Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Oncogene volume 43, pages 3673–3687 (2024)Cite this article

Subjects

Abstract

Oncogenic mutations in KRAS are present in ~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 and 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 an endogenous inhibitor of PP2A activity, Cancerous Inhibitor of PP2A (CIP2A), and phosphorylation of the PP2A substrate, c-MYC. Consistent with these findings, KRASG12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56α, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation in vivo, knockout of B56α 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-B56α through KRAS signaling can promote the MYC-driven initiation of pancreatic tumorigenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Oncogenic KRAS signaling promotes suppression of the PP2A-B56α complex.
Fig. 2: Loss of oncogenic KRAS signaling promotes activation of PP2A-B56α.
Fig. 3: Overexpression of B56α abrogates oncogenic phenotypes.
Fig. 4: Loss of B56α promotes acceleration of acinar-to-ductal metaplasia.
Fig. 5: Loss of B56α leads to altered chromatin accessibility and transcriptional programs associated with oncogenesis.
Fig. 6: Loss of B56α promotes progression of PDAC precursor lesions.
Fig. 7: Re-activation of PP2A-B56α prevents initiation of pancreatic cancer.

Similar content being viewed by others

Data availability

Data from the current study is available from the corresponding author upon reasonable request. RNA- and ATAC-seq have been deposited in GEO repository under: GSE250101.

References

  1. Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016;129:1287–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17–48.

    Article  PubMed  Google Scholar 

  3. Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci. 2014;39:91–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437–450.

    Article  CAS  PubMed  Google Scholar 

  5. Collins MA, Bednar F, Zhang Y, Brisset J-C, Galbán S, Galbán CJ, et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest. 2012;122:639–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Storz P. Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol. 2017;14:296–304.

    Article  CAS  Google Scholar 

  7. Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, et al. Senescence in premalignant tumours. Nature. 2005;436:642.

    Article  CAS  PubMed  Google Scholar 

  8. Sablina AA, Hector M, Colpaert N, Hahn WC. Identification of PP2A complexes and pathways involved in cell transformation. Cancer Res. 2010;70:10474–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sangodkar J, Farrington CC, McClinch K, Galsky MD, Kastrinsky DB, Narla G. All roads lead to PP2A: exploiting the therapeutic potential of this phosphatase. FEBS J. 2016;283:1004–24.

    Article  CAS  PubMed  Google Scholar 

  10. Hydbring P, Larsson L-G. Cdk2: a key regulator of the senescence control function of Myc. Aging Albany 2010;2:244–50.

    Article  CAS  Google Scholar 

  11. Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol. 2008;9:517–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Letourneux C, Rocher G, Porteu F. B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK. EMBO J. 2006;25:727–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lin SS, Bassik MC, Suh H, Nishino M, Arroyo JD, Hahn WC, et al. PP2A regulates BCL-2 phosphorylation and proteasome-mediated degradation at the endoplasmic reticulum*. J Biol Chem. 2006;281:23003–12.

    Article  CAS  PubMed  Google Scholar 

  14. Farrell AS, Allen-Petersen B, Daniel CJ, Wang X, Wang Z, Rodriguez S, et al. Targeting inhibitors of the tumor suppressor PP2A for the treatment of pancreatic cancer. Mol Cancer Res. 2014;12:924–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Janghorban M, Langer EM, Wang X, Zachman D, Daniel CJ, Hooper J, et al. The tumor suppressor phosphatase PP2A-B56α regulates stemness and promotes the initiation of malignancies in a novel murine model. PLoS ONE. 2017;12:e0188910.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kauko O, Laajala TD, Jumppanen M, Hintsanen P, Suni V, Haapaniemi P, et al. Label-free quantitative phosphoproteomics with novel pairwise abundance normalization reveals synergistic RAS and CIP2A signaling. Sci Rep. 2015;5:13099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chang W-H, Liu Y, Hammes EA, Bryant KL, Cerione RA, Antonyak MA. Oncogenic RAS promotes MYC protein stability by upregulating the expression of the inhibitor of apoptosis protein family member Survivin. J Biol Chem. 2023;299:102842.

    Article  CAS  PubMed  Google Scholar 

  18. Wu Y, Gu T-T, Zheng P-S. CIP2A cooperates with H-Ras to promote epithelial–mesenchymal transition in cervical-cancer progression. Cancer Lett. 2015;356:646–55.

    Article  CAS  PubMed  Google Scholar 

  19. Arnold HK, Sears RC. Protein phosphatase 2A regulatory subunit B56α associates with c-Myc and negatively regulates c-Myc accumulation. Mol Cell Biol. 2006;26:2832–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Farrell AS, Sears RC. MYC Degradation. CSH Perspect Med. 2014;4:a014365.

