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Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis.

SUBMITTER: Roe JS

PROVIDER: S-EPMC5726277 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis.

Roe Jae-Seok JS Hwang Chang-Il CI Somerville Tim D D TDD Milazzo Joseph P JP Lee Eun Jung EJ Da Silva Brandon B Maiorino Laura L Tiriac Hervé H Young C Megan CM Miyabayashi Koji K Filippini Dea D Creighton Brianna B Burkhart Richard A RA Buscaglia Jonathan M JM Kim Edward J EJ Grem Jean L JL Lazenby Audrey J AJ Grunkemeyer James A JA Hollingsworth Michael A MA Grandgenett Paul M PM Egeblad Mikala M Park Youngkyu Y Tuveson David A DA Vakoc Christopher R CR

Cell 20170727 5

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of en ...[more]

PMID: 28757253

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Project description:Rationale: The peripheral nervous system (PNS) plays an important role in tumor growth and progression. Schwann cells (SCs), the main glia cells of the PNS, augment cancer metastasis in contact-dependent or contact-independent manner in various malignancies. In the present study, we aimed to determine whether interplay between pancreatic cancer cells and SCs via paracrine signaling contributes to cancer progression. Methods: Immunofluorescence analysis was performed to reveal the distribution of SCs in PDAC tissues and to determine the prognostic value and clinicopathological relevance of the level of intra?tumoral SC markers for patients diagnosed with PDAC. Transwell assays and wound healing assays were carried out to investigate the influence of SC conditioned medium (SCM), SC co?culture, or co-cultured CM on the migratory and invasive abilities of pancreatic cancer cells. The mechanism of SCs induced cancer cells migration and invasion was confirmed using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assays (ELISAs), western blotting, immunofluorescence, immunohistochemistry, siRNA-mediated gene interference, and an in vivo mouse model. Results: Immunofluorescence analysis of tissue samples revealed that there were two different types of SCs distributed in the tumor microenvironment, the presence of which correlated with several clinicopathological characteristics and overall survival for patients with PDAC. Although SCM had no impact on the motility and invasiveness of tumor cells, both co-cultivation with SCs and co?cultured CM enhanced pancreatic cancer cell migration and invasion. Mechanistically, SC?derived Interleukin 6 (IL6), which was induced by co-culture with pancreatic cancer cells, augmented cancer cell migration and invasion by activating STAT3 signaling in cancer cells, while IL6 neutralization or STAT3 downregulation abrogated these effects. Furthermore, Interleukin 1? (IL1?), secreted by tumor cells, activated the nuclear actor (NF)-kappa B pathway in SCs, resulting in increased cytokines production, including IL6, while inhibiting the IL1?-IL1R1 axis led to inactivation of NF-kappa B signaling and downregulated cytokines expression in SCs. Interfering with tumor-neuroglia crosstalk impeded cancer cell dissemination in vivo. Conclusion: Schwann cells were extensively distributed in the PDAC tumor microenvironment and high level of intra-tumoral SC markers could serve as an independent prognostic factor for poor survival of patients with PDAC. The tumor-neuroglia interaction is indispensable for SCs to acquire a tumor-facilitating phenotype. Targeting the tumor-neuroglia interplay might be a promising strategy to treat PDAC.

Dataset Information

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis.

Publications

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis.

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