Cancer cell signaling – Westermarck Lab
Group Leader
Jukka Westermarck
Research Director and Professor of Cancer Biology,
Turku Bioscience
Contact Information
Turku Bioscience P.O. Box 123, BioCity
(Street addr. Tykistökatu 6 B)
FIN-20521 Turku, Finland
+358-294502880 (Jukka Westermarck)
+358-294503790 (Group members)
@westermarcklab.bsky.social Description of the Research
Most characteristics of malignant cell growth are driven by phosphorylation-dependent signaling pathways that are deregulated in cancer cells. Whereas the regulation and function of many oncogenic kinases are well understood, the roles of protein phosphatases in cancer initiation, progression and therapy resistance are yet poorly understood.The focus of our laboratory is to understand the role and regulation of PP2A and other phosphatases in human cancers, and especially function of PP2A inhibitor proteins as human oncoproteins. To achieve this, we use a combination of advanced cell and molecular biology approaches combined with genetically modified mouse cancer models.
We also have special interest on targeted therapies against PP2A inhibitor proteins. Our laboratory identified CIP2A as a novel PP2A inhibitor protein in human malignancies (Cell, 2007), and was the first to demonstrate cancer-promoting roles for both CIP2A and another PP2A inhibitor protein PME-1 (Cancer Research, 2009). Expression of both of these proteins shows a strong association with tumor progression in human patients (Cancer Discovery 2013, Cancer Res. 2021) and their high expression is linked to cancer drug resistance (Cancer Res. 2016, Sci.Transl. Med, 2018). Based both on these results, and on wide-spectrum role of PP2A on cellular signaling, we hypothesize that re-activation of PP2A, via targeting of its endogenous inhibitory proteins such as CIP2A, could be used as a general strategy for multi-target inhibition of chemoresistance in common human cancer types (Sci. Transl. Med. 2021). Our laboratory continues exploring structural determinants of CIP2A to facilitate its targeting (Nat. Comm 2023). On the other hand, inhibition of oncogneic phoshatases, such as DUSP6, appears also a potent novel cancer therapy approach (Embo Mol. Med., 2024).
Funding
The Academy of Finland,
Jane and Aatos Erkko Foundation,
University of Turku Graduate School,
Sigrid Juselius Foundation
Cancer Research Foundation of Finland
Selected Publications
CIP2A inhibits PP2A in human malignancies
Junttila MR, Puustinen P, Niemelä M, Ahola R, Arnold H, Böttzauw T, Ala-aho R, Nielsen C, Ivaska J, Taya Y, Lu SL, Lin S, Chan EKL, Wang XJ, Grénman R, Kast J, Kallunki T, Sears R, Kähäri VM, Westermarck J — Cell. 2007 Jul 13;130(1):51-62
PubMedPME-1 protects ERK pathway activity from PP2A-mediated inactivation in human malignant glioma
Puustinen P, Junttila MR, Vanhatupa S, Sablina AA, Hector ME, Teittinen K, Raheem O, Ketola K, Lin S, Kast J, Haapasalo H, Hahn WC, Westermarck J — Cancer Res. 2009 Apr 1;69(7):2870-2877
PubMedSenescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1
Laine A, Sihto H, Come C, Rosenfeldt MT, Zwolinska A, Niemelä M, Khanna A, Chan EK, Kähäri VM, Kellokumpu-Lehtinen PL, Sansom OJ, Evan GI, Junttila MR, Ryan KM, Marine JC, Joensuu H, Westermarck J — Cancer Discov. 2013 Jan 10;3(2):182-197
PubMedCIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis
Laine A, Nagelli SG, Farrington C, Butt U, Cvrljevic AN, Vainonen JP, Feringa FM, Grönroos TJ, Gautam P, Khan S, Sihto H, Qiao X, Pavic K, Connolly DC, Kronqvist P, Elo LL, Maurer J, Wennerberg K, Medema RH, Joensuu H, Peuhu E, de Visser KE, Narla G, Westermarck J — Cancer Res. 2021 Aug 15;81(16):4319-4331
PubMedPP2A inhibitor PME-1 drives kinase inhibitor resistance in glioma cells
Kaur A, Denisova OV, Qiao X, Jumppanen M, Peuhu E, Ahmed SU, Raheem O, Haapasalo H, Eriksson J, Chalmers AJ, Laakkonen P, Westermarck J — Cancer Res. 2016 Dec 1;76(23):7001-7011
PubMedPP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells
Kauko O, O’Connor CM, Kulesskiy E, Sangodkar J, Aakula A, Izadmehr S, Yetukuri L, Yadav B, Padzik A, Laajala TD, Haapaniemi P, Momeny M, Varila T, Ohlmeyer M, Aittokallio T, Wennerberg K, Narla G, Westermarck J — Sci Transl Med. 2018 Jul 18;10(450):eaaq1093
PubMedDruggable cancer phosphatases
Vainonen JP, Momeny M, Westermarck J — Sci Transl Med. 2021 Apr 7;13(588):eabe2967
PubMedStructural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
Pavic K, Gupta N, Domènech Omella J, Derua R, Aakula A, Huhtaniemi R, Määttä JA, Höfflin N, Okkeri J, Wang Z, Kauko O, Varjus R, Honkanen H, Abankwa D, Köhn M, Hytönen VP, Xu W, Nilsson J, Page R, Janssens V, Leitner A, Westermarck J — Nat Commun. 2023 Feb 28;14(1):1143
PubMedDUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer
Momeny M, Tienhaara M, Sharma M, Chakroborty D, Varjus R, Takala I, Merisaari J, Padzik A, Vogt A, Paatero I, Elenius K, Laajala TD, Kurppa KJ, Westermarck J — EMBO Mol Med. 2024 Jul;16(7):1603-1629
PubMed
