Dissecting the impact of tumor-intrinsic chromosomal instability on the cancer ecosystem

剖析肿瘤内在染色体不稳定性对癌症生态系统的影响

基本信息

批准号：
10651060
负责人：
Samuel F Bakhoum
金额：
$ 73.52万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2023-06-08 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651060
关键词：
ATF6 gene Aneuploidy Anti-Inflammatory Agents Apolipoprotein E Benchmarking Biological Biological Response Modifiers Breast Cancer Model Bypass Cell Communication Cells Chromosomal Instability Chromosomal Loss Chromosome Segregation Chromosome abnormality Chromosomes Chronic Colorectal Cancer Complex Computing Methodologies Coupling Cytosol Data Data Set Dependence Development Disease Progression Drug resistance Ecosystem Equilibrium Event Exhibits Experimental Models Genes Genetic Genetic Epistasis Genetic Transcription Genomics Goals Heterogeneity Human Immune Immune Evasion Immune system Immunocompetent Immunosuppression Infiltration Interferon Type I Interferons KRASG12D Knowledge Ligands LoxP-flanked allele Lung Macrophage Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Mediator Methods Modeling Molecular Mus NF-kappa B Nature Neoplasm Metastasis Nuclear Envelope Pancreas Phenotype Physiological Process Recurrence Role Rupture Sampling Shapes Signal Transduction Source Stimulator of Interferon Genes Stress Tests System T-Lymphocyte Tachyphylaxis Technology Tertiary Protein Structure Testing Therapeutic Tumor Immunity Tumor-Derived Work biological adaptation to stress cancer cell cancer type case control cell type chromosome missegregation computerized tools cytokine data modeling desensitization detection method ds-DNA endoplasmic reticulum stress gene regulatory network genetic manipulation granulocyte human data improved in silico innate immune pathways innovation malignant breast neoplasm micronucleus mouse model neoplastic cell novel strategies paracrine programs receptor response sensor single-cell RNA sequencing therapeutic target therapy resistant tool triple-negative invasive breast carcinoma tumor tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY The goal of this proposal is to discover how ongoing chromosome missegregation events in cancer cells (a process called chromosomal instability, or CIN) alters the tumor ecosystem to promote cancer progression. Chromosome copy number alterations (also referred to as aneuploidy) have long been associated with immune suppressive phenotypes, drug resistance, and metastasis. Beyond aneuploidy, however, it remains unknown whether the ongoing process of chromosome missegregation gives rise to tumor progression. Harnessing ex- perimental tools that enable us to dial-up or dial-down chromosome missegregation rates in otherwise isogenic backgrounds, we have previously found that ongoing chromosome missegregation generates rupture-prone mi- cronuclei, which expose genomic double-stranded DNA (dsDNA) to the cytosol, leading to persistent activation of the cGAS-STING innate immune pathway (1). Yet, instead of promoting a robust type I interferon (IFN) re- sponse, STING activation in cancer cells with CIN promotes noncanonical NF-kB (nc-NF-kB) signaling – through an unknown mechanism – to drive metastasis. The extent to which CIN-driven metastasis is dependent on the immune system remains unknown. We made the surprising observation that CIN drives tumor progression in a cancer cell non-autonomous manner by shaping the interaction between cancer cells and the tumor microenvi- ronment (TME). This finding motivated the development of a fundamentally new, systems-level approach to evaluate the nature and conditional-dependence of cell-cell interactions in the TME called ContactTracing. This method exploits intrinsic biological variance captured by single cell RNA sequencing technologies, to infer cellu- lar responses to ligand-receptor mediated interactions without prior knowledge of downstream target genes. Combining this innovative computational tool with genetic perturbation of CIN and STING we found that CIN engenders a pro-metastatic TME by inducing a cancer cell-intrinsic ER-stress response. In Aim 1, we propose to mechanistically dissect the epistatic relationship between CIN, STING, and ER-stress in the progression of triple negative breast cancer (TNBC) to determine whether ER-stress can represent a therapeutic target in chro- mosomally unstable tumors. We will also test whether an ER-stress response underlies nc-NF-kB activation. Under Aim 2, we will improve causal inference of tumor-derived ligand effects and explore their molecular basis using gene regulatory networks to ask whether CIN-dependent cell-cell interaction networks are conserved across cancer types using both human data and mouse models of breast, pancreatic, and lung cancers. The amalgamation of these approaches, combined with our deep understanding of CIN in cancer, is poised to eluci- date the complex roles of CIN-induced STING signaling on tumor-immune crosstalk during disease progression. Importantly, this work is poised to reveal novel strategies aimed at targeting chromosomally unstable tumors, which are otherwise difficult to treat.

项目概要该提案的目标是发现癌细胞中正在进行的染色体错误分离事件（a 称为染色体不稳定（CIN）的过程改变肿瘤生态系统以促进癌症进展。染色体拷贝数改变（也称为非整倍性）长期以来一直与免疫相关然而，除了非整倍体之外，抑制表型、耐药性和转移仍然未知。正在进行的染色体错误分离过程是否会导致肿瘤进展。外围工具使我们能够在其他同基因中提高或降低染色体错误分离率背景，我们之前发现，持续的染色体错误分离会产生易于破裂的 mi- 克罗核，将基因组双链 DNA (dsDNA) 暴露于胞质溶胶，导致持续激活然而，cGAS-STING 先天免疫途径 (1) 并没有促进强效的 I 型干扰素 (IFN) 重新发挥作用。响应，CIN 癌细胞中的 STING 激活促进非典型 NF-kB (nc-NF-kB) 信号传导 – 通过未知的机制——驱动转移 CIN 驱动的转移程度取决于我们令人惊讶地发现，CIN 会驱动肿瘤的进展。通过塑造癌细胞与肿瘤微环境之间的相互作用来控制癌细胞的非自主方式这一发现推动了一种全新的系统级方法的开发。评估 TME 中细胞间相互作用的性质和条件依赖性，称为“接触追踪”。方法利用单细胞 RNA 测序技术捕获的内在生物学差异来推断细胞在不事先了解下游靶基因的情况下对配体-受体介导的相互作用做出反应。将这种创新的计算工具与 CIN 和 STING 的遗传扰动相结合，我们发现 CIN 在目标 1 中，我们提出通过诱导癌细胞固有的 ER 应激反应来产生促转移 TME。机械地剖析 CIN、STING 和 ER 应激在疾病进展中的上位关系三阴性乳腺癌 (TNBC) 以确定 ER 应激是否可以代表染色体的治疗目标我们还将测试 ER 应激反应是否是 nc-NF-kB 激活的基础。在目标 2 下，我们将改进肿瘤衍生配体效应的因果推断并探索其分子基础使用基因调控网络来询问 CIN 依赖性细胞间相互作用网络是否保守使用乳腺癌、胰腺癌和肺癌的人类数据和小鼠模型来研究跨癌症类型。这些方法的结合，再加上我们对癌症中 CIN 的深入了解，有望阐明确定了 CIN 诱导的 STING 信号在疾病进展过程中对肿瘤免疫串扰的复杂作用。重要的是，这项工作有望揭示针对染色体不稳定肿瘤的新策略，否则很难治疗。