Journal Article In vivo reprogramming drives Kras-induced cancer development

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

92018-05-25 , Springer Nature
膵臓がんが発生する新たなメカニズムを解明 --遺伝子変異とは異なるがんの原因--. 京都大学プレスリリース. 2018-06-01.
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.

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