Triple-negative breast cancer (TNBC) stands as the breast cancer subtype with the highest recurrence and mortality rates, with the lungs being the common site of metastasis. The pulmonary microenvironment plays a pivotal role in the colonization of disseminated tumor cells. Herein, this study highlights the crucial role of exosomal LAP-TGF-β1, the principal form of exosomal TGF-β1, in reshaping the pulmonary vascular niche, thereby facilitating TNBC lung metastasis. Although various strategies have been developed to block TGF-β signaling and have advanced clinically, their significant side effects have limited their therapeutic application. This study demonstrates that in lung metastatic sites, LAP-TGF-β1 within exosomes can remarkably reconfigure the pulmonary vascular niche at lower doses, bolstering the extravasation and colonization of TNBC cells in the lungs. Mechanistically, under the aegis of the acetyltransferase TIP60, a non-canonical KFERQ-like sequence in LAP-TGF-β1 undergoes acetylation at the K304 site, promoting its interaction with HSP90A and subsequent transport into exosomes. Concurrent inhibition of both HSP90A and TIP60 significantly diminishes the exosomal burden of LAP-TGF-β1, presenting a promising therapeutic avenue for TNBC lung metastasis. This study not only offers fresh insights into the molecular underpinnings of TNBC lung metastasis but also lays a foundation for innovative therapeutic strategies.

中文翻译：

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乙酰化LAP-TGF-β1蛋白掺入外泌体促进肺微转移中TNBC细胞传播

三阴性乳腺癌（TNBC）是复发率和死亡率最高的乳腺癌亚型，肺部是常见的转移部位。肺部微环境在播散性肿瘤细胞的定植中起着关键作用。在此，本研究强调了外泌体 LAP-TGF-β1（外泌体 TGF-β1 的主要形式）在重塑肺血管生态位，从而促进 TNBC 肺转移中的关键作用。尽管已经开发出多种策略来阻断 TGF-β 信号传导并在临床上取得进展，但其显着的副作用限制了其治疗应用。这项研究表明，在肺转移部位，外泌体中的 LAP-TGF-β1 可以在较低剂量下显着地重新配置肺血管生态位，促进 TNBC 细胞在肺部的外渗和定植。从机制上讲，在乙酰转移酶 TIP60 的支持下，LAP-TGF-β1 中的非经典 KFERQ 样序列在 K304 位点发生乙酰化，促进其与 HSP90A 相互作用并随后转运到外泌体中。同时抑制 HSP90A 和 TIP60 显着减少 LAP-TGF-β1 的外泌体负荷，为 TNBC 肺转移提供了一种有前景的治疗途径。这项研究不仅为 TNBC 肺转移的分子基础提供了新的见解，而且为创新治疗策略奠定了基础。