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.

项目摘要/摘要脑转移（BM）经常来自非小细胞肺癌（NSCLC），代表最多在美国，与癌症相关的死亡的常见原因，但是我们对BM生物学的理解是基本的。我们的小组最近已经确定过多的染色体不稳定性（CIN）是BM19的标志。在体外研究中在多个独立的NSCLC患者数据集（TCGA，Genie，Ccle和CPTAC）中进行验证。在此提案中详细介绍，我们将CIN确定为NSCLC的标志，该标志是STK11中的突变（编码LKB1）。缺乏LKB1的NSCLC是一种侵略性肿瘤亚型 BM和免疫疗法的抗性，因此是一种相关的原型疾病，可以广泛告知 CIN在BM生物学和癌症免疫逃避中的作用。 cin是由正确染色体的失败引起的有丝分裂期间的分离，导致染色体臂的永久增长和损失和创造容易发生的微核。破裂后，这些微核将DNA暴露于细胞质，激活CGAS刺信号。这似乎会带来Cinhigh癌的难题，作为CGAS-的典型输出刺激激活促进抗肿瘤I型干扰素（IFN）反应。但是，最近显示了 CINHIGH肿瘤的慢性CGAS刺信信号传导特征促进了转移性非经典NF-KB 除了在肿瘤微环境中产生免疫渗透腺苷外，后者还通过自适应增加CGAMP出口和表面核苷酸酶的上调来实现 ENPP1和NT5E。除了促进免疫抑制的能力外，腺苷还渗透血脑屏障，因此可能将BM与CIN联系起来。该提议试图了解癌细胞的适应如何使BM和免疫逃避，即通过调查补品激活CGAS-sting信号传导。在AIM 1中，我建议描绘CIN和CIN的各自贡献 LKB1在体内对转移性行为和免疫疗法抗性的本身损失本身。在AIM 2中，我将执行时空 - 暂时性在体内研究中解决了划定Cin -Intrinsic（即刺激信号）和 - 过时的（例如，腺苷）产生）相互作用，可以使免疫逃避和BM。通过产生遗传扰动 LKB1缺陷型和WT模型，我将研究慢性CGAMP触发的刺痛回收是否是 Cinhigh的标志，LKB1缺陷型NSCLC，有利于免疫渗透肿瘤行为和BM的建立。这些目标共同提供了对建立大脑转移至关重要的相互作用的无与伦比的研究利基市场，将为耐恶性，耐药的Cinhigh肿瘤的治疗发展铺平道路。和杰出导师和合作者的指导以及对无与伦比的科学研究的访问哥伦比亚大学欧文医学中心的环境，这个项目将使我为成功的职业做好准备作为癌症生物学领域的医师科学家。