Chromosomal instability as a driver of non-small cell lung cancer immune evasion and brain metastasis

染色体不稳定性是非小细胞肺癌免疫逃避和脑转移的驱动因素

基本信息

批准号：
10679841
负责人：
Lindsay Anne Caprio
金额：
$ 4.77万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679841
关键词：
Adenosine Behavior Biology Brain CRISPR/Cas technology Cancer Biology Cancer Etiology Cancer Patient Cell Line Cells Cephalic Cessation of life Characteristics Chromosomal Instability Chromosome Arm Chromosome Segregation Chronic Coupled Cytosol DNA Data Set Databases Development Disease Drug resistance Environment Evolution Failure Future GENIE Generations Genetic Genetic Engineering Goals Human Image Immune Evasion Immunosuppression Immunotherapeutic agent Immunotherapy In Situ In Vitro Injections Interferon Type I Investigation KRASG12D Label Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Medical center Mentors Metastatic malignant neoplasm to brain Methods Mitosis Modeling Molecular Mus Mutate Mutation NF-kappa B Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Output Pathway interactions Phosphotransferases Physicians Primary Neoplasm Process Production Proteins Recycling Research Resistance Risk Role Rupture STK11 gene Scientist Signal Transduction Stimulator of Interferon Genes Surface System TP53 gene Tail Testing The Cancer Genome Atlas Tissues Tumor Escape Tumor Promotion Tumor Subtype Universities Up-Regulation Validation Veins Work blood-brain barrier permeabilization cancer cell cancer type career chromosome loss combinatorial ds-DNA ecto-nucleotidase experimental study genome sequencing genomic data immune checkpoint blockade immunoregulation in vivo melanoma micronucleus mouse model multimodality mutant neoplastic cell refractory cancer response spatiotemporal therapeutic development transcriptomics tumor tumor behavior tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT Brain metastasis (BM) frequently arises from non-small cell lung cancer (NSCLC) and represents the most common cause of cancer related death in the US, yet our understanding of BM biology is rudimentary. Our group has recently identified excessive chromosomal instability (CIN) as a hallmark of BM19. In in vitro studies, in addition to validation in multiple independent NSCLC patient datasets (TCGA, GENIE, CCLE, and CPTAC) detailed in this proposal, we have identified CIN as a hallmark of NSCLCs harboring mutations in STK11 (encoding LKB1). LKB1-deficient NSCLCs are an aggressive tumor subtype associated with increased risk of BM and immunotherapy resistance, and thus serves as a relevant archetypical disease that may broadly inform the role of CIN in BM biology and cancer immune evasion. CIN arises from failures in correct chromosome segregation during mitosis, leading to perpetual gains and losses of chromosome arms and the creation of rupture-prone micronuclei. Upon rupture, these micronuclei expose DNA to the cytosol, activating cGAS-STING signaling. This would seemingly present a conundrum for CINhigh cancers, as prototypical outputs of cGAS- STING activation promote anti-tumor type I interferon (IFN) responses. However, it has been recently shown that chronic cGAS-STING signaling characteristic of CINhigh tumors promotes metastatic non-canonical NF-kB output, in addition to immune-evasive adenosine generation in the tumor microenvironment, the latter accomplished through adaptive increases in cGAMP export and upregulation of surface ectonucleotidases ENPP1 and NT5E. In addition to its ability to promote immunosuppression, adenosine also permeabilizes the blood brain barrier and thus may potentially mechanistically link BM to CIN. This proposal seeks to understand how cancer cell adaptations to CIN enable BM and immune evasion, namely through investigation of tonic activation of cGAS-STING signaling. In Aim 1, I propose to delineate the respective contributions of CIN and LKB1 loss per se to metastatic behavior and immunotherapy resistance in vivo. In Aim 2, I will perform spatio- temporal resolved in vivo studies to delineate CIN-intrinsic (i.e., STING signaling) and -extrinsic (e.g. adenosine generation) interactions that enable immune evasion and BM. Through generation of genetic perturbations in LKB1-deficient and WT models, I will investigate whether chronic cGAMP-triggered STING recycling is a hallmark of CINhigh, LKB1-deficient NSCLC that favors immune-evasive tumor behavior and establishment of BM. Together, these aims offer unparalleled study of interactions critical for the establishment of the brain metastatic niche and will pave the way for therapeutic development of malignant, treatment-resistant CINhigh tumors. With the guidance from exceptional mentors and collaborators and access to the unparalleled scientific research environment at Columbia University Irving Medical Center, this project will prepare me for a successful career as a physician-scientist in the field of cancer biology.

项目概要/摘要脑转移（BM）通常由非小细胞肺癌（NSCLC）引起，是最常见的癌症。在美国，这是癌症相关死亡的常见原因，但我们对骨髓生物学的了解还很初级。我们组最近发现过度染色体不稳定（CIN）是 BM19 的一个标志。在体外研究中，除了在多个独立 NSCLC 患者数据集（TCGA、GENIE、CCLE 和 CPTAC）中进行验证之外在该提案中，我们已将 CIN 确定为携带 STK11 突变的 NSCLC 的标志（编码LKB1）。 LKB1 缺陷的 NSCLC 是一种侵袭性肿瘤亚型，与罹患癌症的风险增加相关 BM 和免疫治疗耐药性，因此作为一种相关的原型疾病，可以广泛地提供信息 CIN 在 BM 生物学和癌症免疫逃避中的作用。 CIN 源于正确染色体的失败有丝分裂期间的分离，导致染色体臂的永久获得和损失，并产生易破裂的微核。破裂后，这些微核将 DNA 暴露于细胞质中，激活 cGAS-STING 发信号。这似乎给 CINhigh 癌症带来了一个难题，因为 cGAS 的典型输出 STING 激活可促进抗肿瘤 I 型干扰素 (IFN) 反应。然而最近却被曝光 CINhigh 肿瘤的慢性 cGAS-STING 信号传导特征促进转移性非典型 NF-kB 输出，除了肿瘤微环境中免疫逃避的腺苷生成外，后者通过适应性增加 cGAMP 输出和上调表面核酸酶来实现 ENPP1 和 NT5E。除了促进免疫抑制的能力外，腺苷还具有通透性血脑屏障，因此可能在机制上将 BM 与 CIN 联系起来。该提案旨在了解癌细胞对 CIN 的适应如何实现 BM 和免疫逃避，即通过补品的研究激活 cGAS-STING 信号传导。在目标 1 中，我建议描述 CIN 和 LKB1 损失本身导致体内转移行为和免疫治疗耐药。在目标 2 中，我将执行空间- 时间分辨体内研究描绘 CIN 内在（即 STING 信号传导）和外在（如腺苷）生成）相互作用，从而实现免疫逃避和 BM。通过产生遗传扰动 LKB1 缺陷和 WT 模型，我将研究慢性 cGAMP 触发的 STING 回收是否是一种 CINhigh、LKB1 缺陷的 NSCLC 的标志有利于免疫逃避肿瘤行为和 BM 的建立。总之，这些目标提供了对建立脑转移至关重要的相互作用的无与伦比的研究。并将为恶性、难治性 CIN 高肿瘤的治疗开发铺平道路。和杰出导师和合作者的指导以及无与伦比的科学研究的机会哥伦比亚大学欧文医学中心的环境，这个项目将为我的成功职业生涯做好准备作为癌症生物学领域的医师科学家。