肿瘤细胞治疗研究
英文原题：Necroptosis triggers inflammatory interferon signatures in patient-derived metastatic breast cancer organoids.
乳腺癌（BC）是全球女性中最常见的癌症类型，也是复发、疾病进展和转移的基础。
乳腺癌（BC）是全球女性中最常见的癌症类型，也是复发、疾病进展和转移的基础。对化疗和程序性细胞死亡（PCD）（包括凋亡）的耐药性强烈影响BC治疗的成功，并且仍然是一个重大挑战。尽管坏死性凋亡——一种裂解性的、通过损伤相关分子模式（DAMP）释放的、高度免疫原性的PCD模式——可能克服凋亡耐药性，但迫切需要生理学和转化人类模型来模拟BC中的坏死性凋亡和PCD耐药性。在此，我们应用3D患者来源的转移性人乳腺类器官（hMOs），通过单细胞CITE测序、延时活细胞明场和免疫荧光共聚焦显微镜以及生化方法来模拟凋亡耐药性、坏死性凋亡和炎症信号传导。Smac模拟物触发的凋亡可在一组BC hMOs中得到证实。在用caspase抑制诱导凋亡耐药性后，BC hMOs迅速发生坏死性凋亡，并伴有显著的MLKL磷酸化。坏死性细胞死亡之前，炎症性细胞因子和趋化因子（包括干扰素）的转录显著上调，这些因子可激活NK 细胞。最后，在转移性BC hMOs中，坏死性凋亡以及炎症信使的表达和释放可在抑制线性泛素化后被减弱。我们描述了一种新的实验平台，用于模拟PCD、炎症和坏死性凋亡，该平台允许进行治疗性筛选以克服患者来源的转移性BC hMOs中的化疗耐药性。利用该平台，我们发现了坏死性凋亡诱导的干扰素信号传导，表明Smac模拟物和坏死性凋亡可作为针对转移性BC的潜在免疫治疗策略。
Breast cancer (BC) is the most common type of cancer among women worldwide and underlies relapse, disease progression, and metastasis. Resistance to chemotherapy and programmed cell death (PCD), including apoptosis, strongly affects BC therapy success and remains a major challenge. Although necroptosis, a lytic, and via damage-associated molecular patterns (DAMP) release, highly immunogenic mode of PCD, might overcome apoptosis resistance, there is an urgent need for physiological and translational human models to model necroptosis and PCD resistance in BC. Here, we apply 3D patient-derived, metastatic human mammary organoids (hMOs) to model apoptosis resistance, necroptosis, and inflammatory signaling using single-cell CITE-sequencing, time-lapse live cell brightfield, and immunofluorescent confocal microscopy, as well as biochemical approaches. Smac mimetic-triggered apoptosis could be confirmed in a panel of BC hMOs. Upon inducing apoptosis resistance with caspase inhibition, BC hMOs rapidly undergo necroptosis with profound MLKL phosphorylation. Necroptotic cell death was preceded by prominent transcriptional upregulation of inflammatory cyto- and chemokines, including interferons, that activate natural killer cells. Finally, necroptosis and the expression and release of inflammatory messengers in metastatic BC hMOs could be attenuated upon the inhibition of linear ubiquitination. We describe a novel experimental platform to model PCD, inflammation, and necroptosis that allows therapeutic screening to overcome chemotherapy resistance in patient-derived metastatic BC hMOs. With this platform, we identified necroptosis-induced interferon signaling, suggesting Smac mimetics and necroptosis as a potential immunotherapy strategy against metastatic BC.
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