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最具侵袭性和有效的乳腺癌之一。 治疗方法缺乏选择。一个潜在的治疗途径与衰老细胞有关。细胞衰老 在组织动态平衡的许多方面起着重要的作用。当衰老的自然过程发生时 伴随着来自环境的压力和侮辱，身体不同器官和组织中的细胞可以 经历衰老，这是一个生长受阻并退出细胞周期的阶段，为了 防止受损细胞进一步繁殖。衰老细胞的一个决定性特征是它们的衰老-- 相关分泌表型(SASP)，一组细胞因子、蛋白酶和生长因子，它们是 被认为是招募免疫系统的细胞来清除受损细胞。接触SASP的时间长短 影响微环境的变化。在胚胎发育期间，伤口愈合，抑制 肿瘤生长和免疫细胞的募集，已定义细胞的短暂、可逆衰老 种群和由此产生的SASP促进了生物体的最佳适合度。另一方面，当 衰老细胞是慢性存在的，SASP可能有更多的负面影响，包括促进 肿瘤发生和转移的环境。在TNBC方面，目前还没有已知的研究表明 评估衰老和SASP如何影响TNBC进展。 在我的初步研究中，我利用了ATTAC小鼠模型(=通过激活的细胞凋亡 Caspase 8)。在这个模型中，衰老细胞在药物诱导的自杀基因盒的控制下表达 P16INK4a调控序列。当给予诱导药物AP20187时，表达p16INK4a的衰老细胞 被细胞凋亡消除了。因此，我拨款的第一个目的是评估局部和系统性衰老的影响。 细胞对ATTAC小鼠体内同基因TNBC细胞生长和转移的影响初步数据 提示宿主衰老细胞的持续清除会导致肿瘤生长减慢。在此基础上， 在第二个目标下，我希望分析抗衰老药物(消除衰老细胞的药物)对 癌症治疗药物(即免疫检查点抑制剂)对TNBC的疗效。目前还没有已知的研究 然而，人们已经研究了免疫检查点抑制剂和衰老之间的关系 TNBC。因此，完成这些目标将不仅提供关于跨国公司增长如何受到这两个因素影响的洞察力 将微环境和系统作为一个整体，也有可能发现独特的 更有效的TNBC治疗的药理学目标。

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.