In vivo reprogramming drives Kras-induced cancer development

Hirofumi Shibata,Shingo Komura,Yosuke Yamada,Bunya Kuze,Satoko Sakurai,Yoshiya Kawaguchi,Knut Woltjen,Takuya Yamamoto,Nao Sankoda,Yatsuji Ito,Mio Kabata,Tomoyo Ukai,Hironori Haga,Yasuhiro Yamada,Akito Tanaka

doi:10.1038/s41467-018-04449-5

Abstract

The faithful shutdown of the somatic program occurs in the early stage of reprogramming. Here, we examined the effect of in vivo reprogramming on Kras-induced cancer development. We show that the transient expression of reprogramming factors (1–3 days) in pancreatic acinar cells results in the transient repression of acinar cell enhancers, which are similarly observed in pancreatitis. We next demonstrate that Kras and p53 mutations are insufficient to induce ERK signaling in the pancreas. Notably, the transient expression of reprogramming factors in Kras mutant mice is sufficient to induce the robust and persistent activation of ERK signaling in acinar cells and rapid formation of pancreatic ductal adenocarcinoma. In contrast, the forced expression of acinar cell-related transcription factors inhibits the pancreatitis-induced activation of ERK signaling and development of precancerous lesions in Kras-mutated acinar cells. These results underscore a crucial role of dedifferentiation-associated epigenetic regulations in the initiation of pancreatic cancers.

Highlights

The faithful shutdown of the somatic program occurs in the early stage of reprogramming
pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a spectrum of preneoplastic lesions with ductal morphology that are designated as pancreatic intraepithelial neoplasia (PanIN) 13
We show that reprogramming-mediated repression of somatic cell enhancers, which is associated with early stage of reprogramming, in conjunction with Kras mutation results in rapid development of PDAC

Summary

Introduction

The faithful shutdown of the somatic program occurs in the early stage of reprogramming. The forced expression of acinar cell-related transcription factors inhibits the pancreatitisinduced activation of ERK signaling and development of precancerous lesions in Kras-mutated acinar cells. These results underscore a crucial role of dedifferentiation-associated epigenetic regulations in the initiation of pancreatic cancers. These cancer cells were readily reprogrammable into iPSCs that are capable of differentiating into non-cancerous kidney cells[8] These results raised the possibility that reprogramming-associated epigenetic regulation has a significant impact on childhood cancer development, which is in agreement with recent observations that childhood cancers harbor relatively few genetic mutations. Current consensus holds that pancreatic cancer arises through a stepwise progression with characteristic genetic mutations for each histologically distinguishable stage

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