In vivo reprogramming drives Kras-induced cancer development

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.

Exploring the links between cancer and placenta development

“…Notably, activation of TLR3-dependent innate immune responses, which are in part shared with the cGAS-STING pathway, is required for efficient cellular reprogramming [ 38 ]. Also, in vivo reprogramming drives Kras-induced cancer development [ 39 ]. Collectively, these findings indicate a strong link among the triad of inflammation, cellular reprogramming and cancer development.…”

Human Pluripotent Stem Cell-Derived Tumor Model Uncovers the Embryonic Stem Cell Signature as a Key Driver in Atypical Teratoid/Rhabdoid Tumor

“…Notably, a premature termination of the in vivo reprogramming in mice causes the development of pediatric cancer-like tumors with activation of the ESC-like signature (Ohnishi et al, 2014). In addition, the transient expression of reprogramming factors in Kras mutant mice causes the development of alfa-fetoprotein (AFP)-producing cancers, which simultaneously express pluripotency-associated genes and exhibit activation of the ESC-like signature (Shibata et al, 2018). Collectively, activation of the ESC-like signature is involved in the development and progression of particular types of cancer.…”

G9a methyltransferase governs cell identity in the lung and is required for KRAS G12D tumor development and propagation

“…The impaired regenerative capacity of AT2 cells observed by G9a loss, impelled us to examine the outcome of G9a deletion in Kras-dependent tumor initiation -an event that was previously shown to require cell fate alterations in other tissue contexts (Shibata et al, 2018). To assess the impact on tumor initiation we deleted G9a using a conditional allele of G9a (Ehmt2 fl/fl) together with conditional KrasG12D in the absence or presence of p53 loss (KPE: Kras lsl.G12D/wt : Trp53 fl/fl ; Ehmt2 fl/fl and KE: Kras lsl.G12D/wt ; Ehmt2 fl/fl ) KPE mice showed a striking reduction in tumor formation and significant decrease in tumor burden in comparison to KP mice, which translated to a significant increase in overall survival (Figures 6G-figure supplement 7A,B).…”