    Google Scholar 

  21. Wang J, Okkeri J, Pavic K, Wang Z, Kauko O, Halonen T, et al. Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56. EMBO Rep. 2017;18:437–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sears R, Leone G, DeGregori J, Nevins JR. Ras enhances Myc protein stability. Mol Cell. 1999;3:169–79.

    Article  CAS  PubMed  Google Scholar 

  23. Seeling JM, Miller JR, Gil R, Moon RT, White R, Virshup DM. Regulation of β-Catenin signaling by the B56 subunit of protein phosphatase 2A. Science. 1999;283:2089–91.

    Article  CAS  PubMed  Google Scholar 

  24. Martinez AKF, Storz P. Mimicking and manipulating pancreatic acinar-to-ductal metaplasia in 3-dimensional cell culture. J Vis Exp. (144), e59096, https://doi.org/10.3791/59096 (2019).

  25. Shi G, DiRenzo D, Qu C, Barney D, Miley D, Konieczny SF. Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia. Oncogene. 2013;32:1950–8.

    Article  CAS  PubMed  Google Scholar 

  26. Tinsley SL, Allen-Petersen BL. PP2A and cancer epigenetics: a therapeutic opportunity waiting to happen. NAR Cancer. 2022;4:zcac002-.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Muthalagu N, Monteverde T, Raffo-Iraolagoitia X, Wiesheu R, Whyte D, Hedley A, et al. Repression of the Type I interferon pathway underlies MYC- and KRAS-dependent evasion of NK and B cells in pancreatic ductal adenocarcinoma. Cancer Discov. 2020;10:872–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Aakula A, Sharma M, Tabaro F, Nätkin R, Kamila J, Honkanen H, et al. RAS and PP2A activities converge on epigenetic gene regulation. Life Sci Alliance. 2023;6:e202301928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vogt M, Stankovic ND, Garcia YC, Hofstetter J, Schneider K, Kuybu F. et al. Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2. Gut. 2024;73:1509–1528.

    Article  CAS  PubMed  Google Scholar 

  30. Thomas D, Radhakrishnan P. Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis. Mol Cancer. 2019;18.

  31. Leonard D, Huang W, Izadmehr S, O'Connor CM, Wiredja DD, Wang Z. Selective PP2A enhancement through biased heterotrimer stabilization. Cell. 2020;181:688–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kemp SB, Cheng N, Markosyan N, Sor R, Kim I-K, Hallin J, et al. Efficacy of a small molecule inhibitor of KrasG12D in immunocompetent models of pancreatic cancer. Cancer Discov. 2022;13:298–311.

    Article  PubMed Central  Google Scholar 

  33. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005;7:469–83.

    Article  CAS  PubMed  Google Scholar 

  34. Hosein AN, Dougan SK, Aguirre AJ, Maitra A. Translational advances in pancreatic ductal adenocarcinoma therapy. Nat Cancer. 2022;3:272–86.

    Article  PubMed  Google Scholar 

  35. Sodir NM, Kortlever RM, Barthet VJA, Campos T, Pellegrinet L, Kupczak S. et al. Myc instructs and maintains pancreatic adenocarcinoma phenotype. Cancer Discov. 2020;10(4):588–607.

    Article  CAS  PubMed  Google Scholar 

  36. Khanna A, Okkeri J, Bilgen T, Tiirikka T, Vihinen M, Visakorpi T, et al. ETS1 mediates MEK1/2-dependent overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) in human cancer cells. PLoS ONE. 2011;6:e17979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 2000;14:2501–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Pavic K, Gupta N, Omella JD, Derua R, Aakula A, Huhtaniemi R, et al. Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A. Nat Commun. 2023;14:1143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cristóbal I, Torrejón B, Madoz-Gúrpide J, Rojo F, García-Foncillas J. PP2A plays a key role in inflammation and cancer through tristetraprolin activation. Ann Rheum Dis. 2017;76:e11.

    Article  PubMed  Google Scholar 

  40. McHugh WM, Russell WW, Fleszar AJ, Rodenhouse PE, Rietberg SP, Sun L, et al. Protein phosphatase 2A activation attenuates inflammation in murine models of acute lung injury. Am J Physiol-Lung Cell Mol Physiol. 2016;311:L903–12.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Clark AR, Ohlmeyer M. Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration. Pharmacol Ther. 2019;201:181–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sangodkar J, Perl A, Tohme R, Kiselar J, Kastrinsky DB, Zaware N, et al. Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth. J Clin Investig. 2017;127:2081–90.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Tohmé R, Izadmehr S, Gandhe S, Tabaro G, Vallabhaneni S, Thomas A, et al. Direct activation of PP2A for the treatment of tyrosine kinase inhibitor–resistant lung adenocarcinoma. JCI Insight. 2019;4:e125693.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kauko O, O’Connor CM, Kulesskiy E, Sangodkar J, Aakula A, Izadmehr S, et al. PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells. Sci Transl Med. 2018;10:eaaq1093.

