Buqué Aitziber, Beltrán-Visiedo Manuel, Sato Ai, Galassi Claudia, Petroni Giulia, Galluzzi Lorenzo
Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
Cell Death Discov. 2025 Jun 10;11(1):273. doi: 10.1038/s41420-025-02555-0.
Mitochondrial permeability transition (MPT)-driven necrosis and necroptosis are regulated variants of cell death that can drive inflammation or even promote antigen-specific immune responses. In oncological settings, indolent inflammatory reactions have been consistently associated with accelerated disease progression and resistance to treatment. Conversely, adaptive immune responses specific for tumor-associated antigens are generally restraining tumor development and contribute to treatment sensitivity. Here, we harnessed female C57BL/6J mice lacking key regulators of MPT-driven necrosis and necroptosis to investigate whether whole-body defects in these pathways would influence mammary carcinogenesis as driven by subcutaneous slow-release medroxyprogesterone acetate (MPA, M) pellets plus orally administered 7,12-dimethylbenz[a]anthracene (DMBA, D), an in vivo model that recapitulates multiple facets of the biology and immunology of human hormone receptor positive (HR) breast cancer. Our data demonstrate that female mice bearing a whole-body, homozygous deletion in peptidylprolyl isomerase F (Ppif), which encodes a key regulator of MPT-driven necrosis commonly known as CYPD, but not female mice with systemic defects in necroptosis as imposed by the whole body-deletion homozygous of receptor-interacting serine-threonine kinase 3 (Ripk3) or mixed lineage kinase domain like pseudokinase (Mlkl), are more susceptible to M/D-driven carcinogenesis than their wild-type counterparts. These findings point to CYPD as to an oncosuppressive protein that restrains HR mammary carcinogenesis in mice, at least potentially via MPT-driven necrosis.
线粒体通透性转换（MPT）驱动的坏死和坏死性凋亡是细胞死亡的调控变体，可引发炎症甚至促进抗原特异性免疫反应。在肿瘤学背景下，惰性炎症反应一直与疾病进展加速和治疗耐药性相关。相反，针对肿瘤相关抗原的适应性免疫反应通常会抑制肿瘤发展并提高治疗敏感性。在此，我们利用缺乏MPT驱动的坏死和坏死性凋亡关键调节因子的雌性C57BL/6J小鼠，研究这些通路的全身缺陷是否会影响由皮下缓释醋酸甲羟孕酮（MPA，M）颗粒加口服7,12-二甲基苯并[a]蒽（DMBA，D）驱动的乳腺癌发生，这是一种可概括人类激素受体阳性（HR）乳腺癌生物学和免疫学多个方面的体内模型。我们的数据表明，肽基脯氨酰异构酶F（Ppif）发生全身纯合缺失的雌性小鼠更易发生M/D驱动的致癌作用，Ppif编码一种MPT驱动的坏死的关键调节因子，通常称为CYPD；而受体相互作用丝氨酸苏氨酸激酶3（Ripk3）或混合谱系激酶结构域样假激酶（Mlkl）全身纯合缺失导致坏死性凋亡存在全身缺陷的雌性小鼠则不然。这些发现表明CYPD是一种肿瘤抑制蛋白，至少可能通过MPT驱动的坏死来抑制小鼠HR乳腺癌的发生。
