Abstract C080: Decoding the MYC-PDAC nexus: Unveiling the impact of PP2A-C subunit methylation on tumor onset and advancement
Authors: Vidhi Shah, Alexander Smith, Gabriel Cohn, Motoyuki Tsuda, Goutham Narla, Jonathan Brody, Brett Sheppard, Rosalie Sears
Journal: Cancer Research (2024)

Abstract Introduction: Persistent disruptions in MYC regulation and the inactivation of the serine/threonine protein phosphatase 2A (PP2A) are prevalent among individuals diagnosed with pancreatic ductal adenocarcinoma (PDAC). While it is known that PP2A influences MYC activity by facilitating its degradation, the precise mechanism by which this occurs remains unclear. Small molecule activators PP2A (SMAPs) regulate the holoenzyme assembly consisting of a scaffolding-A subunit and a catalytic-C subunit, and over 40 distinct substrate directing regulatory-B subunits. PP2A heterotrimerization is regulated by post-translational modifications of the catalytic C subunit, notably methylation of L309, which impacts B subunit binding affinity to the AC dimer and thus the substrate selectivity. In this study, we aim to investigate whether the deregulation of MYC, attributed to the loss of PP2A-C subunit methylation, contributes to the initiation and progression of PDAC. Methods: We investigated the influence of SMAPs on MYC’s stability using clinical specimens, cellular, and mouse models. Clinical specimens consisted of tissue microarray (TMA) from patients with pancreatitis and PDAC. Cellular models involved ex-vivo acinar cell assays and proximity ligation assays. Mouse models included caerulein-induced pancreatitis, genetic mouse models like Ptf1a-Cre; LSL-KRASG12D (KC) and LSL-Kras G12D;P53 R172H/+;Pdx1-Cre (KPC), along with pharmacological inhibition studies with SMAPs. Results and discussion: Our TMA data revealed a consistent pattern of Methyl-PP2A-C (Methyl-C) loss and an increase in the stable and active phosphoform of MYC (p62MYC) throughout the sequential stages of PDAC progression, starting from normal tissue and advancing to acinar-to-ductal metaplasia, PanINs, and finally PDAC. In ex-vivo ADM assays, treatment with small molecule activators of PP2A (SMAPs), specifically DT061, significantly reduced the transformation of acinar cells to duct-like cells compared to untreated cells from both wild-type (WT) and KC mice. This suggests that PP2A plays a crucial role in the early events that drive the formation of pancreatic lesions. Moreover, SMAPs demonstrated the ability to alleviate caerulein-induced inflammation in normal mice, as well as suppress the development of pancreatic PanIN lesions and collagen deposition in caerulein-treated KC mice. These effects were associated with decreased levels of p62MYC and increased Methyl-C staining in both WT and KC mice treated with caerulein. Additionally, in KPC mice, treatment with DT061 resulted in reduced PDAC tumor growth, accompanied by decreased levels of p62MYC. Conclusion: Our results provide compelling evidence that small molecule activators of PP2A (SMAPs), through their ability to downregulate MYC, hold significant promise as a therapeutic strategy for individuals at high risk of developing PDAC, particularly those with chronic pancreatitis. This approach has the potential to effectively prevent PDAC development and mitigate its onset in this high-risk population. Citation Format: Vidhi Shah, Alexander Smith, Gabriel Cohn, Motoyuki Tsuda, Goutham Narla, Jonathan Brody, Brett Sheppard, Rosalie Sears. Decoding the MYC-PDAC nexus: Unveiling the impact of PP2A-C subunit methylation on tumor onset and advancement [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C080.