Understanding programs of invasion and metastasis in head and neck cancer

了解头颈癌的侵袭和转移程序

基本信息

批准号：
10679102
负责人：
Sidharth Venkata Puram
金额：
$ 16.39万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-10-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10679102
关键词：
3-Dimensional Advisory Committees Applied Skills Appointment Atlases Automobile Driving Award Biochemical Biochemistry Biological Biological Assay Brain CRISPR/Cas technology Cancer Model Cell Line Cells Cellular Assay Cellular biology Cessation of life ChIP-seq Chemicals Chromatin Clinical Coculture Techniques Collaborations Communication Complement Cultured Cells Data Set Development Disease Distant Metastasis Doctor of Philosophy Drug Design Enhancers Environment Epigenetic Process Epithelium Extracapsular FGF7 gene Fibroblasts Flow Cytometry Fostering Gene Expression Genes Genetic Transcription Genome Genomics Glioma Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and Neck Surgery Heterogeneity Histone Acetylation Histone H3 Human ITGA5 gene Immune In Vitro International Invaded LAMC2 gene Laboratories Leadership Ligands Link Lysine MMP2 gene Malignant - descriptor Malignant Neoplasms Maps Mass Spectrum Analysis Mediating Mentors Mesenchymal Metastatic Neoplasm to Lymph Nodes Microfluidic Microchips Modeling Morbidity - disease rate National Cancer Advisory Board Neoplasm Metastasis Oncogenes Oncology Operative Surgical Procedures Pathway interactions Patients Phenotype Population Positioning Attribute Process Professional counselor Prognosis Proliferating Radiation therapy Recording of previous events Regulation Reporter Research Research Institute Research Proposals Role STAT3 gene Signal Pathway Signal Transduction Solid Neoplasm Sorting Stromal Cell-Derived Factor 1 Surgical Oncology TGFBI gene Techniques Testing The Cancer Genome Atlas Training Transcriptional Regulation Transforming Growth Factor beta Translating Transposase Treatment outcome Tumor Biology Tumor Cell Invasion Tumor Subtype Tumor Suppressor Proteins Universities Washington advanced disease cancer cell career chemotherapy differential expression epigenetic regulation experimental study in vivo inhibitor innovation innovative technologies interest lymph nodes lymphatic Invasion member molecular oncology mortality neoplastic cell novel therapeutics overexpression patient derived xenograft model pharmacologic post-doctoral training programs receptor single-cell RNA sequencing skills small hairpin RNA small molecule targeted treatment therapeutically effective transcription factor transcriptome sequencing treatment response tumor tumor behavior tumor heterogeneity

项目摘要

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.

项目概要人类癌症的肿瘤内异质性与不良的治疗反应和预后相关。头颈部鳞状细胞癌 (HNSCC) 是一种异质性惊人的肿瘤，新增病例超过 550,000 例每年。不幸的是，这种异质性代表了靶向治疗和治疗的重大挑战反应，肿瘤内异质性的详细图谱刚刚开始被定义。在我攻读博士学位期间训练我和 Azad Bonni 博士一起利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，它启发我了解驱动特定生物程序的信号通路。我将这些技能应用到神经胶质瘤的研究中，最终定义了转录因子 STAT3 的双重作用：肿瘤抑制基因和癌基因 5,6,7。为了进行博士后训练，我加入了 Bradley 博士的实验室 Bernstein，转录、表观遗传学和创新技术方面的专家，结合我对肿瘤的兴趣异质性与我对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，确定了相关的部分上皮间质 (p-EMT) 程序伴有淋巴结转移、淋巴管侵犯和囊外扩展8。我们还细化了肿瘤利用我们的单细胞从批量 RNA 测序方法（例如癌症基因组图谱）中进行亚型分析配置文件。该提案的目标是 (1) 确定 2D 和 3D 头部内的表达异质性和颈部癌症模型并确定合适的 p-EMT 模型，（2）研究癌症相关成纤维细胞及其配体对恶性癌细胞状态的调节影响，包括潜在的转录和表观遗传机制，(3) 定义 p-EMT 下游的信号通路并辨别其肿瘤行为中的功能重要性。 Tim Ley 博士和 Greg Longmore 博士是杰出的导师，在专业领域拥有丰富的学员经验学术职位。 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 Siteman 癌症和麦克唐纳基因组研究所副主任圣路易斯华盛顿大学 (WUSTL)，国家癌症咨询委员会成员，前委员会主席国家研究所基因组研究所科学顾问。同样，格雷格·朗莫尔博士是分子肿瘤学、EMT 和细胞生物学领域的世界专家，被任命为分子肿瘤学联合主任 WUSTL 癌症环境研究所肿瘤学兼整合通讯主任。一个杰出研究咨询委员会 (RAC) 将提供额外指导，包括 Ting Wang 博士、Dr. 何塞·泽瓦洛斯和罗布·米特拉博士。 K08 奖项将为我提供在我的领域取得成功的理想机会职业目标。详细的培训计划包括 RAC 和技术/领导技能的发展，这将对于向独立过渡具有无价的价值。研究将在著名研究机构 WUSTL 进行该学院促进合作、强调知识交流并拥有无与伦比的设施。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Malignant cell-specific CXCL14 promotes tumor lymphocyte infiltration in oral cavity squamous cell carcinoma.

DOI：
10.1136/jitc-2020-001048
发表时间：
2020-09
期刊：
Journal for immunotherapy of cancer
影响因子：
10.9
作者：
Parikh A;Shin J;Faquin W;Lin DT;Tirosh I;Sunwoo JB;Puram SV
通讯作者：
Puram SV

Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity.

DOI：
10.1038/s41588-020-00726-6
发表时间：
2020-11
期刊：
Nature genetics
影响因子：
30.8
作者：
Kinker GS;Greenwald AC;Tal R;Orlova Z;Cuoco MS;McFarland JM;Warren A;Rodman C;Roth JA;Bender SA;Kumar B;Rocco JW;Fernandes PACM;Mader CC;Keren-Shaul H;Plotnikov A;Barr H;Tsherniak A;Rozenblatt-Rosen O;Krizhanovsky V;Puram SV;Regev A;Tirosh I
通讯作者：
Tirosh I

Molecular margins in head and neck cancer: Current techniques and future directions.