Understanding programs of invasion and metastasis in head and neck cancer

项目摘要 人类癌症的肿瘤内异质性与不良治疗反应和预后相关。头 颈部鳞状细胞癌（HNSCC）是一种显著异质性肿瘤，新发病例超过55万例 每一年。不幸的是，这种异质性是靶向治疗和治疗的主要挑战 反应，肿瘤内异质性的详细地图刚刚开始定义。在我读博士的时候。培训 与阿扎德·邦尼博士一起，我用复杂的生物化学研究了大脑发育的正常过程。 技术1，2，3，4，这启发了我去理解驱动特定生物程序的信号通路。 我将这些技术应用于神经胶质瘤的研究，最终确定了转录因子STAT 3的双重作用， 肿瘤抑制基因和癌基因5，6，7.为了我的博士后训练，我加入了布拉德利博士的实验室 伯恩斯坦，一位转录、表观遗传学和创新技术方面的专家，联合收割机， 异质性与我在头颈外科肿瘤学的临床兴趣。使用单细胞RNA-seq，我们 定义了HNSCC的第一个图谱，确定了与HNSCC相关的部分上皮-间质（p-EMT）程序， 伴有淋巴结转移、淋巴管浸润和囊外扩张8.我们还改进了肿瘤 从批量RNA-seq方法（如癌症基因组图谱）中进行亚型分型， 数据区.本提案的目的是（1）确定2D和3D头部内的表达异质性 和颈部癌模型，并确定合适的p-EMT模型，（2）研究癌症相关的成纤维细胞及其配体对恶性癌细胞状态的调节影响，包括潜在的转录调控。 和表观遗传机制，以及（3）定义p-EMT下游的信号传导通路，并识别其 在肿瘤行为中的重要作用。 博士Tim Ley和Greg Longmore博士是杰出的导师，在专业领域拥有广泛的学员历史 学术职位。Ley博士是肿瘤学、基因组学和肿瘤生物学领域的国际知名领导者， 任命包括副主任Siteman癌症和麦克唐纳基因组研究所在 华盛顿大学圣路易斯分校（WUSTL），国家癌症咨询委员会成员，前董事会主席 国家基因组研究所的科学顾问。同样，格雷格·朗莫尔博士是一位 分子肿瘤学、EMT和细胞生物学方面的世界专家，被任命为分子生物学和分子生物学联合主任。 肿瘤学和癌症环境研究所，WUSTL的整合通信主任。一个 特殊的研究咨询委员会（RAC）将提供额外的指导，包括王婷博士， Jose Zevallos和Rob Mitra博士。K 08奖将为我提供一个理想的机会，在我的 职业目标。详细的培训计划包括RAC和技术/领导技能的发展， 这对过渡到独立是非常宝贵的。研究将在WUSTL进行，这是一项享有盛誉的研究。 该研究所促进合作，强调智力交流，并拥有无与伦比的设施。

PROJECT SUMMARY Intra-tumoral heterogeneity in human cancers is associated with poor treatment response and prognosis. Head and neck squamous cell carcinoma (HNSCC) is a strikingly heterogeneous tumor, with over 550,000 new cases per year. Unfortunately, this heterogeneity represents a major challenge in targeted therapy and treatment responses, with detailed maps of intra-tumoral heterogeneity just starting to be defined. During my Ph.D. training with Dr. Azad Bonni, I studied normal processes of brain development using sophisticated biochemistry techniques 1,2,3,4, which inspired me to understand the signaling pathways that drive specific biological programs. I applied these skills to studies of glioma, ultimately, defining a dual role for the transcription factor STAT3 as a tumor suppressor and an oncogene 5,6,7. For my post-doctoral training, I joined the laboratory of Dr. Bradley Bernstein, an expert in transcription, epigenetics, and innovative technology, to combine my interests in tumor heterogeneity with my clinical interests in head and neck surgical oncology. Using single cell RNA-seq, we defined the first atlas of HNSCC, identifying a partial epithelial-to-mesenchymal (p-EMT) program associated with lymph node metastasis, lymphovascular invasion, and extracapsular extension8. We also refined tumor subtyping from bulk RNA-seq approaches such as the Cancer Genome Atlas by leveraging our single cell profiles. The objectives of this proposal are to (1) determine expression heterogeneity within 2D and 3D head and neck cancer models and identify suitable models of p-EMT, (2) investigate the regulatory influence of cancer-associated fibroblasts and their ligands on malignant cancer cell states, including the underlying transcriptional and epigenetic mechanisms, and (3) define the signaling pathways downstream of p-EMT and discern their functional importance in tumor behaviors. Dr. Tim Ley and Dr. Greg Longmore are exceptional mentors with an extensive history of trainees in major academic positions. Dr. Ley is an internationally renowned leader in oncology, genomics, and tumor biology, with appointments including Associate Director of the Siteman Cancer and the McDonnell Genome Institute at Washington University St. Louis (WUSTL), National Cancer Advisory Board Member, and former Chair of Board of Scientific Counselors for National Institute Genome Research Institute. Similarly, Dr. Greg Longmore is a world expert in molecular oncology, EMT, and cell biology, with appointments as Co-Director of Molecular Oncology and Director of the Integrating Communications within the Cancer Environment Institute, WUSTL. An exceptional Research Advisory Committee (RAC) will provide additional guidance, including Dr. Ting Wang, Dr. Jose Zevallos, and Dr. Rob Mitra. The K08 award will provide me with the ideal opportunity to succeed in my career goals. The detailed training plan includes a RAC and development of technical/leadership skills that will be invaluable for a transition to independence. Research will be carried out at WUSTL, a prestigious research institute that fosters collaboration, emphasizes intellectual exchange, and boasts unparalleled facilities.