Quiescence and epithelial-mesenchymal transition in HNSCC

大多数头颈部鳞状细胞癌（HNSCC）患者在治疗和切除原发肿瘤后数月、数年甚至数十年将死于由播散性肿瘤细胞（DTC）发展的转移。在原发性肿瘤切除后的几年内，即使手术切缘没有癌症，大约50%的患者也会发生远处器官或局部复发。这种潜伏期表明DTC在未来转移的部位以休眠、非增殖状态存活。这种状态被称为静止，一种非承诺的和可逆的生长停滞，可以由不同的，主要是压力相关的信号引起。导致这种静止的诱导和维持，从而导致后来转移形成的因素尚未得到严格的研究。大多数HNSCC患者患有肺和淋巴结转移，而骨转移非常罕见。然而，在>30%的HNSCC患者中，在骨髓中可检测到DTC。为了首先到达这些遥远的部位，这些上皮细胞必须获得移动性。他们通过上皮间质转化（EMT）实现这一点，EMT是一种高度保守的胚胎细胞程序，允许上皮细胞获得间质性状，如流动性和侵袭性。与此同时，细胞经历细胞周期停滞，限制了它们的增殖。最近显示，应激激活的蛋白激酶p38细胞调节体内HNSCC中延长静止期的程序的诱导。在另一项研究中，p38的药理学抑制导致EMT转录因子（TF）Snail、Slug和ZEB的基因表达减少。本研究表明，诱导休眠和调节EMT的关键转录因子之间的可能联系。本研究的目的是确定的机制，调节进入和退出的静止DTC和阐明可能的连接与因素导致或维持HNSCC的EMT。我将在已经建立的HNSCC小鼠模型中测试，所提出的休眠调节剂是否与骨髓DTC的静止相关联，而不是与肺和淋巴结中DTC的生长相关联。我将进一步测试细胞因子TGF β 2的上调是否在HNSCC静止诱导中起作用，因为它已被鉴定为人类乳腺癌中休眠基因签名的一部分，并且是维持骨髓干细胞静止所必需的。由于TGF β信号也是一种已知的EMT诱导因子，我将阐明已知的EMT和静止诱导转录因子之间是否存在串扰。这样，我们也许有一天能够设计出一种治疗方法，（I）使DTC保持永久静止，从而使患者保持慢性但无症状的微小残留疾病，或者（II）选择性地靶向这些静止DTC部署的生存机制以根除它们。

The majority of head and neck squamous cell carcinoma (HNSCC) patients will die of metastases that develop from disseminated tumor cells (DTCs), months, years or even decades after treatment and removal of the primary tumor. Within years after primary tumor resection, approximately 50% of patients develop distant organ or loco regional recurrences, even if the surgical margins were free of cancer. This latency suggests that DTCs survive in a dormant, non-proliferative state at the site of future metastases. This state is known as quiescence, an uncommitted and reversible growth arrest that can be brought about by different, mostly stress associated, signals. The factors leading to induction and upkeep of this quiescence, and thus to the formation of metastases later on, have not been toughly investigated, yet. Most HNSCC patients suffer from lung and lymph node metastases, while bone metastases are very rare. Yet in >30% of HNSCC patients, DTCs are detectable in the bone marrow. In order to reach these distant sites in the first place, these epithelial cells have to acquire mobility. They achieve this through an epithelial mesenchymal transition (EMT), a highly conserved embryonic cellular program which allows epithelial cells to acquire mesenchymal traits like mobility and invasiveness. At the same time, cells undergo a cell-cycle arrest, limiting their proliferation.The stress activated protein kinase p38 cells was recently shown to regulate the induction of a program of prolonged quiescence in HNSCC in vivo. In a different study, the pharmacological inhibition of p38 led to a reduced gene expression of the EMT transcription factors (TF) Snail, Slug and ZEB. This research demonstrates a possible connection between the induction of dormancy and regulation of transcription factors crucial in EMT.The aim of this research is to identify the mechanisms regulating entry and exit of quiescence in DTCs and elucidate the possible connection with factors leading to or maintaining an EMT in HNSCC. I will test in an already established HNSCC mouse model, whether proposed dormancy regulators are linked to quiescence in bone marrow DTCs vs. growth of DTCs in lungs and lymphnodes. I will further test if the upregulation of the cytokine TGFbeta2 plays a part in HNSCC quiescence induction, since it has been identified as part of a dormancy gene signature in human breast cancer and is required to maintain bone marrow stem cells in quiescence. As TGFbeta signaling is also a known inducer of EMT, I will elucidate if there is crosstalk between known EMT and quiescence inducing transcription factors.It is of utmost importance to understand the quiescence of these DTCs. This way we may one day be able to devise a treatment that (I) either keeps the DTCs in permanent quiescence, thus keeping the patient in chronic yet asymptomatic minimal residual disease, or (II) selectively targets the survival mechanisms deployed by these quiescent DTCs to eradicate them.