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

• 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
• 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

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.

项目摘要 这项提议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 这一过程称为染色体不稳定性，或CIN）改变了肿瘤生态系统，以促进癌症进展。 染色体拷贝数改变（也称为非整倍性）长期以来与免疫缺陷相关。 抑制性表型、耐药性和转移。然而，除了非整倍性， 染色体错误分离的持续过程是否导致肿瘤进展。利用前- 实验工具，使我们能够拨号或拨号下降染色体误分离率，否则等基因 背景，我们以前已经发现，持续的染色体错误分离产生破裂倾向的MI， cronuclei，将基因组双链DNA（dsDNA）暴露于胞质溶胶，导致持续激活 cGAS-STING先天免疫途径（1）。然而，与其促进强有力的I型干扰素（IFN）， 在CIN癌细胞中，STING激活通过促进非经典NF-κ B（nc-NF-kB）信号传导， 一种未知的机制来驱动转移。CIN驱动的转移在多大程度上取决于 免疫系统仍然未知。我们发现了令人惊讶的观察结果，即CIN在一定程度上推动了肿瘤进展。 通过塑造癌细胞与肿瘤微环境之间的相互作用， 元件（TME）。这一发现促使开发了一种全新的系统级方法， 评估TME中细胞间相互作用的性质和条件依赖性，称为ContactTracing。这 该方法利用单细胞RNA测序技术捕获的内在生物学差异来推断细胞内的DNA序列。 对配体-受体介导的相互作用的更大响应而无需下游靶基因的先验知识。 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 通过诱导癌细胞内在ER应激反应产生促转移TME。在目标1中，我们建议 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应激是否可以代表慢性乳腺癌的治疗靶点。 不稳定的肿瘤我们还将测试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依赖的细胞间相互作用网络是否保守 使用人类数据和乳腺癌、胰腺癌和肺癌的小鼠模型来研究癌症类型。的 这些方法的融合，结合我们对癌症中CIN的深刻理解，有望阐明 在疾病进展过程中，CIN诱导的STING信号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