The Role of MK2 pathway on head and neck cancer epithelial-to-mesenchymal transiston and tumor metastasis

肿瘤转移对所有癌症患者来说仍然是一个毁灭性的问题，也是美国头颈部鳞状细胞癌（HNSCC）患者癌症相关死亡的主要原因。一个重要的生物学和临床问题是肿瘤的转移和治疗抵抗是如何调节的。调节这两个过程的一种机制是上皮-间质转化（EMT）。我们已经确定MAPKAPK2 （MK2）通路是辐射介导的肿瘤EMT的潜在调节因子。然而，MK2激活通过DNA甲基化对上皮基因沉默的影响尚不清楚；MK2通路对循环肿瘤细胞（ctc）的生成是否重要；MK2是否可以作为预测HNSCC患者无转移生存期的生物标志物。本研究的目的是确定HNSCC EMT是否可以通过MK2通路激活来调节肿瘤转移。我们假设MK2激活可以通过上皮基因沉默增加HNSCC转移，通过EMT上调ctc，并作为转移性或复发性HNSCC的预后标志物。我们建议的工作集中在两个具体目标上。首先，使用MK2野生型和敲除细胞系（在有或没有放疗的情况下）增加我们对MK2生物学的了解，以及它如何通过上皮基因沉默和EMT基因表达直接影响DNA甲基组；MK2活化如何调节肿瘤生长、EMT和循环肿瘤细胞（CTCs）的产生；以及高MK2磷酸化水平是否可以预测HNSCC患者的局部区域和远处无转移生存。其次，我们已经获得了一种经过I期测试的MK2抑制剂，我们将开始对这种化合物进行放射治疗的临床前测试。研究MK2生物学的意义将为肿瘤EMT调控治疗耐药和促进转移提供更好的体内生物学机制。这项工作的总体临床影响将使我们能够制定更好的治疗策略，旨在改善肿瘤控制和患者的长期生存。我的长期研究目标是确定参与HNSCC转移的分子决定因素，并确定可药物靶点来解决这一重大问题。这项临床前工作将为未来的精准医学试验奠定基础，该试验旨在对表达高MK2磷酸化的患者进行分层，并使用MK2抑制剂和放疗进行积极干预。

Tumor metastasis remains a devastating problem for all cancer patients and 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 is how tumor metastasis and treatment resistance are regulated. One mechanism that can regulate both these processes is epithelial-to-mesenchymal transition (EMT). 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 epithelial gene silencing through DNA methylation; whether MK2 pathway is important for generation of circulating tumor cells (CTCs); and whether MK2 can be used as a biomarker to prognosticate HNSCC patient metastasis-free survival. The objective of this current proposal is to determine if HNSCC EMT can regulate tumor metastasis via MK2 pathway activation. We hypothesize that MK2 activation can increase HNSCC metastasis through epithelial gene silencing, upregulation of CTCs via EMT and serve as a prognostic marker for metastatic or recurrent HNSCC. Our proposed work is focused on two specific goals. First, increase our knowledge of MK2 biology using MK2 wildtype and knockout cell lines (in the presence or absence of radiotherapy) and how it can directly affect the DNA methylome through epithelial gene silencing and EMT gene expression; how MK2 activation can regulate tumor growth, EMT and the production of circulating tumor cells (CTCs); and whether high MK2 phosphorylation levels can prognosticate HNSCC patient loco-regional and distant metastasis-free survival. Second, we have access to a Phase I tested MK2 inhibitor which we will begin preclinical testing of this compound with radiotherapy. The significance of studying MK2 biology will provide a better in vivo biological mechanism linking how tumor EMT can regulate treatment resistance and facilitate metastasis. The overall clinical impact of this work will allow us to develop better treatment strategies aimed at improving tumor control and long-term patient survival. My long-term research goal is to identify the molecular determinants involved in HNSCC metastasis and to identify druggable targets to address this significant problem. This preclinical work will lay the foundation for a future precision medicine trial aimed at stratifying patients who express high MK2 phosphorylation for active intervention with a MK2 inhibitor and radiotherapy.