Systematic mapping of genetic vulnerabilities in head and neck cancer

项目总结/摘要 大量的突变会导致癌症，但观察到的这些突变的非随机组合 导致转化的研究突出了标志性途径和网络在癌症进展中的重要性。 虽然许多途径与癌症有关，但肿瘤异质性源于不同的诱变剂， 起源组织、进展程度等导致每个病例表现出改变的途径的独特子集。 总的来说，癌症类型及其起源之间的这种多样性，加上巨大的遗传和 肿瘤的表观遗传异质性使靶向癌症治疗的发展复杂化。的 这个项目的前提是癌症突变汇聚成遗传相互作用网络，这些网络 汇集所有种类的突变，包括致癌突变频率低的基因，以及肿瘤 抑制基因谱因此，我们假设，通过系统地映射这些网络在两个细胞系和 在临床相关的患者来源的异种移植物（PDX）模型中， 鉴定关注头颈部鳞状细胞癌（HNSCC），这种疾病导致超过 全球每年有250，000人死亡，因此，目标相应地侧重于使用最先进的高通量 通过CRISPR-Cas和偶联的单细胞分析进行上位性作图，以系统地询问 单个基因和基因对的功能，同时还显著地测定肿瘤异质性的影响。 为此，我们的目标是利用>50个HNSCC细胞系和>50个PDX模型的广泛组。使 在这个庞大的集合中筛选，我们将利用集中的文库和细胞条形码策略， 我们通过整合的合并实验有效地筛选基因和细胞组。再加上严格的 在体外和体内药物和靶向基因验证的临床前模型，我们预计我们的综合 实验和计算框架将导致对潜在肿瘤的前所未有的见解 生物学以及解开临床上可操作的遗传弱点，以推进精确的实践， 肿瘤学

Project Summary/Abstract A vast number of mutations contribute to cancer, but the observed non-random combinations of these leading to transformation highlight the importance of hallmark pathways and networks in cancer progression. While many pathways have been implicated in cancer, tumor heterogeneity stemming from different mutagens, tissue of origin, degree of progression, etc. leads to each case exhibiting a unique subset of altered pathways. Taken together, this diversity among cancer types and their origins, compounded by the huge genetic and epigenetic heterogeneity of tumors has complicated the development of targeted cancer treatments. The premise of this project is that cancer mutations converge into genetic interaction networks, and these networks bring together mutations of all varieties, including genes with low frequency of oncogenic mutations, and tumor suppressor profiles. We thus hypothesize that by systematically mapping these networks in both cell lines and in clinically relevant patient-derived xenograft (PDX) models, new molecular targets for cancer therapy can be identified. Focusing on head and neck squamous cell carcinomas (HNSCC), a disease that results in over 250,000 deaths each year worldwide, the aims correspondingly focus on using state-of-the-art high-throughput epistasis mapping via CRISPR-Cas and coupled single-cell analyses to enable systematic interrogation of the functions of individual genes and gene-pairs while notably also assaying the impact of tumor heterogeneity. Towards this we aim to utilize an extensive panel of >50 HNSCC cell lines and >50 PDX models. To enable screening across this vast collection we will utilize focused libraries and cell barcoding strategies that will allow us to efficiently screen across genes and cell panels via integrated pooled experiments. Coupled with rigorous in vitro and in vivo drug and targeted genetic validations in preclinical models, we anticipate our integrated experimental and computational framework will result in unprecedented insights into the underlying tumor biology as well as unraveling of clinically actionable genetic vulnerabilities to advance the practice of precision oncology.