Lymphoma angiogenesis is orchestrated by noncanonical signaling pathways

Angiogenesis is a hallmark of the tumor microenvironment that correlates with the prognosis of aggressive B cell lymphoma. Targeting established angiocrine pathways in lymphoma failed to improve treatment efficacy. Here, we model Myc-driven B cell lymphoma-induced angiogenesis. Few lymphoma cells are sufficient to activate the angiogenic switch in lymph nodes. The unique morphology of dense microvessels emerges without tip cell guidance and rests on blood endothelial cell (BEC) proliferation and aberrant sprouting. The transcriptional response of BECs is inflammation independent. Conventional HIF1alpha or Notch signaling routes prevalent in solid tumors are not involved. Instead, a non-conventional hypersprouting morphology is orchestrated by lymphoma-provided VEGF-C and lymphotoxin (LT). Interference with VEGFR-3/VEGF-C and LT/LTbR loops abrogated angiogenesis, thus revealing targets to block lymphomagenesis. Gene expression in lymph node stromal cells (BEC, LEC, FRC, DN) were compared with each other and tumor versus naïve. For tumor and naïve, each cell type was measured in three biological replicates with two technical replicates each (2*4*3*2=48 samples).