Conceptually novel cancer therapies - targeting cellular senescence and senescence-associated essentialities in lymphomaFollow-up Proposal "Investigating senescence-associated cancer stemness in clinical treatment failure"

在被诊断为肿瘤类型或阶段的癌症患者中，系统治疗的低效疾病控制是导致死亡的主要原因，该肿瘤类型或阶段不再能够通过手术手段进行治疗。人们普遍认为，无凋亡能力的亚克隆将在治疗过程中被选择，并最终导致临床进展和患者死亡。尤其是对于传统的化疗药物，细胞凋亡缺陷被认为是临床治疗失败的关键分子机制。我们的实验室长期以来一直有兴趣阐明癌基因或治疗诱导的衰老(OIS或TIS)作为(前)肿瘤细胞的应激诱导失败安全程序的分子控制和生物学特性。衰老的终末增殖停滞--在这方面可与细胞凋亡相媲美--是另一个终极细胞周期退出程序。因此，细胞衰老是一种肿瘤抑制原理，它在癌症形成过程中对充分转化施加障碍，或在治疗过程中抑制肿瘤生长。然而，与凋亡不同的是，存活的衰老细胞可能会持续较长时间，并由于其大量的促炎分泌而发挥非细胞自主作用，被称为衰老相关分泌表型(SASP)。这种慢性分泌物是否具有免疫原性、肿瘤监视作用，或者更确切地说，具有促有丝分裂作用，从而促进肿瘤，这是一个科学争论的问题。在之前的资助期间，我们研究了持续衰老细胞的细胞自主变化，并确定干细胞途径的细胞自主表观遗传激活，即重新编程为潜在的自我更新能力或“干性”，是持久停滞条件的一个潜在有害特征。衰老相关干细胞(SAS)将非干细胞实体肿瘤细胞转化为从头开始的癌症干细胞，因此，人们发现，由于遗传开关或自发地重新进入周期，“衰老后”细胞出现了特别激进的复发。由于我们可以将SAS与激活的Wnt信号联系起来，遗传或药物的Wnt抑制反过来又消除了那些衰老后的人所施加的增强的肿瘤侵袭性，而不是与完全相同的个体相比，而不是衰老的淋巴瘤。虽然这一发现在衰老对肿瘤细胞生物学的重塑影响方面是新的和挑衅性的，但关键问题仍然是，在无偏见的模型和临床标本中观察到的治疗失败是否与SAS有关，而不是与细胞凋亡不敏感有关。因此，在这个后续的项目应用中，我们的目标是揭示SAS作为治疗失败的驱动因素的遗传暗示，并寻求评估潜在的分子机制，作为创新的顺序衰老细胞的潜在靶点-消除“衰老”治疗策略。

Inefficient disease control by systemic therapy is the major reason for death in cancer patients diagnosed with a tumor type or stage no longer treatable by surgical means in curative intent. It’s widely believed that apoptosis-incapable subclones will be selected for in the course of therapy and eventually account for clinical progression and patient death. Especially with respect to conventional chemotherapeutic agents, apoptotic defects are considered the pivotal molecular mechanism underlying treatment failure in the clinic.Our laboratory has a long-standing interest in elucidating molecular control and biological properties of oncogene- or therapy-induced senescence (OIS or TIS, respectively) as a stress-inducible failsafe program in (pre-)neoplastic cells. The senescent terminal proliferative arrest – comparable to apoptosis in this regard – operates as another ultimate cell-cycle exit program. Accordingly, cellular senescence is a tumor-suppressive principle that imposes a barrier to full-blown transformation during cancer formation, or attenuates tumor growth in response to therapy. However, unlike apoptosis, viable senescent cells may persist for extended periods of time, and exert non-cell-autonomous effects due to their massive pro-inflammatory secretion, termed the “senescence-associated secretory phenotype (SASP)”. Whether such chronic secretion has immunogenic, tumor-surveilling or rather mitogenic, thus, tumor-promoting consequences, is an issue of scientific debate. In the previous funding period, we examined cell-autonomous alterations in persistent senescent cells, and identified cell-autonomous epigenetic activation of stem cell pathways, i.e. reprogramming into latent self-renewal capacity or “stemness”, as a potentially detrimental feature of the lasting arrest condition. Senescence-associated stemness (SAS) converted non-stem bulk tumor cells into de novo cancer stem cells, hence, was found to account for particularly aggressive relapses emerging from “post-senescent” cells that – either due to a genetic switch or spontaneously – managed to re-enter the cycle. Since we could link SAS to activated Wnt signaling, genetic or pharmacological Wnt inhibition, in turn, abolished the enhanced tumor aggressiveness exerted otherwise by those post-senescent as compared to the very same individual but never senescent lymphomas. While this discovery was novel and provocative in terms of the remodeling impact senescence has on tumor cell biology, the key question remained, whether treatment failure observed in unbiased models and clinical specimens might be causally related to SAS, not apoptotic insensitivity. In this follow-up project application, we therefore aim at unveiling genetic hints for SAS as a driver of treatment failure and seek to evaluate underlying molecular mechanisms as potential targets of innovative sequential senescent cells-eliminating “senolytic” treatment strategies.