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

肿瘤类型或分期不能通过手术手段治疗的癌症患者死亡的主要原因是全身治疗控制效率低下。人们普遍认为，在治疗过程中会选择无凋亡能力的亚克隆，最终导致临床进展和患者死亡。特别是对于传统的化疗药物，细胞凋亡缺陷被认为是临床上治疗失败的关键分子机制。我们的实验室长期致力于阐明癌基因或治疗诱导的衰老（分别为OIS或TIS）的分子控制和生物学特性，作为（预）肿瘤细胞中应激诱导的故障安全程序。衰老末期的增殖停止——在这方面与细胞凋亡类似——是另一个最终的细胞周期退出程序。因此，细胞衰老是一种肿瘤抑制原理，在癌症形成过程中对完全转化施加障碍，或在治疗反应中减弱肿瘤生长。然而，与细胞凋亡不同的是，有活力的衰老细胞可以持续较长时间，并由于其大量的促炎分泌而发挥非细胞自主作用，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、肿瘤监测或促有丝分裂性，从而促进肿瘤的后果，是一个科学争论的问题。在之前的资助期内，我们研究了持续衰老细胞的细胞自主改变，并确定了干细胞途径的细胞自主表观遗传激活，即重编程为潜在的自我更新能力或“干性”，这是持久停滞条件的潜在有害特征。衰老相关干细胞（SAS）将非干细胞的大块肿瘤细胞转化为新生的癌症干细胞，因此，研究人员发现，“后衰老”细胞出现的特别具有攻击性的复发——要么是由于基因开关，要么是自发的——设法重新进入了这个循环。由于我们可以将SAS与激活的Wnt信号联系起来，遗传或药理学上的Wnt抑制，反过来，与同一个体但从未衰老的淋巴瘤相比，消除了那些衰老后的肿瘤侵袭性的增强。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颖和具有挑衅性的，但关键问题仍然存在，在无偏倚模型和临床标本中观察到的治疗失败是否可能与SAS有因果关系，而不是凋亡不敏感。因此，在这个后续的项目申请中，我们旨在揭示SAS作为治疗失败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消除“衰老”治疗策略的潜在靶点。

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.