The role of chromosomal instability in tumor evolution

项目总结/摘要 染色体数目不稳定性（CIN）是癌症的一个标志，它是由染色体片段错误引起的。 有丝分裂时的再分化。CIN在肿瘤演变中的作用知之甚少，特别是它如何支持肿瘤的发生。 诸如转移和免疫逃避的过程仍然未知。除了为基因组异质性提供燃料外， 然而，我的研究最近表明，CIN也通过炎症促进慢性炎症。 产生胞质DNA。这反过来又被cGAS-STING细胞溶质DNA传感机制所感知， 在正常情况下，其响应于病毒感染而被激活。令人惊讶的是，癌细胞吸收了这一点 慢性炎症反应扩散到远处器官。在这个建议中，我将测试中心假设 CIN下游的炎症是一个有吸引力的治疗弱点， 选择性地针对染色体不稳定的肿瘤。我将研究是否恢复细胞自主 (Aim 1）或非细胞自主（目的2）对炎症的反应可用于消除否则的抗原。 退化和染色体不稳定的肿瘤细胞。根据目标1，我将测试是否恢复正常的细胞 对胞质DNA的反应可以选择性地靶向充满胞质DNA的肿瘤细胞。我要... 切割cGAS-STING轴上游的调控途径，目的是确定癌细胞如何 避免致命的抗病毒反应和I型干扰素反应。具体来说，我会调查- 门控MST 1是否通过干扰素调节蛋白的抑制性磷酸化阻止干扰素信号传导 因子3（IRF 3）。这种可能性将激发MST 1抑制剂作为靶向治疗的策略的潜在用途。 染色体不稳定的肿瘤此外，我将研究肿瘤细胞是否依赖于自分泌M-CSF信号， naling以加强生存和迁移程序，这在细胞溶质的存在下特别重要， DNA.在目标2下，我将检验染色体不稳定肿瘤细胞中cGAS激活促进肿瘤细胞增殖的假设。 先天性免疫激活，并在肿瘤微环境中增强STING信号传导， 恢复抗肿瘤免疫力。我将测试这是否可以通过抑制ENPP 1来实现，ENPP 1是一种额外的- 参与STING激活剂cGAMP水解的细胞酶。我还将探讨是否使用 已知促进染色体分离错误的Plk 4抑制剂可用于增强抗肿瘤免疫抑制剂。 免疫治疗和电离辐射的免疫效应。最后，单细胞测序和细胞因子分析 将适用于确定CIN塑造免疫微环境的其他机制， 尽管存在强大的免疫浸润，肿瘤细胞仍能茁壮成长。识别这些自适应机制- nisms将有助于开发增强DNA损伤的全身免疫效应的疗法。 治疗，如电离辐射。总之，这项工作将导致新的战略的发展， 利用CIN，一种致命的特性，以获得治疗益处。 !

PROJECT SUMMARY/ABSTRACT Numerical chromosomal instability (CIN) is a hallmark of cancer and it results from errors in chromosome seg- regation during mitosis. The role of CIN in tumor evolution is poorly understood and specifically how it supports processes such as metastasis and immune evasion remains unknown. In addition to fueling genomic hetero- geneity, my research has recently demonstrated that CIN also promotes chronic inflammation through the generation of cytosolic DNA. This, in turn, is sensed by the cGAS-STING cytosolic DNA sensing machinery, which, under normal conditions, is activated in response to viral infection. Strikingly, cancer cells co-opt this chronic inflammatory response to spread to distant organs. In this proposal, I will test the central hypothesis that inflammation downstream of CIN represents an attractive therapeutic vulnerability that can be harnessed to selectively target chromosomally unstable tumors. I will examine whether restoration of cell-autonomous (Aim 1) or non-cell autonomous (Aim 2) responses to inflammation can be used to eliminate otherwise ag- gressive and chromosomally unstable tumor cells. Under Aim 1, I will test whether restoring normal cellular responses to cytosolic DNA could selectively target tumor cells that are replete with cytosolic DNA. I will dis- sect regulatory pathways upstream of the cGAS-STING axis with the goal of determining how cancer cells avoid what is an otherwise lethal anti-viral response and type I interferon response. Specifically, I will investi- gate whether MST1 prevents interferon signaling through inhibitory phosphorylation of Interferon Regulatory Factor 3 (IRF3). Such a possibility would invoke the potential use of MST1 inhibitors as a strategy to target chromosomally unstable tumors. Furthermore, I will examine whether tumor cells rely on autocrine M-CSF sig- naling to reinforce survival and migration programs that are particularly critical in the presence of cytosolic DNA. Under Aim 2, I will test the hypothesis that cGAS activation in chromosomally unstable tumor cells pro- motes innate immune activation and that potentiating STING signaling in the tumor microenvironment would restore anti-tumor immunity. I will test whether this can be achieved through the inhibition of ENPP1, an extra- cellular enzyme involved in the hydrolysis of the STING activator, cGAMP. I will also explore whether the use of a Plk4 inhibitor, known to promote chromosome segregation errors, can be used to augment the anti-tumor immune effect of immune therapies and ionizing radiation. Finally, single-cell sequencing and cytokine profiling will be adapted to identify additional mechanisms by which CIN shapes the immune microenvironment allowing tumor cells to thrive despite the presence of a robust immune infiltrate. Identification of these adaptive mecha- nisms would enable the development of therapies that augment the systemic immune effect of DNA damaging therapies such as ionizing radiation. In summary, this work will lead to the development of novel strategies that exploit CIN, an otherwise deadly property, for the purpose of a therapeutic benefit. !