Uncovering the spatial landscape of molecular interactions within the tumor microenvironment through latent spaces

Cell Systems, Journal Year: 2023, Volume and Issue: 14(4), P. 285 - 301.e4

Published: April 1, 2023

Language: Английский

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Translating the multifaceted use of liquid biopsy to management of early disease in pancreatic adenocarcinoma

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: March 13, 2025

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality, primarily due to late stage at diagnosis. This review examines the multifaceted applications liquid biopsy and circulating tumor DNA (ctDNA) analysis in diagnosis management PDAC. We current literature on technological advancements such as next generation sequencing (NGS) digital droplet PCR (ddPCR) well multi-omics technologies, highlighting their potential for accurate molecular subtyping through ctDNA analysis. highlights significant role assessment behavior, disease subtyping, prediction monitoring treatment response, evaluation minimal residual disease. discuss implications integrating techniques into clinical practice its challenges limitations. By drawing insights from recent studies, this aims provide comprehensive overview how can enhance early strategies underscore need additional prospective studies trials validate feasibility accuracy order establish utility, with ultimate goal routine incorporation improve patient outcomes transform landscape

Language: Английский

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Pancreatic Cancer Precursor Lesions – Can Immunotherapy Prevent Progression into Pancreatic Ductal Adenocarcinoma?

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217662 - 217662

Published: March 1, 2025

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a 5-year survival rate only 12.5%. Early detection PDAC or addressing risk factors for development are ways to improve outcomes. can arise from precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and less frequent, cystic (MCN), other rare variants. High-risk lesions harbor substantial chance evolving into PDAC. Such often be found in resected specimens adjacent cancer. Unfortunately, recognizing that need tricky, resections frequently end major surgical interventions. Thus, better handle desperately needed. We mapped immune microenvironments (IMEs) PanINs, IPMNs, MCNs on cellular level using multiplex immunofluorescence computational imaging technology compared findings PDACs normal tissues. distinct potentially targetable mechanisms immunosuppression between two main PanIN IMPN. Immunosuppression IPMNs seems partly mediated by programmed cell death protein 1 ligand (PD-L1) expression antigen-presenting cells (APCs). By contrast, elevated numbers regulatory T (Tregs) seem key players PanINs. treating high-risk anti-PD-1 PanINs agents targeting Tregs, such as anti-lymphocyte associated 4 (anti-CTLA-4) antibodies, could reverse their immunosuppressive state. Reversal will restore immunosurveillance eventually prevent progression also review relevant published ongoing non-surgical treatment approaches

Language: Английский

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CODAvision: best practices and a user-friendly interface for rapid, customizable segmentation of medical images

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

Abstract Image-based machine learning tools have emerged as powerful resources for analyzing medical images, with deep learning-based semantic segmentation commonly utilized to enable spatial quantification of structures in images. However, customization and training algorithms requires advanced programming skills intricate workflows, limiting their accessibility many investigators. Here, we present a protocol software automatic images guided by graphical user interface (GUI) using the CODAvision algorithm. This workflow simplifies process microanatomical enabling users train highly customizable models without extensive coding expertise. The outlines best practices creating robust datasets, configuring model parameters, optimizing performance across diverse biomedical image modalities. enhances usability CODA algorithm ( Nature Methods , 2022) streamlining parameter configuration, training, evaluation, automatically generating quantitative results comprehensive reports. We expand beyond original implementation serial histology demonstrating numerous modalities biological questions. provide sample data types including histology, magnetic resonance imaging (MRI), computed tomography (CT). demonstrate use this tool applications metastatic burden vivo deconvolution spot-based transcriptomics datasets. is designed researchers interest rapid design basic understanding anatomy.

Language: Английский

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Stromal Cells in Early Inflammation-Related Pancreatic Carcinogenesis—Biology and Its Potential Role in Therapeutic Targeting

Cancers, Journal Year: 2025, Volume and Issue: 17(9), P. 1541 - 1541

Published: May 1, 2025

The stroma of healthy pancreases contains various non-hematopoietic, non-endothelial mesenchymal cells. It is altered by chronic inflammation which in turn a major contributor to the development pancreatic adenocarcinoma (PDAC). In PDAC, plays decisive and well-investigated role for tumor progression therapy response. This review addresses central stromal cells early inflammation-driven PDAC. focuses on subpopulations cells, i.e., fibroblasts, stellate multipotent particularly their activation functional alterations upon including different types carcinoma-associated fibroblasts. second part, current knowledge impact activated acinar-to-ductal metaplasia transition intraepithelial neoplasia summarized. Finally, putative strategies target signaling carcinogenesis are reflected. summary, data show that resulting fibrotic changes has pro- anti-carcinogenetic effects but, overall, creates carcinogenesis-promoting microenvironment. However, this dynamic process therapeutic targeting specific pathways requires in-depth molecular interplay cell types.

