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:
    10647832
  • 负责人:
  • 金额:
    $ 31.49万
  • 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#年癌症死亡的第二大原因。 到2030年,美国。PDAC的区别特征之一是异常高的频率 神经周围侵袭(PNI),一种肿瘤-神经串扰的组织病理学表现,癌细胞借此招募, 向周围神经迁移并侵入周围神经。这些肿瘤与神经的相互作用可能是生化的,电学的, 和代谢性质,并涉及肿瘤和非肿瘤细胞。虽然已经变得很明显 肿瘤内神经在肿瘤的发生、发展、复发、治疗抵抗、 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,这项提议旨在执行全面的空间解析 人PDAC全转录组筛选与PNI相关的细胞型特异性基因 应用CRISPR激活(CRISPRa)在新的原位器官移植模型中的功能作用。它是 预计这项工作将发现一组以前不为人知的PNI调解人,并提供高分辨率 肿瘤-神经相互作用组的分子互联图,将指导治疗的发展。 以往使用整体或单细胞/核RNA测序来研究PNI分子介体的工作缺乏空间 背景。第一个目标是应用转录和蛋白质组数字空间图谱(数字信号处理器;纳米串)方法 针对福尔马林固定石蜡包埋的人类PDAC切片进行了优化,以保留空间关系 在不同的单元类型/状态之间。通过对从定制队列中创建的组织微阵列执行DSP PDAC患者的肿瘤空间注释为有和没有PNI的区域,提取基因的能力 从患者间遗传异质性中分离出的与PNI相关的表达差异很大 增强版。第二个目标将调查入围名单中的~20人之间的潜在因果关系 候选基因与PNI发病的关系 靶向表达单引导RNAs的胰腺癌组织原位移植 或更多候选基因(KrasLSL-G12D/+;Trp53FL/FL;Rosa26LSL-dCas9-VPR-mNeonGreen;sgRNA)进入同源基因 收件人。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。这项研究的长期目标是成功地开发 扰乱肿瘤微环境中适应性肿瘤-神经串扰的治疗方法。 这项研究提案是广泛的职业发展计划的一部分,该计划包括正规教育 机会和研讨会/会议报告,使首席调查员能够成为 翻译癌症生物学领域的独立内科医生兼科学家。一个多元化且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咨询委员会成员和合作者 医学院致力于支持和指导首席研究员实现这一目标。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution.
  • DOI:
    10.3389/fonc.2022.929950
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Shiau, Carina;Su, Jennifer;Guo, Jimmy A.;Hong, Theodore S.;Wo, Jennifer Y.;Jagadeesh, Karthik A.;Hwang, William L.
  • 通讯作者:
    Hwang, William L.
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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:
    10428889
  • 财政年份:
    2022
  • 资助金额:
    $ 31.49万
  • 项目类别:
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