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bioRxiv · 10.1101/2023.07.01.547283

KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development

Tinsley, S. L.·Shelley, R. A.·Mall, G. K.·Chianis, E. R. D.·Dhiman, A.·Baral, G.·Kothandaraman, H.·Thoma, M. C.·Daniel, C.·Lanman, N. A.·Pasca di Magliano, M.·Narla, G.·Solorio, L.·Dykhuizen, E.·Sears, R. C.·Allen-Petersen, B.
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Abstract

Oncogenic mutations in KRAS are present in approximately 95% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are considered the initiating event of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. While it is well established that KRAS mutations drive the activation of oncogenic kinase cascades during pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (PP2A) has been implicated in suppressing KRAS-driven cellular transformation. However, low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRASG12D induces the expression of both an endogenous inhibitor of PP2A activity, Cancerous Inhibitor of PP2A (CIP2A), and the PP2A substrate, c-MYC. Consistent with these findings, KRASG12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation in vivo, knockout of B56 promoted KRASG12D tumorigenesis by accelerating acinar-to-ductal metaplasia (ADM) and the formation of PanIN lesions. The process of ADM was attenuated ex vivo in response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (SMAPs). Together, our results suggest that suppression of PP2A-B56 through KRAS signaling can promote the MYC-driven initiation of pancreatic tumorigenesis.

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Tinsley, S. L., Shelley, R. A., Mall, G. K., Chianis, E. R. D., Dhiman, A., Baral, G., Kothandaraman, H., Thoma, M. C., Daniel, C., Lanman, N. A., Pasca di Magliano, M., Narla, G., Solorio, L., Dykhuizen, E., Sears, R. C., Allen-Petersen, B.. 2023-07-03. KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development. https://doi.org/10.1101/2023.07.01.547283

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