In vivo proteomic labeling reveals diverse proteomes for therapeutic targets. Wang et al.
Description
Proteomics has played a revolutionary role in medical sciences. However, the barrier between isolated samples and in vivo intact microenvironment has posed a huge challenge that hinders the next-generation development of proteomics. Here, we successfully generated an in vivo protein labeling (IVPL) model based on a new labeling substrate set and homemade APEX2-EGFPf/f mice. The Btn-Ph-3F substrate exhibits good stability in organs possessing complex microenvironments and diverse degrading enzymes, while APEX2-EGFPf/f mice can be mated with any commercial Cre mice, enabling specific proteomic labeling for customized cell groups in distant organs in vivo. Moving beyond profiling in situ proteome for intestinal epithelium, mammary glands, and Treg cells within tumors, we further achieved labeling of trace amounts of exogenous proteomics of exosomes derived from cancer patients in live mice, and identified essential players such as LDHAL6A that eventually persist and promote pathological progression in recipient cells in vivo. Inhibition of LDHAL6A combined with paclitaxel treatment effectively suppressed triple-negative breast cancer growth and metastasis. Our work not only establishes an advanced model for in vivo proteomic labeling, but also profiles ultimately exosomal actors in recipient organs for targeted therapy.