Integrative transcriptomic characterization of matched primary and hepatic metastases of pancreatic ductal adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers due to its high metastasis rate in liver. However, little is known about the molecular features of hepatic metastases due to difficulty in obtaining fresh tissues and low tumor cellularity. Methods and Results: We conducted RNA sequencing for synchronous surgically resected PTs and the paired HMs from 14 hepatic oligometastatic PDACs and experimentally validated our findings in specimens from 35 of such cases. The comprehensive analysis of gene expressions showed largely similarity between PTs and HMs. However, hepatic metastases also showed unique characteristics, such as stronger abilities of proliferation, downregulation of EMT activity and metabolic rewiring. More interesting, altered tumor microenvironments were observed in hepatic metastases, especially higher proportion of tumor infiltrating M2 macrophage and upregulation of complement cascade. Further experiments demonstrate that expression of C1q increased continuously from normal to PTs to HMs, C1q was mainly produced from M2 macrophage, and C1q promoted migration and invasion of PDAC cells. Conclusion: Taken together, we found potential factors that contribute to different stages of PDAC metastasis. Our study broadens the understandings of molecular mechanisms driving PDAC metastasis. To decipher the transciptomic heterogeneity between HMs and paired PTs and unravel the molelcular mechanisms of PDAC metastasis, 33 freshly frozen specimens from 14 treatment-naϊve PDACs (6 N-PT-HM trios, 7 PT-HM pairs, and 1 HM) were subjected to RNA sequencing. ----------------------------------------------------------- Authors state "Raw data was available from National Omics Data Encyclopedia (NODE) database (http://www.biosino.org/node/project/detail/OEP000481). Restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of NODE committee."