Li Xiuling, Li Senlin, Li Haotian, Wu Guo, Zhao Huijie, Liu Shaomin, Xu Xiaoding, Saw Phei Er
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China.
Sci China Life Sci. 2025 May 7. doi: 10.1007/s11427-024-2887-x.
Breast cancer remains the most prevalent malignancy among women worldwide, with triple-negative breast cancer (TNBC) representing its most aggressive and lethal subtype. TNBC is characterized by high rates of recurrence and lung metastasis after surgery, severely impacting patient quality of life. Recent studies highlight the critical role of metabolic reprogramming in driving cancer recurrence, migration, and invasion. While the underlying mechanisms remain complex and not fully elucidated, transcriptomic analyses comparing primary and metastatic breast cancer tissues from TNBC and Luminal patients have identified lysophosphatidylcholine acyltransferase 1 (LPCAT1) as a key enzyme upregulated in lung metastases and TNBC. LPCAT1 is strongly associated with poor prognosis due to its activation of the TGFβ signaling pathway. This activation is driven by LPCAT1's ability to increase cellular ATP levels, fostering a high-energy state that stimulates ATPase activity. Consequently, ATP-dependent chromatin remodeling via the BAF complex, which includes double PHD finger 2 (DPF2) as a critical subunit, regulates gene transcription essential for tumor progression. Through the LPCAT1-DPF2-TGFBR2 axis, TNBC cells enhance TGFβ signaling, promoting malignant behavior and metastasis. Addressing this, we developed a reduction-responsive nanoparticle platform for the systemic delivery of LPCAT1-targeted siRNA (siLPCAT1), which has shown significant efficacy in suppressing TNBC tumor growth and metastasis. These findings suggest that nanoparticle-mediated siLPCAT1 delivery represents a promising therapeutic strategy for advanced TNBC treatment.
乳腺癌仍然是全球女性中最常见的恶性肿瘤，三阴性乳腺癌（TNBC）是其中最具侵袭性和致命性的亚型。TNBC的特点是术后复发率和肺转移率高，严重影响患者的生活质量。最近的研究强调了代谢重编程在驱动癌症复发、迁移和侵袭中的关键作用。虽然其潜在机制仍然复杂且尚未完全阐明，但对TNBC和Luminal患者的原发性和转移性乳腺癌组织进行的转录组分析已确定溶血磷脂酰胆碱酰基转移酶1（LPCAT1）是在肺转移和TNBC中上调的关键酶。LPCAT1因其激活TGFβ信号通路而与不良预后密切相关。这种激活是由LPCAT1增加细胞ATP水平的能力驱动的，从而形成一种高能状态，刺激ATP酶活性。因此，通过BAF复合物进行的ATP依赖染色质重塑（其中包括双PHD指蛋白2（DPF2）作为关键亚基）调节肿瘤进展所必需的基因转录。通过LPCAT1-DPF2-TGFBR2轴，TNBC细胞增强TGFβ信号，促进恶性行为和转移。针对这一问题，我们开发了一种还原响应纳米颗粒平台，用于全身递送靶向LPCAT1的小干扰RNA（siLPCAT1），该平台在抑制TNBC肿瘤生长和转移方面已显示出显著疗效。这些发现表明，纳米颗粒介导的siLPCAT1递送代表了一种有前景的晚期TNBC治疗策略。
