Impact of local and systemic cellular senescence toward Triple Negative Breast Cancer growth and drug therapy

摘要 三阴性乳腺癌被认为是乳腺癌最具侵袭性的形式之一， 缺乏治疗选择。一种潜在的治疗途径与衰老细胞有关。细胞衰老 在组织内环境稳定的许多方面发挥重要作用。随着自然衰老过程的发生 沿着来自环境的压力和损害，身体各种器官和组织中的细胞可以 经历衰老，这是一个生长停滞并退出细胞周期的阶段， 防止受损细胞的进一步扩散。衰老细胞的一个定义特征是它们的衰老- 相关分泌表型（SASP），一组细胞因子，蛋白酶和生长因子， 它被认为可以招募免疫系统的细胞来清除受损的细胞。暴露于SASP的时间长度 影响着微环境的变化。在胚胎发育，伤口愈合，抑制 肿瘤生长和免疫细胞的募集，确定细胞的短暂可逆衰老 种群和由此产生的SASP促进生物体的最佳适应性。另一方面当 虽然衰老细胞是长期存在的，但SASP可能具有更多的负面影响，包括促进衰老细胞的生长， 肿瘤发生和转移的环境。在TNBC方面，还没有进行过已知的研究， 评估衰老和SASP如何影响TNBC进展。 在我的初步研究中，我使用了ATTAC小鼠模型（=通过激活的细胞凋亡）， 胱天蛋白酶8）。在该模型中，衰老细胞在以下控制下表达药物诱导的自杀基因盒： p16 Ink 4a调控序列。当给予诱导药物AP 20187时，表达p16 ink 4a的衰老细胞被激活。 通过凋亡消除。因此，我的赠款的第一个目的是评估局部和系统衰老的影响， 细胞对同基因TNBC细胞在作为宿主的ATTAC小鼠中的生长和转移的影响。初步数据 表明宿主衰老细胞的连续清除导致肿瘤生长减少。在此基础上， 在第二个目标下，我希望分析senolytics（消除衰老细胞的药物）对 癌症治疗剂（即免疫检查点抑制剂）对TNBC的功效。没有已知的研究 然而，研究免疫检查点抑制剂与衰老之间的关系， TNBC。因此，这些目标的完成不仅将提供有关TNBC增长如何受到两者影响的见解， 微环境和系统作为一个整体，但也有可能发现独特的 更有效的TNBC治疗的药理学靶点。

ABSTRACT Triple negative breast cancer is considered one of the most aggressive forms of breast cancer and efficacious treatment options are lacking. A potential therapeutic avenue is related to senescent cells. Cellular senescence engages in important roles for many aspects of tissue homeostasis. As the natural process of aging occurs along with stresses and insults from the environment, cells in various organs and tissues of the body can undergo senescence, a phase of arrested growth and exit from the cell cycle that is established in order to prevent further propagation of damaged cells. A defining feature of senescent cells is their senescence- associated secretory phenotype (SASP), a group of cytokines, proteases, and growth factors, which are thought to recruit cells of the immune system to clear out damaged cells. Length of exposure to the SASP impacts what happens to the microenvironment. During embryonic development, wound healing, suppression of tumor growth, and recruitment of immune cells, short-lived, reversible senescence of defined cell populations and the resultant SASP promote optimal fitness for the organism. On the other hand, when senescent cells are present chronically, the SASP can have more negative effects, which include promoting an environment for tumorigenesis and metastasis. In terms of TNBC, no known studies have been carried out that assess how senescence and the SASP impact TNBC progression. In my preliminary studies, I have utilized the ATTAC mouse model (=Apoptosis through Activated Caspase 8). In this model, senescent cells express a drug-inducible suicide gene cassette under the control of p16Ink4a regulatory sequences. When given an inducing drug, AP20187, senescent cells expressing p16ink4a are eliminated by apoptosis. Thus, the first aim of my grant is to assess the effect of local and systemic senescent cells on growth and metastasis of the syngeneic TNBC cells in the ATTAC mice as hosts. The preliminary data suggest that continuous clearance of host senescent cells results in reduced tumor growth. Based on this, under a second aim I wish to analyze the impact that senolytics (drugs that eliminate senescent cells) have on the efficacy of cancer therapeutics (i.e. immune checkpoint inhibitors) towards TNBC. No known studies have yet been done that look at the relationship between immune checkpoint inhibitors and senescence towards TNBC. Thus, completion of these aims will provide not only insight on how TNBC growth is affected by both the microenvironment and the system as a whole, but also the possibility of discovering unique pharmacological targets for more effective TNBC treatments.