamamatsu's MoxiePlex™ is a research use only platform that captures up to 10 fluorescent markers simultaneously, enabling precise spatial mapping of proteins on cancer and immune cells within the tumor microenvironment. Designed to support the complex needs of spatial proteomics research while maintaining workflow simplicity, MoxiePlex may in the future be developed for clinical applications, especially in areas like immunotherapy response profiling. "This partnership reflects a shared vision to unlock the true potential of spatial proteomics through innovation and accessibility," said James Butler, VP of Marketing at Hamamatsu Corporation (the US subsidiary of Hamamatsu Photonics). "With MoxiePlex and SpaceIQ™ combined, we're delivering a solution that meets the demands of advanced cancer research today, while paving the way for future development of clinical integrations." By combining the high-resolution imaging capabilities of MoxiePlex™ with the explainable, multi-modal analytics of SpaceIQ™, the joint offering creates a streamlined, plug-and-play ecosystem. Researchers can move from image capture to actionable insights—such as spatial immune cell profiling, pathway activation analysis, and biomarker stratification—with unprecedented speed, clarity, and scalability. "We're excited to partner with Hamamatsu to bridge the gap between image generation and spatial intelligence," said Dr. Dusty Majumdar, CEO of PredxBio. "Our joint solution makes it possible to explore not only what proteins are expressed, but where and how they drive disease biology—empowering researchers and drug developers with insights that matter." PredxBio and Hamamatsu are jointly committed to simplifying spatial workflows while enhancing biological resolution. The integration supports spatially resolved proteomic data in support of translational research, biomarker validation, and clinical trial optimization. About PredxBio PredxBio is a spatial analytics company headquartered in Pittsburgh, PA, powering next-generation cancer therapeutics with its AI-driven spatial biomarkers. PredxBio's proprietary approaches delve into the mechanism of action of drugs and predict patient outcomes with over 90% accuracy. By transforming multiplexed biopsy images and multi-modal spatial data into actionable insights – and revealing the network biology of cancer – PredxBio is setting new standards for biomarker discovery and clinical research. In partnership with leading pharmaceutical companies and research institutions, PredxBio is accelerating drug discovery and advancing personalized medicine to impact cancer patients globally. For more information, visit innovation. About Hamamatsu Photonics Hamamatsu Photonics is a global photonics technology leader offering cutting-edge imaging and optical systems. Its MoxiePlex™ is a 10-color multiplex immunofluorescence imaging platform for research use that is designed to advance spatial proteomics research —starting with immuno-oncology and expanding into broader pathology applications. Info Click here if you are interested in registering for updates about MoxiePlex. If you would like to specifically discuss engaging PredxBio regarding MoxiePlex, please contact: Don Ariyakumar MoxiePlex Strategic Product Manager [email protected] Information furnished by Hamamatsu Corporation is believed to be reliable. However, no responsibility is assumed for possible inaccuracies or omissions. Specifications are subject to change without notice. SOURCE Hamamatsu Corporation WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

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