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

概念性新颖的癌症疗法——针对淋巴瘤中的细胞衰老和衰老相关的本质后续提案“研究临床治疗失败中与衰老相关的癌症干性”

• 批准号: 274248610
• 负责人: Professor Dr. Clemens A. Schmitt
• 金额: --
• 依托单位: Molekulares Krebsforschungszentrum (MKFZ) (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/274248610?language=en
• 关键词: Conceptually; novel; cancer; therapies; targeting

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.

全身治疗的疾病控制效率低下是诊断为肿瘤类型或阶段的癌症患者死亡的主要原因，这些肿瘤类型或阶段不再能通过手术手段治愈。人们普遍认为，在治疗过程中会选择无增殖能力的亚克隆，并最终导致临床进展和患者死亡。特别是相对于传统的化疗药物，细胞凋亡缺陷被认为是关键的分子机制，治疗失败的clinic. OIS或TIS，分别在阐明癌基因或治疗诱导的衰老（分别）的分子控制和生物学特性作为一种应激诱导的故障安全程序（前）肿瘤细胞。衰老的终末增殖停滞-在这方面与凋亡相当-作为另一个最终的细胞周期退出程序起作用。因此，细胞衰老是一种肿瘤抑制原理，其在癌症形成期间对完全转化施加屏障，或响应于治疗而减弱肿瘤生长。然而，与凋亡不同，存活的衰老细胞可以持续延长的时间段，并且由于其大量促炎分泌而发挥非细胞自主效应，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、肿瘤监视性或促有丝分裂性，因此，肿瘤促进性后果，是一个科学争论的问题。在上一个资助期，我们检查了持续衰老细胞中的细胞自主改变，并确定了干细胞通路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“干细胞性”，作为持久停滞条件的潜在有害特征。衰老相关的干细胞（SAS）将非干细胞肿瘤细胞转化为新生癌症干细胞，因此，发现可以解释从“后衰老”细胞出现的特别积极的复发，这些细胞-由于遗传开关或自发-设法重新进入周期。由于我们可以将SAS与激活的Wnt信号传导联系起来，因此与同一个体但从未衰老的淋巴瘤相比，遗传或药理学Wnt抑制反过来消除了那些衰老后的淋巴瘤所产生的增强的肿瘤侵袭性。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，即在无偏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，而不是凋亡不敏感性。因此，在这个后续项目申请中，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，作为创新的连续衰老细胞消除“衰老”治疗策略的潜在目标。