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MK2 Activation Research

MK2 Activation research by Gregory N. Gan, M.D., Ph.D., Junior Faculty, Kansas Institute for Precision Medicine COBRE.

Tumor metastasis (when cancer spreads to another organ or system) is devastating for cancer patients. Tumor metastasis is the major cause of cancer related death in head and neck squamous cell carcinoma (HNSCC) patients in the US. An important biologic and clinical question in cancer is: what cellular pathways become activated leading to treatment resistance and how is cancer metastasis regulated? Epithelial-to-mesenchymal transition (EMT) is thought to potentially regulate both processes. We have identified the MAPKAPK2 (MK2) pathway as a potential regulator of radiation-mediated tumor EMT. However, it remains unknown what effect MK2 activation has on:

  1. tumor specific gene expression pathway
  2. whether MK2 pathway is necessary for generating circulating tumor cells (CTCs); and
  3. whether MK2 can be used as a biomarker to predict local or distant cancer recurrence.

The objective of this project is to determine if HNSCC EMT can regulate tumor metastasis via MK2 pathway activation. We think that MK2 activation is crucial.

This work has two main objectives.

  1. Increase our knowledge of MK2 biology (with and without radiotherapy). We want to know how it can directly affect the DNA methylome through epithelial gene silencing and EMT gene expression. We also want to learn how the MK2 pathway can regulate tumor growth, EMT and the production of circulating tumor cells (CTCs). Will high MK2 phosphorylation levels predict HNSCC patient survival?

  2. Begin preclinical testing of repurposed or novel compounds which can target and disrupt the p38-MK2 interaction.

The significance of studying MK2 biology will provide a better understanding of how tumor EMT can regulate treatment resistance and metastasis. The clinical impact of this work will allow us to develop better treatment strategies. We want to improve tumor control and long-term patient survival. The long-term research goal is to identify the molecular determinants involved in HNSCC metastasis. We want to identify targets for drugs to address this problem. This preclinical work will lay the foundation for a future precision medicine clinical trial.

Anti-oxidant metabolism Cell proliferation EMT Inflammatory cytokine production
Anti-oxidant metabolism Cell proliferation EMT Inflammatory cytokine production.

Research Publications

Anti-oxidant metabolism Cell proliferation EMT Inflammatory cytokine production.

Berggren KL, Restrepo Cruz S, Hixon MD, Cowan A, Keysar SB, Craig S, James J, Barry M, Ozbun MA, Jimeno A, McCance DJ, Beswick EJ, Gan GN. MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma. Oncogene. 2019 Aug 15. Epub PMID: 31417185

Ray AL, Berggren KL, Restrepo Cruz S, Gan GN, Beswick EJ. Inhibition of MK2 suppresses IL-1, IL-6, and TNF- dependent colorectal cancer growth. Int J Cancer. 2018 Apr 15;142(8):1702-1711. PMID: 29197088

Gan GN, Eagles J, Keysar SB, Wang G, Glogowska MJ, Altunbas C, Anderson RT, Le PN, Morton JJ, Frederick B, Raben D, Wang XJ, Jimeno A. Hedgehog signaling drives radioresistance and stroma-driven tumor repopulation in head and neck squamous cancers. Cancer Res 2014 Dec 1;74(23)

Gregory Gan portrait
Gregory N. Gan, M.D., Ph.D.
Assistant Professor, Department of Radiation Oncology and Department of Cancer Biology, University of Kansas School of Medicine
Director of Technology and Oligometastasis Program
Junior Faculty, Kansas Institute for Precision Medicine COBRE
Professor, Pathology & Laboratory Medicine