CCBE1 is a secreted extracellular matrix protein essential for lymphatic and cardiac vascular development during embryogenesis 1. Mechanistically, CCBE1 functions by enhancing proteolysis of VEGF-C, activating VEGFR3-dependent lymphangiogenic signaling 23. During cardiac development, CCBE1 is expressed in cardiac progenitors and the epicardium, where it is required for proper coronary vessel formation 1. Additionally, CCBE1 promotes angiogenesis through VEGFC-mediated VEGFR2 activation 3. CCBE1 mutations cause Hennekam lymphangiectasia-lymphedema syndrome 1, characterized by lymphatic malformations, primary lymphedema, and cardiac defects 1. In cancer contexts, CCBE1 expression is dysregulated and protumorigenic. Elevated CCBE1 in colorectal and rectal cancers correlates with increased lymphatic vessel density, lymph node metastasis, and poor prognosis 24. Cancer-associated fibroblasts secrete CCBE1 to promote tumor lymphangiogenesis and metastasis 2. TGF-β signaling negatively regulates CCBE1 transcription, and loss of this pathway correlates with elevated CCBE1 in tumors 2. Beyond cancer, CCBE1 loss drives secondary lymphedema, and CCBE1 restoration via transcription factor E2F8 represents a therapeutic strategy 5.