    Article  PubMed  PubMed Central  Google Scholar 

  45. McClinch K, Avelar RA, Callejas D, Izadmehr S, Wiredja D, Perl A, et al. Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer. Cancer Res. 2018;78:2065–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Avelar RA, Armstrong AJ, Carvette G, Gupta R, Puleo N, Colina JA, et al. Small molecule mediated stabilization of PP2A modulates the Homologous Recombination pathway and potentiates DNA damage-induced cell death. Mol Cancer Ther. 2023;22:599–615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Allen-Petersen BL, Risom T, Feng Z, Wang Z, Jenny ZP, Thoma MC, et al. Activation of PP2A and inhibition of mTOR synergistically reduce MYC signaling and decrease tumor growth in pancreatic ductal adenocarcinoma. Cancer Res. 2018;79:209–19.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Strickler JH, Satake H, George TJ, Yaeger R, Hollebecque A, Garrido-Laguna I, et al. Sotorasib in KRAS p.G12C–mutated advanced pancreatic cancer. N Engl J Med. 2022;388:33–43.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Zhang J, Darman L, Hassan MS, Holzen UV, Awasthi N. Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements provide hope (Review). Oncol Rep. 2023;50:206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Federico AD, Ricciotti I, Favorito V, Michelina SV, Scaparone P, Metro G, et al. Resistance to KRAS G12C inhibition in non-small cell lung cancer. Curr Oncol Rep. 2023;25:1017–29.

    Article  PubMed  Google Scholar 

  51. Aiello NM, Rhim AD, Stanger BZ. Orthotopic injection of pancreatic cancer cells. Cold Spring Harb Protoc. 2016;2016:pdb.prot078360.

    Article  PubMed  Google Scholar 

  52. Chen S, Zhou Y, Chen Y, Gu J. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics. 2018;34:i884–90.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    Article  CAS  PubMed  Google Scholar 

  54. Liao Y, Smyth GK, Shi W. The subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res. 2013;41:e108–e108.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnetJ. 2011;17:10–2.

    Article  Google Scholar 

  57. Li H, Durbin R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics. 2009;25:1754–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ramírez F, Ryan DP, Grüning B, Bhardwaj V, Kilpert F, Richter AS, et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016;44:W160–5.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26:841–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yu G, Wang L-G, He Q-Y. ChIPseeker: an R/Bioconductor package for ChIP peak annotation, comparison and visualization. Bioinformatics. 2015;31:2382–3.

    Article  CAS  PubMed  Google Scholar 

  62. Heberle H, Meirelles GV, Silva FR, da, Telles GP, Minghim R. InteractiVenn: a web-based tool for the analysis of sets through Venn diagrams. BMC Bioinform. 2015;16:169.

    Article  Google Scholar 

  63. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44:W90–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Daniel CJ, Sun X-X, Chen Y, Zhang X, Dai M-S, Sears RC. The Myc gene, methods and protocols. Methods Mol Biol. 2021;2318:69–85.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank the Pasca di Magliano lab (University of Michigan) for providing cell lines and historical histology slides for use; the Sears lab (OHSU) for providing cell lines, antibodies, mouse models, and technical support; the Ogris lab for providing antibodies; and finally, the Narla lab (University of Michigan) for providing antibodies, DT061 stocks, and technical support for experiments. We would like to thank the Purdue Institute for Cancer Research (NIH grant P30 CA023168), the Purdue Histology Core, the Collaborative Core for Cancer Bioinformatics (C3B), and the Purdue Genomics Facility for their contributions to the data produced in this publication. We would also like to thank all the members of the BAP lab for editing of the manuscript and other helpful suggestions. G.N. acknowledges the support of the Rogel Cancer Center and is a Rogel Scholar. RC Sears was supported by NCI U01 CA224012, R01 CA186241, and DoD PA210068 and the Brenden-Colson Center Foundation. S. L. Tinsley was supported by the Frederick N. Andrews Fellowship and the SIRG grant administered through the Institute for Cancer Research. R. A. Shelley and ERD. Chianis were supported by the Institute for Cancer Research Summer Undergraduate Research Experience and support from the Purdue University Institute for Cancer Research, P30CA023168. B. L. Allen-Petersen was supported by the NIH NCI 1K22CA237620-01A1, Pancreatic Cancer Action Network 22-20-ALLE, Concern Foundation, and Ross-Lynn Scholars Research Grant.

