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: 8889662
• 负责人: CHRISTINE H CHUNG
• 金额: $ 4.1万
• 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 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889662
• 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; differential expression; 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; receptor; 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-�) 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-�1, 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-� 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(申请人提供)：头颈部鳞状细胞癌(HNSCC)是全球第六大最常见的癌症，发病的风险因素包括吸烟、饮酒和人类乳头瘤病毒(HPV)感染。HPV阳性(+)/p16(+)肿瘤患者预后良好[3年总生存率(OS)：~80%]，而HPV阴性(-)肿瘤患者预后较差(~50%)。因此，迫切需要提高对HPV(-)/p16(-)患者的治疗水平和临床疗效。Smad4(或DPC4)在转化生长因子-β(TGFR-�)信号转导中起核心作用。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，其组织学特征与人类疾病相似。在我们的初步研究中，我们发现Smad4的表达状态在一组HNSCC细胞系中差异表达，并与上皮向间充质转化(EMT)相关。此外，稳定的Smad4基因敲除(KD)诱导了EMT样表型和更多的侵袭。经转化生长因子-�1刺激后，SCC25-Smad4KD和FaDu(Smad4缺失的HNSCC细胞系)与SCC25-Smad4对照相比，Smad2的激活增强。我们还发现，从HNSCC患者获得的肿瘤中有14/77(18%)存在明显的Smad4缺失，表明与p16(-)肿瘤显著相关[13/53，25%的p16(-)对1/24，4%的p16(+)]。因为p16阳性是一个很强的替代标记物 HPV感染，绝大多数Smad4(-)肿瘤为HPV(-)。患有Smad4(-)肿瘤的患者存活率低，转移率增加。在这一应用中，我们建议：1)确定Smad4非依赖的Smad2激活的机制及其对转化生长因子-�抑制物敏感性的影响；2)使用体内原位小鼠模型确定Smad4非依赖的Smad2激活在转移过程中的作用，该模型允许对肿瘤与微环境的相互作用进行公正的评估。识别新的治疗靶点和预测反应的生物标志物将允许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。