加州大学Tien Peng课题组近日取得一项新成果。经过不懈努力，他们研究出肿瘤基质中对衰老细胞清除剂敏感的p16^Ink4a+成纤维细胞重编程肺癌代谢与可塑性。相关论文于2025年11月3日发表在《细胞—干细胞》杂志上。

该研究组发现了富含衰老表型的p16^Ink4a+癌症相关成纤维细胞，这些成纤维细胞促进了Kras和p53突变驱动的侵袭性肺腺癌（LUAD）对脂肪酸的摄取和利用。

此外，p16^Ink4a+癌症相关成纤维细胞对肺癌代谢的重新连接也将肿瘤细胞的身份改变为与小鼠和人类LUAD进展相关的高度可塑性/去分化状态。他们的体外抗衰老筛选平台鉴定出XL888，一种HSP90抑制剂，在体内清除p16^Ink4a+癌症相关成纤维细胞。晚期LUAD建立后给予XL888可显著减轻肿瘤负担，同时可塑性肿瘤细胞减少。他们的研究确定了肿瘤基质的一种可药物成分，该成分满足肿瘤细胞获得更具攻击性表型的代谢需求。

据了解，衰老已被证明可以抑制或促进肿瘤的发生。要解决这一矛盾，需要对衰老细胞在原生肿瘤生态位中的空间定位和功能特征进行研究。

附：英文原文

Title: Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity

Author: Jin Young Lee, Nabora Reyes, Sang-Ho Woo, Nancy C. Allen, Tsukasa Kadota, Andrew Lechner, Ritusree Biswas, Sakshi Goel, Fia Stratton, Chaoyuan Kuang, Tatsuya Tsukui, Vincent Auyeung, Aaron S. Mansfield, Lindsay M. LaFave, Tien Peng

Issue&Volume: 2025-11-03

Abstract: Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identify p16Ink4a+ cancer-associated fibroblasts enriched with senescent phenotypes that promote fatty acid uptake and utilization by aggressive lung adenocarcinoma (LUAD) driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by p16Ink4a+ cancer-associated fibroblasts also alters tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our ex vivo senolytic screening platform identifies XL888, an HSP90 inhibitor, that clears p16Ink4a+ cancer-associated fibroblasts in vivo. XL888 administration after establishment of advanced LUAD significantly reduces tumor burden concurrent with the loss of plastic tumor cells. Our study identifies a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.

DOI: 10.1016/j.stem.2025.10.005

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00373-X