Recently, the team of Lingyi Kong/Chao Zhang from the School of Traditional Chinese Medicine of the University of China published their latest research results entitled “The incorporation of acetylated LAP-TGF-β1 proteins into exosomes promotes TNBC dissemination in lung micro-metastasis”. Pei Yu, a postdoctoral fellow at the School of Traditional Chinese Medicine, and Yubao Han, a master's degree graduate of the class of 2019, are the co-first authors of this article, Prof. Lingyi Kong and Associate Researcher Chao Zhang are the co-corresponding authors, and China Pharmaceutical University (CPU) is the first corresponding author of this article.
Triple-negative breast cancer (TNBC) is the breast cancer subtype with the highest recurrence and mortality rates, and the lung is a common site of metastasis. A large body of evidence suggests that TNBC metastases in the lungs are often formed by repeated spreading of TNBC lung micrometastatic foci (from one to many) rather than multiple metastases of tumor cells directly originating from the primary site of breast cancer.TNBC lung micrometastatic tumor foci are able to provide a favorable “soil” for the formation of a large number of lung metastatic tumor foci by altering the vascular microenvironment. “. Exosomes are one of the key mediators of intercellular communication, and the “molecular cargo” of tumor-derived exosomes (including proteins and nucleic acids) can regulate cellular behavior, but how the “molecular cargo” of TNBC exosomes affects the vascular microenvironment and promotes the formation of large numbers of metastatic tumor foci in the lungs is not clear. The molecular details of how TNBC exosomes affect the vascular microenvironment and contribute to the formation of massive metastatic tumor foci in the lung remain elusive.
The present study reveals the critical role of TNBC exosome-loaded LAP-TGF-β1 in remodeling the pulmonary vascular ecological niche and promoting TNBC lung metastasis. Although various strategies to block the TGF-β signaling pathway have been developed and achieved clinical progress, their severe side effects have limited their clinical application. In the present study, we found that at the site of lung metastasis, LAP-TGF-β1 on TNBC exosomes could significantly remodel the pulmonary vascular ecological niche and promote the extravasation and colonization of TNBC cells in the lungs at a dose much lower than that of free TGF-β1. Further studies revealed the presence of a nonclassical KFERQ-like sequence in the TGFB1 region of LAP-TGF-β1, whose K304 site undergoes acetyltransferase TIP60-mediated acetylation, facilitating interaction with HSP90A for translocation to exosomes. Simultaneous inhibition of HSP90A and TIP60 significantly reduced the exosomal load of LAP-TGF-β1 and effectively inhibited TNBC lung metastasis. This study not only provides new insights into the molecular basis of TNBC lung metastasis, but also lays the foundation for the development of novel therapeutic strategies.
This research work was supported by the National Natural Science Foundation of China under Grant Nos. 82304713 and 82274073, and the Excellence Postdoctoral Program of Jiangsu Province under Grant No. 2022ZB291.
