Smad4-independent TGF-b signaling in p16-negative HNSCC

p16 阴性 HNSCC 中不依赖 Smad4 的 TGF-b 信号传导

• 批准号: 8700647
• 负责人: CHRISTINE H CHUNG
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700647
• 关键词: Alcohol consumption; Biological; Biological Markers; Bone Morphogenetic Proteins; CDKN2A gene; Cell Cycle; Cell Line; Cells; Clinical; Clinical Treatment; Clinical Trials; Complex; Dependence; Development; Evaluation; Event; Future; Gene Expression; Genes; Genetic; Head and Neck Squamous Cell Carcinoma; Health; Histology; Human Papillomavirus; Human papilloma virus infection; In Vitro; Incidence; Investigation; Knock-in Mouse; Laboratories; Ligands; MADH4 gene; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Mus; Neoplasm Metastasis; Nuclear; Nuclear Translocation; Oncogenic; Oral cavity; Outcome; Pathway interactions; Patient Selection; Patients; Phenotype; Phosphotransferases; Play; Primary Neoplasm; Proliferating; Regulation; Risk Factors; Role; Second Messenger Systems; Signal Transduction; Smad4 Protein; Staging; Stimulus; Surrogate Markers; Survival Rate; Techniques; Tobacco use; Transcriptional Regulation; Transforming Growth Factor beta; Variant; clinically significant; epithelial to mesenchymal transition; experience; human disease; improved; in vivo; inhibitor/antagonist; keratinocyte; keratinocyte differentiation; meetings; metastatic process; mouse model; new therapeutic target; novel therapeutics; outcome forecast; patient population; response; second messenger; treatment response; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide, and risk factors for development include tobacco use, alcohol consumption, and human papillomavirus (HPV) infection. Patients with HPV positive (+)/p16 (+) tumors have a favorable prognosis [3-year overall survival (OS): ~80%] while patients with HPV-negative (-) tumors of similar stage, typically p16-negative (-), experience a worse OS (~50%). Consequently, there is a great need to improve the treatment and clinical response of HPV (-)/p16 (-) patients. Smad4 (or DPC4) plays a central role in transforming growth factor-beta (TGF-ß) signaling. Recently, conditional Smad4 loss (Smad4-/-) in the mouse oral cavity was shown to cause spontaneous tumors with histology reminiscent of the human disease. In our preliminary investigations, Smad4 expression status was found to be differentially expressed across a panel of HNSCC cell lines and associated with epithelial-to- mesenchymal transition (EMT). Additionally, stable knockdown (KD) of Smad4 induced EMT-like phenotypes and increased invasion. After stimulation with TGF-ß1, SCC25-Smad4 KD and FaDu (Smad4-null HNSCC cell line) demonstrated enhanced activation of Smad2 compared to SCC25-scramble control. We also determined Smad4 loss was evident in 14/77 (18%) tumors obtained from HNSCC patients demonstrating a significant association with p16 (-) tumors [13/53, 25% of p16 (-) vs. 1/24, 4% of p16 (+)]. As p16 positivity is a strong surrogate marker for HPV infection, the vast majority of Smad4 (-) tumors are HPV (-). Patients with Smad4 (-) tumors experienced poor survival and an increased incidence of metastasis. In this application, we propose to; 1) determine the mechanism of Smad4-independent Smad2 activation and its effect on TGF-ß inhibitor sensitivity in HNSCC, and 2) determine the role of Smad4-independent Smad2 activation in the metastatic process using an in vivo orthotopic mouse model which allows for an unbiased evaluation of tumor- microenvironment interactions. Identification of novel therapeutic targets and predictive biomarkers of response will allow for appropriate patient selection in future clinical trials, and potentially impact the survival of HNSCC patients with particularly poor clinical outcome.

描述（由申请人提供）：头颈鳞状细胞癌 (HNSCC) 是全球第六大常见癌症，其发生的危险因素包括吸烟、饮酒和人乳头状瘤病毒 (HPV) 感染。 )/p16 (+) 肿瘤预后良好 [3 年总生存 (OS)：约 80%]，而具有相似分期的 HPV 阴性 (-) 肿瘤（通常为 p16 阴性）患者(-)，经历了较差的 OS (~50%)，因此非常需要改善 HPV (-)/p16 (-) 患者的治疗和临床反应，Smad4（或 DPC4）在其中发挥着核心作用。最近，小鼠口腔中的条件性 Smad4 缺失 (Smad4-/-) 被证明会导致自发性肿瘤，其组织学类似于人类疾病。研究发现，Smad4 的表达状态在一组 HNSCC 细胞系中存在差异表达，并且与上皮间质转化 (EMT) 相关。此外，Smad4 的稳定敲低 (KD) 会诱导 EMT 样表型并在 TGF 刺激后增加侵袭。 -ß1、SCC25-Smad4 KD 和 FaDu（Smad4-null HNSCC 细胞系）与 SCC25-scramble 对照相比，Smad2 的激活增强。我们还确定，在从 HNSCC 患者获得的 14/77 (18%) 肿瘤中，Smad4 丢失很明显，证明与 p16 (-) 肿瘤显着相关 [13/53，p16 (-) 的 25% vs. 1/24，4% p16 (+)] 作为 p16 阳性的有力替代标记。 HPV 感染，绝大多数 Smad4 (-) 肿瘤是 HPV (-)。在本申请中，我们建议： 1) 确定 Smad4 的机制； -HNSCC 中独立的 Smad2 激活及其对 TGF-β 抑制剂敏感性的影响，以及 2) 使用体内原位小鼠模型确定独立于 Smad4 的 Smad2 激活在转移过程中的作用它可以对肿瘤-微环境相互作用进行公正的评估，从而可以在未来的临床试验中选择适当的患者，并可能影响临床结果特别差的 HNSCC 患者的生存。