PO.MCB04.02 · 分子与细胞生物学
衰老相关分泌表型驱动PGCC的生命周期和卵裂球样重编程以促进治疗抵抗
Senescence-associated secretory phenotype drives PGCC‘s lifecycles and blastomere-like reprogramming to promote therapeutic resistance
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：多倍体巨型癌细胞（PGCC）是应激反应性的肿瘤亚群，与治疗抵抗和不良预后相关。尽管既往研究已表征了它们的衰老样表型和发育重编程能力，但仍有两个核心问题知之甚少，包括支配PGCC生命周期进展的时间动态，以及衰老在塑造其生物学中的确切机制作用。
方法：我们使用有丝分裂去稳定剂长春新碱（VCR）诱导PGCC形成，并通过活细胞荧光成像追踪其生命周期。我们在体外评估了增殖活性、EMT、卵裂球样特征和分化潜能，并在体内评估了致瘤性。在机制上，我们使用基因沉默和药理学抑制来探究SASP细胞因子。
结果：VCR激活了PGCC中一种基于核内复制（endoreplication）的生命周期，取代了经典的有丝分裂。PGCC逐渐表现出增殖降低，但EMT增强、进行性的卵裂球样干性以及多谱系分化。PGCC群体及其后代均获得了时间/剂量依赖性的恶性特征和致瘤能力。PGCC部分采纳了衰老，以SASP细胞因子升高为标志。沉默IL1beta/IL6/IL8或抑制其受体可抑制PGCC的形成、出芽、EMT和干性，从而将SASP确定为PGCC稳态和命运的关键因素。
结论：我们的工作阐明了PGCC的生命周期演变，并确立SASP作为其生命周期以及具有侵袭性、治疗抵抗性后代出现的关键驱动因素，架起了衰老、发育重编程与癌症进展之间的桥梁。
查看英文原文 English abstract
Background: Polyploid giant cancer cells (PGCCs) are stress-responsive tumor subpopulations linked to treatment resistance and poor prognosis. While prior studies have characterized their senescent-like phenotypes and capacity for developmental reprogramming, two core questions remain poorly understood, including the temporal dynamics governing PGCC's lifecycle progression and the precise mechanistic role of senescence in shaping their biology.
Methods: We induced PGCC formation using vincristine (VCR), a mitotic destabilizer, and tracked their lifecycle via live-cell fluorescence imaging. We assessed proliferative activity, EMT, blastomere-like features, and differentiation potential in vitro , alongside tumorigenicity in vivo . Mechanistically, we interrogated SASP cytokines using genetic silencing and pharmacologic inhibition.
Results: VCR activated an endoreplication-based lifecycle in PGCCs, replacing canonical mitosis. PGCCs progressively exhibited reduced proliferation but enhanced EMT, progressive blastomere-like stemness, and multilineage differentiation. Both PGCC populations and their progeny acquired time/dose-dependent malignant traits and tumorigenic capacity. PGCCs partially adopted senescence, marked by elevated SASP cytokines. Silencing IL1beta/IL6/IL8 or inhibiting their receptors suppressed PGCC formation, budding, EMT, and stemness, thus identifying SASP as critical for PGCC homeostasis and fate.
Conclusion: Our work delineates PGCCs' lifecycle evolution and establishes SASP as a key driver of their lifecycle and the emergence of aggressive, therapy-resistant progeny, bridging senescence, developmental reprogramming, and cancer progression.
利益披露 Disclosure
Z. Zhang, None..
X. Li, None..
X. Tian, None..
L. Deng, None..
J. Dong, None..
J. Liu, None.