Elucidating cancer-intrinsic mechanisms of perineural invasion in pancreatic cancer

阐明胰腺癌神经周围浸润的癌症内在机制

基本信息

  • 批准号:
    10428889
  • 负责人:
  • 金额:
    $ 31.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer death in the United States by 2030. One of the differentiating hallmarks of PDAC is an exceptionally high frequency of perineural invasion (PNI), a histopathologic manifestation of tumor-nerve crosstalk whereby cancer cells recruit, migrate towards and invade peripheral nerves. These tumor-nerve interactions may be biochemical, electrical, and metabolic in nature and involve both neoplastic and non-neoplastic cells. While it has become apparent that intra-tumoral nerves play an important role in cancer initiation, progression, recurrence, treatment resistance, metastasis, and survival, the diverse molecular mechanisms underlying tumor-nerve crosstalk remain largely unknown. To address this gap in knowledge, this proposal aims to perform a comprehensive spatially-resolved whole transcriptome screen in human PDAC to identify cell-type specific genes linked to PNI and dissect their functional roles by applying CRISPR activation (CRISPRa) in a novel orthotopic organoid transplant model. It is anticipated that this work will uncover a set of previously unknown mediators of PNI and provide a high-resolution molecular interconnectivity map of the tumor-nerve interactome, which will guide therapeutic development. Prior work studying molecular mediators of PNI using bulk or single-cell/nucleus RNA-sequencing lacked spatial context. The first aim applies a transcriptomic and proteomic digital spatial profiling (DSP; Nanostring) approach optimized for formalin-fixed paraffin-embedded sections of human PDAC to preserve the spatial relationships among different cell types/states. By performing DSP on tissue microarrays created from a custom cohort of PDAC patients with tumors spatially annotated for regions with and without PNI, the ability to extract gene expression differences that associate with PNI isolated from inter-patient genetic heterogeneity is greatly enhanced. The second aim will investigate the potential causal relationships between a shortlist of ~20 candidate genes and the development of PNI by performing an arrayed in vivo CRISPRa screen involving orthotopically transplanting pancreatic cancer organoids expressing single-guide RNAs (sgRNAs) targeting one or more candidate genes (KrasLSL-G12D/+;Trp53FL/FL;Rosa26LSL-dCas9-VPR-mNeonGreen;sgRNA) into syngeneic recipients. The density and properties of intra-tumoral nerves/PNI will be assessed using multiplexed imaging and machine learning approaches. The long-term goal of this research is the successful development of therapeutics that disrupt adaptive tumor-nerve crosstalk in the tumor microenvironment. The research proposal is part of an extensive career development plan that includes formal educational opportunities and seminar/conference presentations to enable the principal investigator to become an independent physician-scientist in translational cancer biology. A diverse and experienced team of mentors, scientific advisory committee members, and collaborators at MIT, MGH, DFCI, HMS, and Columbia University School of Medicine is committed to supporting and guiding the principal investigator toward achieving this goal.
项目摘要/摘要 胰腺导管腺癌(PDAC)预计将成为2010年癌症死亡的第二大原因。 美国到2030年。PDAC的区别标志之一是异常高的频率, 神经周侵袭(PNI),肿瘤-神经串扰的组织病理学表现,由此癌细胞募集, 向周围神经迁移并侵入。这些肿瘤-神经相互作用可以是生物化学的,电的, 并且涉及肿瘤细胞和非肿瘤细胞。虽然很明显 肿瘤内神经在癌症发生、发展、复发、治疗抗性 转移和生存,肿瘤-神经串扰背后的不同分子机制在很大程度上仍然存在 未知为了解决这一知识差距,本提案旨在执行一项全面的空间分辨 在人PDAC中进行全转录组筛选,以鉴定与PNI相关的细胞类型特异性基因,并分析其 通过在新的原位类器官移植模型中应用CRISPR激活(CRISPRa)来发挥功能作用。是 预计这项工作将揭示一组以前未知的PNI调解人,并提供一个高分辨率 肿瘤-神经相互作用组的分子互连图,这将指导治疗的发展。 先前的工作使用批量或单细胞/细胞核RNA测序研究PNI的分子介导物缺乏空间 上下文第一个目标应用转录组学和蛋白质组学数字空间分析(DSP; Nanostring)方法 优化福尔马林固定石蜡包埋的人类PDAC切片,以保留空间关系 在不同的细胞类型/状态之间。通过对从自定义队列中创建的组织微阵列进行DSP, 具有肿瘤的PDAC患者在空间上注释有和没有PNI的区域,提取基因的能力, 与从患者间遗传异质性分离的PNI相关的表达差异是巨大的, 增强第二个目标将调查约20个候选名单之间的潜在因果关系 候选基因和PNI的发展,通过进行阵列体内CRISPRa筛选, 原位移植胰腺癌类器官,表达靶向一个 或多个候选基因(KrasLSL-G12 D/+; Trp 53 FL/FL; Rosa 26 LSL-dCas 9-VPR-mNeonGreen;sgRNA)整合到同源重组中。 受惠人士肿瘤内神经/PNI的密度和性质将使用多路成像进行评估 和机器学习方法。本研究的长期目标是成功开发 在肿瘤微环境中破坏适应性肿瘤-神经串扰的治疗剂。 该研究提案是一个广泛的职业发展计划的一部分,其中包括正规教育 机会和研讨会/会议介绍,使主要研究者成为一个 癌症转化生物学领域的独立医生兼科学家。一个多元化和经验丰富的导师团队, 麻省理工学院、麻省理工学院、DFCI、HMS和哥伦比亚大学的科学顾问委员会成员和合作者 医学院致力于支持和指导主要研究者实现这一目标。

项目成果

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William L Hwang其他文献

William L Hwang的其他文献

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{{ truncateString('William L Hwang', 18)}}的其他基金

Elucidating cancer-intrinsic mechanisms of perineural invasion in pancreatic cancer
阐明胰腺癌神经周围浸润的癌症内在机制
  • 批准号:
    10647832
  • 财政年份:
    2022
  • 资助金额:
    $ 31.51万
  • 项目类别:
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