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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151580 | GEO | 2020/06/02

REPOSITORIES: GEO

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Project description:We previously proposed a clinically meaningful intermediate metastatic state defined by a limited number of new metastases (≤5) after 3 months of follow-up, termed oligometastasis that has the curative potential by local cancer treatments as in contrast to the incurable widespread polymetastatic dissemination. While animal models of polymetastasis exist and this phenotype can be further enhanced upon serial in vivo passage, animal models of oligometastasis are not available. Here, we report the creation of an oligometastasis model of MDA-MB-435 human tumor in nude mice in which the oligometastatic phenotype exhibits stability during successive in vivo testing, and satisfies the criteria of ≤ 5 total body macroscopic metastases definition of the human cancer oligometastatic state. In parallel, we also developed an MDA-MB-435 polymetastatic model in which the polymetastatic dissemination pattern was either poly-foci at lung, or involved multiple anatomic sites including lung, heart, muscle, ovaries, kidney, brain and pleura. We have conducted microRNA expression profiling of cell lines derived from distinct lungs of oligo- and poly-metastatic animals. Animal model-derived microRNA expression features that discriminate oligometastatic cell lines from those of polymetastases accurately identify oligometastatic patients who failed to develop widespread metastases (P=0.005). These results demonstrate the clinical relevance of the oligo- and polymetastatic animal models we have developed and their potential in elucidating the molecular underpinnings of oligometastasis progression. We developed a stable human tumor (MDA-MB-435-GFP) xenograft model of oligometastatic and polymetastatic progression by conducting three consecutive rounds of experimental lung colonization assays. In the first round, we generated oligometastases-like lung derivative MDA-MB-435-L1-GFP (L1) or polymetastases-like MDA-MB-435-L1Mic-GFP (L1Mic) cell lines. We subsequently generated three oligometastatic L1 lung cell lines as well as four polymetastatic L1Mic lung cell lines from seven distinct animals of the second in vivo passage for further biological characterization and for microRNA expression analysis.

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

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