Author information

Authors and Affiliations

  1. Purdue University Interdisciplinary Life Sciences Program (PULSe), Purdue University, West Lafayette, IN, USA

    Samantha L. Tinsley, Emily C. Dykhuizen & Brittany L. Allen-Petersen

  2. Department of Biological Sciences, Purdue University, West Lafayette, IN, USA

    Samantha L. Tinsley, Ella Rose D. Chianis, Rebecca A. Shelley, Gaganpreet K. Mall, Garima Baral & Brittany L. Allen-Petersen

  3. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA

    Alisha Dhiman & Emily C. Dykhuizen

  4. Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, USA

    Harish Kothandaraman, Luis Solorio, Nadia Atallah Lanman, Emily C. Dykhuizen & Brittany L. Allen-Petersen

  5. Department of Molecular Medicine and Genetics, Oregon Health and Sciences University, Portland, OR, USA

    Mary C. Thoma, Isabel A. English, Colin J. Daniel & Rosalie C. Sears

  6. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA

    Luis Carlos Sanjuan Acosta & Luis Solorio

  7. Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA

    Nadia Atallah Lanman

  8. Department of Internal Medicine, Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA

    Marina Pasca di Magliano & Goutham Narla

  9. Brenden-Colson Center for Pancreatic Care, Oregon Health and Sciences University, Portland, OR, USA

    Rosalie C. Sears

Authors
  1. Samantha L. Tinsley
    View author publications

    Search author on:PubMed Google Scholar

  2. Ella Rose D. Chianis
    View author publications

    Search author on:PubMed Google Scholar

  3. Rebecca A. Shelley
    View author publications

    Search author on:PubMed Google Scholar

  4. Gaganpreet K. Mall
    View author publications

    Search author on:PubMed Google Scholar

  5. Alisha Dhiman
    View author publications

    Search author on:PubMed Google Scholar

  6. Garima Baral
    View author publications

    Search author on:PubMed Google Scholar

  7. Harish Kothandaraman
    View author publications

    Search author on:PubMed Google Scholar

  8. Mary C. Thoma
    View author publications

    Search author on:PubMed Google Scholar

  9. Isabel A. English
    View author publications

    Search author on:PubMed Google Scholar

  10. Colin J. Daniel
    View author publications

    Search author on:PubMed Google Scholar

  11. Luis Carlos Sanjuan Acosta
    View author publications

    Search author on:PubMed Google Scholar

  12. Luis Solorio
    View author publications

    Search author on:PubMed Google Scholar

  13. Nadia Atallah Lanman
    View author publications

    Search author on:PubMed Google Scholar

  14. Marina Pasca di Magliano
    View author publications

    Search author on:PubMed Google Scholar

  15. Goutham Narla
    View author publications

    Search author on:PubMed Google Scholar

  16. Emily C. Dykhuizen
    View author publications

    Search author on:PubMed Google Scholar

  17. Rosalie C. Sears
    View author publications

    Search author on:PubMed Google Scholar

  18. Brittany L. Allen-Petersen
    View author publications

    Search author on:PubMed Google Scholar

Contributions

BLA-P, RCS, and SLT designed experiments. SLT, ERDC, RAS, GKM, GB, MCT, IAE, CJD, and BLA-P performed and analyzed experiments. GN and MPdM provided key resources. AD, HK, NAL, and ECD performed bioinformatic analysis. LCSA and LS performed image analysis. BLA-P and RCS secured funds and provided supervision. BLA-P and SLT wrote and revised the manuscript. All authors reviewed and finalized the manuscript.

Corresponding author

Correspondence to Brittany L. Allen-Petersen.

Ethics declarations

Competing interests

G.N. receives research support from RAPPTA Therapeutics, and has an equity interest and receives consulting fees from RAPPTA Therapeutics. R.C.S serves on the scientific advisory board for RAPPTA and Larkspur, and receives sponsored research support from Cardiff Oncology and AstraZeneca. L.S. receives sponsored research support from Eli Lilly and Company. All other authors have no potential conflicts of interest.

Ethics approval and consent to participate

All methods were performed in accordance with relevant guidelines and regulations. All animal studies were performed in compliance with Purdue University (West Lafayette, IN) animal use guidelines after approval by the Purdue Institutional Animal Care and Use Committee (PACUC #1910001962).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tinsley, S.L., Chianis, E.R.D., Shelley, R.A. et al. KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development. Oncogene 43, 3673–3687 (2024). https://doi.org/10.1038/s41388-024-03196-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41388-024-03196-w

This article is cited by

Search

Advanced search

Quick links