Endothelial Cell Autophagy Suppresses Metastasis In Mouse Mammary and Pancreatic Neuroendocrine Tumor Models

Autophagy, a key lysosomal degradation pathway regulating metabolic adaptation in cancer, plays fundamental roles in both the tumor and host stromal compartments during cancer progression. An important unanswered question is whether and how autophagy in specific host stromal elements, such as endothelial cells, influences metastasis. Here, we scrutinize how the genetic loss of autophagy in endothelial cells impacts primary tumor progression and metastasis in the Polyoma Middle T (<i>PyMT</i>) model of luminal B breast cancer. In both autochthonous and orthotopic mammary transplant models, <i>PyMT</i> primary tumor growth is significantly delayed upon endothelial cell Atg12 or Atg5 genetic deletion (<i>Atg12 or 5</i> ECKO), which correlates with increased tumor cell apoptosis and HIF1α activation. In contrast, <i>PyMT</i>-bearing <i>Atg12</i> ECKO mice exhibit increased metastasis, as well as higher rates of primary tumor and lung metastatic recurrence following surgical resection of <i>PyMT</i> primary tumors. Experimental metastasis assays further corroborate that loss of endothelial cell autophagy in <i>Atg12</i> ECKO host animals promotes PyMT metastatic colonization and outgrowth, resulting in increased lung metastases compared to controls. Similarly, in the Rat Insulin Promoter T antigen pancreatic neuroendocrine tumor (RT2-PNET) model, endothelial cell deletion of <i>Atg12</i> promotes liver micro-metastases. Taken together, these results from distinct preclinical cancer models reveal that endothelial cell autophagy suppresses metastatic seeding and progression and broach that autophagy inhibition in host endothelial cells may adversely influence the efficacy of systemic autophagy-lysosomal pathway inhibition in the clinical oncology setting.