Inflammatory Signaling and Fibroblast-Cancer Cell Interactions Transfer from a Harmonized Human Single-cell RNA Sequencing Atlas of Pancreatic Ductal Adenocarcinoma to Organoid Co-Culture
Inflammatory Signaling and Fibroblast-Cancer Cell Interactions Transfer from a Harmonized Human Single-cell RNA Sequencing Atlas of Pancreatic Ductal Adenocarcinoma to Organoid Co-Culture
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DOI：
10.1101/2022.07.14.500096
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发表时间：
2022-07
期刊：
影响因子：
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通讯作者：
B. Kinny-Köster;Samantha Guinn;Joseph A Tandurella;Jacob T. Mitchell;Dimitri N. Sidiropoulos;Melanie Loth-Melan
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文献类型：
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作者：
B. Kinny-Köster;Samantha Guinn;Joseph A Tandurella;Jacob T. Mitchell;Dimitri N. Sidiropoulos;Melanie Loth-Melan
胰腺导管腺癌（PDAC）是一种破坏性的恶性肿瘤，由富含癌症相关成纤维细胞（CAF）的异质肿瘤微环境驱动，CAF影响其整体免疫抑制成分。我们通过利用我们现有的患者来源的类器官（PDO）模型和新的PDO-CAF共培养物来检查PDAC中的炎症。我们首先确定了干扰素γ治疗后主要组织相容性复合物II类表达的诱导。同时，我们整理了6个已发表的单细胞RNA测序数据集（174，394个细胞）的图谱，其中包括61个PDAC（142，807个细胞）和16个非恶性样本。通过结合计算机模拟和体外PDO共培养，我们定义了上皮肿瘤细胞中炎症过程的基因表达模式。根据计算推断，我们研究了上皮肿瘤细胞和CAFs之间的相互作用，重点是VEGF-A和ITGB 1途径。这项工作，整合计算和生物学方法，突出了收敛的价值，以加速我们对PDAC关键驱动因素的理解。我们建立了PDO-CAF共培养物来模拟肿瘤细胞相互作用，并使用迁移学习验证PDAC肿瘤单细胞RNA-seq图谱的发现。这种从人类到实验系统的双向方法促进了PDAC生物学的询问，包括与CAF和肿瘤细胞之间的VEGF-A串扰相关的炎症的作用。
Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy driven by a heterogeneous tumor microenvironment enriched with cancer associated fibroblasts (CAFs) that influence its overall immunosuppressive composition. We examined inflammation in PDAC by leveraging our existing patient-derived organoid (PDO) model and a novel PDO-CAF co-culture. We first identified induction of major histocompatibility complex class II expression following treatment with interferon gamma. In parallel, we collated an atlas of 6 published single-cell RNA-sequencing datasets (174,394 cells) combining 61 PDAC (142,807 cells) and 16 non-malignant samples. By combining in silico modeling and in vitro PDO co-culture, we define a gene expression pattern of inflammatory processes in epithelial tumor cells. Following computational inferences, we examined interactions between epithelial tumor cells and CAFs, focusing on VEGF-A and ITGB1 pathways. This work, integrating computational and biological approaches, highlights the value of convergence to accelerate our understanding of key drivers of PDAC. Statement of Significance We established PDO-CAF co-cultures to model tumor cell interactions and validated discoveries using transfer learning into a single-cell RNA-seq atlas of PDAC tumors. This bidirectional approach from human to experimental systems facilitates interrogation of PDAC biology, including the role of inflammation associated with VEGF-A crosstalk between CAFs and tumor cells.