Park Margaret A, Gumpper-Fedus Kristyn, Krishna Somashekar G, Genilo-Delgado Maria C, Brantley Stephen, Hart Phil A, Dillhoff Mary E, Gomez Maria F, Basinski Toni L, Mok Shaffer R, Luthra Anjuli K, Fleming Jason B, Mohammadi Amir, Centeno Barbara A, Jiang Kun, Karolak Aleksandra, Jeong Daniel, Chen Dung-Tsa, Stewart Paul A, Teer Jamie K, Cruz-Monserrate Zobeida, Permuth Jennifer B
Department of Gastrointestinal (GI) Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL 33612, USA.
Int J Mol Sci. 2024 Dec 7;25(23):13164. doi: 10.3390/ijms252313164.
Intraductal papillary mucinous neoplasms (IPMN) are commonly detected pancreatic cysts that may transform into pancreatic ductal adenocarcinoma (PDAC). Predicting which IPMNs will progress to PDAC remains a clinical challenge. Moreover, identifying those clinically evident IPMNs for which a surveillance approach is best is a dire clinical need. Therefore, we aimed to identify molecular signatures that distinguished between PDAC with and without clinical evidence of an IPMN to identify novel molecular pathways related to IPMN-derived PDAC that could help guide biomarker development. Data from the Oncology Research Information Exchange Network (ORIEN) multi-institute sequencing project were utilized to analyze 66 PDAC cases from Moffitt Cancer Center and The Ohio State University Wexner Medical Center, for which tumor whole transcriptome sequencing datasets were generated. Cases were classified based on whether a tumor had originated from an IPMN ( = 16) or presumably through the pancreatic intraepithelial neoplasia (PanIN) pathway ( = 50). We then performed differential expression and pathway analysis using Gene-Set Enrichment Analysis (GSEA) and Pathway Analysis with Down-weighted Genes (PADOG) algorithms. We also analyzed immune profiles using the Tumor-Immune Microenvironment Deconvolution web portal for Bulk Transcriptomics (TIMEx). Both GSEA and TIMEx indicate that PanIN-derived PDAC tumors enrich inflammatory pathways (complement, hedgehog signaling, coagulation, inflammatory response, apical surface, IL-2/STAT5, IL-6/STAT3, EMT, KRAS signaling, apical junction, IFN-gamma, allograft rejection) and are comparatively richer in almost all immune cell types than those from IPMN-derived PDAC. IPMN-derived tumors were enriched for metabolic and energy-generating pathways (oxidative phosphorylation, unfolded protein response, pancreas beta cells, adipogenesis, fatty acid metabolism, protein secretion), and the most significantly upregulated genes (padj < 0.001) included mucin 2 (MUC2) and gastrokine-2 (GKN2). Further, the metabolic-linked gene signature enriched in the IPMN-derived samples is associated with a cluster of early-stage and long-survival (top 4th quartile) PDAC cases from The Cancer Genome Atlas (TCGA) expression database. Our data suggest that IPMN-derived and PanIN-derived PDACs differ in the expression of immune profiles and metabolic pathways. These initial findings warrant validation and follow-up to develop biomarker-based strategies for early PDAC detection and treatment.
导管内乳头状黏液性肿瘤（IPMN）是常见的胰腺囊肿，可能会转变为胰腺导管腺癌（PDAC）。预测哪些IPMN会进展为PDAC仍然是一项临床挑战。此外，确定哪些临床上明显的IPMN最适合采用监测方法是迫切的临床需求。因此，我们旨在识别区分有或无IPMN临床证据的PDAC的分子特征，以确定与IPMN衍生的PDAC相关的新分子途径，这有助于指导生物标志物的开发。利用肿瘤学研究信息交换网络（ORIEN）多机构测序项目的数据，分析了来自莫菲特癌症中心和俄亥俄州立大学韦克斯纳医学中心的66例PDAC病例，这些病例生成了肿瘤全转录组测序数据集。根据肿瘤是否起源于IPMN（n = 16）或可能通过胰腺上皮内瘤变（PanIN）途径（n = 50）对病例进行分类。然后，我们使用基因集富集分析（GSEA）和加权基因通路分析（PADOG）算法进行差异表达和通路分析。我们还使用肿瘤免疫微环境反卷积网络门户进行批量转录组学（TIMEx）分析免疫图谱。GSEA和TIMEx均表明，PanIN衍生的PDAC肿瘤富集炎症通路（补体、刺猬信号、凝血、炎症反应、顶端表面、IL-2/STAT5、IL-6/STAT3、EMT、KRAS信号、顶端连接、IFN-γ、同种异体移植排斥），并且几乎在所有免疫细胞类型中都比IPMN衍生的PDAC更丰富。IPMN衍生的肿瘤富含代谢和能量产生通路（氧化磷酸化、未折叠蛋白反应、胰腺β细胞、脂肪生成、脂肪酸代谢、蛋白质分泌），上调最显著的基因（padj < 0.001）包括黏蛋白2（MUC2）和胃动素2（GKN2）。此外，在IPMN衍生样本中富集的代谢相关基因特征与来自癌症基因组图谱（TCGA）表达数据库的一组早期和长期存活（前四分之一）PDAC病例相关。我们的数据表明，IPMN衍生的和PanIN衍生的PDAC在免疫图谱和代谢途径的表达上存在差异。这些初步发现需要验证和随访，以制定基于生物标志物的早期PDAC检测和治疗策略。
