Investigating the role of the Notch atypical ligand delta-like homologue 1 (DLK1) in adrenocortical carcinoma

肾上腺皮质癌(ACC)是一种罕见的侵袭性肿瘤，发生在肾上腺皮质，肾上腺皮质是产生类固醇的外层。早期诊断和手术切除是长期生存的关键。在许多病例中，癌症在确诊时已经扩散，预后黯淡，晚期疾病的五年存活率低于15%。唯一被批准的药物治疗是米托坦，但它的耐受性很差，往往无法阻止疾病的进展。正确识别ACC对于确保其及时管理是非常重要的。目前的做法是根据临床、生化和放射学特征预测恶性肿瘤。一旦肿块被切除，组织学诊断是基于肿瘤的性质和对恶性潜能的进一步预测。这通常是复杂的，特别是在边缘案件中。因此，寻找新的有助于疾病诊断、预后和监测的生物标志物是非常重要的。目前尚不清楚哪些细胞参与了ACC的发展，也不知道已建立的肿瘤中的哪些细胞对化疗药物具有耐药性，并可能导致肿瘤的复发。我们最近在肾上腺中发现了一组新的细胞，我们认为这可能是肾上腺癌的前兆。这些细胞表达一种名为类增量同源1(DLK1)的蛋白质。DLK1通常不存在于大多数健康的人体组织中。然而，DLK1在其他恶性肿瘤中的表达也有报道，在其中一些肿瘤中，DLK1的表达增加与预后较差有关。这使得DLK1不仅作为ACC的一个新的生物标志物，而且作为这种恶性肿瘤的发展的参与者以及作为新的治疗干预的潜在靶点，成为一个有吸引力的进一步研究的选择。在这个项目中，我将从两个方面研究DLK1在肾上腺皮质癌中的作用。首先，我将研究它在这种情况下作为潜在的新生物标记物的作用。我将通过观察采集的肿瘤样本和血液中DLK1的表达，看看是否与存活率以及疾病的临床和生化表现有关。此外，我还将观察DLK1+的肾上腺皮质癌细胞，并描述它们与癌症中其他细胞的不同之处。为了实施这个项目，我与德国研究这种疾病的最大团队之一(维尔茨堡大学法斯纳赫特教授)以及我当地的病理学部门开展了合作，以获得超过100个ACC的组织切片以及临床记录，以评估呈现的细节和长期结果。我正在从伦敦的四个外科中心收集ACC肿瘤样本。从我们当地的医院，我也从其他非癌症疾病的手术患者身上收集正常的肾上腺组织。此外，我将使用两个新的患者来源的肾上腺皮质癌细胞株进行实验，该细胞系是通过与科罗拉多大学丹佛大学合作开发的，此外还有商业上可用的H295R细胞系。这个项目将细胞生物学研究与临床重点相结合。它有望识别和表征一种新的用于ACC诊断和预后的分子生物标记物，提供定义这种恶性肿瘤的细胞群的新生物学，并识别可能服从于新的治疗干预的靶点。

Adrenocortical carcinoma (ACC) is a rare, aggressive tumour occurring in the adrenal cortex, the steroid-producing outer layer of the adrenal gland. Early diagnosis and surgical resection is crucial to long-term survival. In many cases, the cancer has spread by the time of diagnosis and the prognosis is bleak, with five-year survival rate in advanced disease under 15%. The only approved medical treatment is the drug mitotane but it is poorly tolerated and often fails to prevent disease progression. It is important to correctly identify ACC to ensure its prompt management. Current practice revolves around prediction of malignancy based upon clinical, biochemical and radiological features. Once a mass has been removed, histological diagnosis is based upon properties of the tumour and a further prediction of malignant potential. This is often complex especially in borderline cases. Therefore it is important to identify new biological markers that can aid in the diagnosis, prognosis and monitoring of disease. It is not known which cells are involved in the development of ACC, nor is it known which cells within an established tumour confer resistance to chemotherapeutic drugs and may be responsible for tumour relapse. We have recently identified a novel population of cells in the adrenal gland, which we believe might be the precursor of adrenal cancer. These cells express a protein called delta-like homologue 1 (DLK1). DLK1 is not normally found in most healthy human tissues. However, expression has been reported in other malignancies and in some of these increased DLK1 expression is associated with a worse prognosis. This makes it an attractive option for further investigation not only as a novel biomarker in ACC but also as a player in the development of this malignancy and as such a potential target for novel therapeutic intervention.In this project I will be investigating the role of DLK1 in adrenocortical carcinoma on two fronts. First, I will be studying its role as a potential novel biomarker in this condition. I will be doing this by looking at expression of DLK1 in collected tumour samples and in blood and seeing if there is a relationship with survival rates as well as clinical and biochemical presentation of disease. In addition, I will also be looking at DLK1+ adrenocortical carcinoma cells and characterising how they differ from other cells in the cancer.To carry out this project, I have developed collaborations with one of the largest groups investigating this condition from Germany (Prof. Fassnacht, University of Würzburg) and also my local pathology department to gain access to over 100 tissue sections of ACC along with the clinical records to assess details of presentation and long-term outcomes.I am collecting ACC tumour samples from four surgical centres across London. From our local hospital I am also collecting normal adrenal tissue from patients having surgery for other non-cancerous pathologies. In addition, I will be performing experiments using two new patient derived adrenocortical carcinoma cells lines through a collaboration developed with University of Colorado Denver in addition the commercially available, H295R cell line.This project combines cellular biological investigation with a clinical focus. It has the promise to identify and characterise a new molecular biomarker for diagnosis and prognosis of ACC, to deliver new biology defining a cell population in this malignancy and to identify targets which may be amenable to novel therapeutic intervention.