Guinn Samantha, Perez Brayan, Tandurella Joseph A, Ramani Mili, Lee Jae W, Zabransky Daniel J, Kartalia Emma, Patel Jignasha, Zlomke Haley, Nicolson Norman, Shin Sarah, Barrett Benjamin, Sun Nicholas, Hernandez Alexei, Coyne Erin, Cannon Courtney, Gross Nicole E, Charmsaz Soren, Cho Yeonju, Leatherman James, Lyman Melissa, Mitchell Jacob, Kagohara Luciane T, Goggins Michael G, Lafaro Kelly J, He Jin, Shubert Christopher, Burns William, Zheng Lei, Fertig Elana J, Jaffee Elizabeth M, Burkhart Richard A, Ho Won Jin, Zimmerman Jacquelyn W
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
bioRxiv. 2025 Jan 8:2025.01.07.631784. doi: 10.1101/2025.01.07.631784.
Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, in part resulting from cellular heterogeneity that supports overall tumorigenicity. Cancer associated fibroblasts (CAF) are key determinants of PDAC biology and response to systemic therapy. While CAF subtypes have been defined, the effects of patient-specific CAF heterogeneity and plasticity on tumor cell behavior remain unclear. Here, multi-omics was used to characterize the tumor microenvironment (TME) in tumors from patients undergoing curative-intent surgery for PDAC. In these same patients, matched tumor organoid and CAF lines were established to functionally validate the impact of CAFs on the tumor cells. CAFs were found to drive epithelial-mesenchymal transition (EMT) and a switch in tumor cell classificiaton from classical to basal subtype. Furthermore, we identified CAF-specific interleukin 8 (IL-8) as an important modulator of tumor cell subtype. Finally, we defined neighborhood relationships between tumor cell and T cell subsets.
胰腺导管腺癌（PDAC）的预后极差，部分原因是支持整体肿瘤发生的细胞异质性。癌症相关成纤维细胞（CAF）是PDAC生物学特性和对全身治疗反应的关键决定因素。虽然已定义了CAF亚型，但患者特异性CAF异质性和可塑性对肿瘤细胞行为的影响仍不清楚。在此，采用多组学方法对接受PDAC根治性手术患者肿瘤中的肿瘤微环境（TME）进行表征。在这些相同患者中，建立了匹配的肿瘤类器官和CAF系，以功能验证CAF对肿瘤细胞的影响。发现CAF可驱动上皮-间质转化（EMT）以及肿瘤细胞分类从经典亚型向基底亚型的转变。此外，我们确定CAF特异性白细胞介素8（IL-8）是肿瘤细胞亚型的重要调节因子。最后，我们定义了肿瘤细胞与T细胞亚群之间的邻域关系。