Language: Английский

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Antigen-presenting cancer-associated fibroblasts in murine pancreatic tumors differentially control regulatory T cell phenotype and function via CXCL9 and CCL22

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a complex tumor microenvironment (TME) including stromal cells that influence resistance to therapy. Recent studies have revealed cancer-associated fibroblasts (CAFs) are heterogeneous in origin, gene expression, and function. Antigen-presenting CAFs (apCAFs), defined major histocompatibility (MHC)-II expression can activate effector CD4 + T the potential contribute anti-cancer immune response, but also induce regulatory cell (Treg) differentiation. Whether apCAFs promote or restrain antitumor response remains uncertain. Using clones of KPC murine PDAC model differing sensitivity checkpoint blockade (ICB), we found immunosensitive (sKPC) tumors were higher apCAF infiltration than resistant (rKPC) tumors. IMC analysis showed proximity both sKPC rKPC implicating interaction within TME. apCAF-depleted tumor-bearing mice had diminished ICB. from activated tumor-infiltrating induced Treg However, transcriptomic Tregs overexpressed for immunosuppressive genes rKPCs relative sKPCs, this associated with differential chemokine signaling depending on origin. Together these data implicate as important mediators modulation which could facilitate development more effective anti-tumor based approaches patients.

Language: Английский

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Three-dimensional assessments are necessary to determine the true, spatially-resolved composition of tissues

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 6, 2023

Methods for spatially resolved cellular profiling using thinly cut sections have enabled in-depth quantitative tissue mapping to study inter-sample and intra-sample differences in normal human anatomy disease onset progression. These methods often profile extremely limited regions, which may impact the evaluation of heterogeneity due sub-sampling. Here, we applied CODA, a deep learning-based platform, reconstruct three-dimensional (3D) microanatomy grossly cancer-containing pancreas biospecimens obtained from individuals who underwent pancreatic resection. To compare inter- heterogeneity, assessed bulk composition cohort two-dimensional (2D) whole slide images (WSIs) thick slabs that were digitally reconstructed 3D serial sections. demonstrate marked under sampling 2D assessments, simulated number WSIs microarrays (TMAs) necessary represent compositional data within 10% error reveal tens hundreds TMA cores are sometimes needed. We show spatial correlation different structures decay significantly span microns, demonstrating histological not be representative their neighboring tissues. In sum, assessments accurately assess abnormal specimens order determine neoplastic content. results emphasize importance efforts.

Language: Английский

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Spatial transcriptomic analysis drives PET imaging of tight junction protein expression in pancreatic cancer theranostics

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Dec. 30, 2024

Molecular imaging using positron emission tomography (PET) provides sensitive detection and mapping of molecular targets. While cancer-associated fibroblasts integrins have been proposed as targets for pancreatic ductal adenocarcinoma (PDAC), herein, spatial transcriptomics proteomics human surgical samples are applied to select PDAC We find that selected cancer cell surface markers spatially correlated provide specific localization, whereas the correlation between immune-related or fibroblast is low. Claudin-4 expression increases ~16 fold in compared with normal pancreas, tight junction localization confers low background tissue. develop a peptide-based agent targeted claudin-4 accumulation ~25% injected activity per cubic centimeter (IA/cc) metastases ~18% IA/cc tumors. Our work motivates data-driven approach selection

Language: Английский

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3D histology reveals that immune response to pancreatic precancers is heterogeneous and depends on global pancreas structure

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 6, 2024

SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer for which few effective therapies exist. Immunotherapies specifically are ineffective in pancreatic cancer, part due to its unique stromal and immune microenvironment. intraepithelial neoplasia, or PanIN, the main precursor lesion PDAC. Recently it was discovered that PanINs remarkably abundant grossly normal pancreas, suggesting vast majority will never progress cancer. Here, through construction of 48 samples cm 3 -sized human pancreas tissue, we profiled microenvironment 1,476 3D at single-cell resolution better understand early evolution tumor determine how inflammation may play role progression. We found bulk strongly correlates PanIN cell fraction. response around heterogeneous, with distinct hotspots cold spots appear disappear span tens microns. Immune generally mark locations higher grade dysplasia near acinar atrophy. The composition these dominated by naïve, cytotoxic, regulatory T cells, associated fibroblasts, macrophages, little similarity less-inflamed PanINs. By mapping FOXP3+ cells 3D, present density larger lesions compared smaller PanINs, initiation not exhibit an immunosuppressive response. This analysis demonstrates while common pancreases most individuals, pivotal role, both microscopic scale, demarcating regions significance

Language: Английский

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From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression

Carcinogenesis, Journal Year: 2024, Volume and Issue: 45(11), P. 801 - 816

Published: Nov. 1, 2024

This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to ductal adenocarcinoma through a dual lens intrinsic molecular alterations and extrinsic microenvironmental influences. PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving initiation. Key additional in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control genomic stability, crucial for from low-grade high-grade dysplasia. Additional neoplastic cells, including epigenetic modifications chromosomal alterations, can further contribute progression. In parallel these microenvironment, fibroblast activation, extracellular matrix remodeling, immune modulation, plays pivotal role initiation Crosstalk between stromal cells influences nutrient support evasion, contributing development, growth, survival. underscores intricate interplay cell-intrinsic drivers cell-extrinsic factors, shaping predisposition, initiation, Future research aims unravel interactions develop targeted therapeutic strategies early detection techniques, aiming alleviate severe impact cancer by addressing both genetic predispositions environmental

Language: Английский

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