Pancreatic Neuroendocrine Tumors Secrete Apolipoprotein E to Induce Tip Endothelial Cells That Remodel the Tumor–Stroma Ratio and Promote Cancer Progression

A low tumor-stroma ratio (TSR) in pancreatic neuroendocrine tumors (pNET) is associated with a significantly poorer patient prognosis. Although the tumor stroma represents an attractive therapeutic target, recent clinical trials have not been successful. In this study, we aimed to dissect the mechanisms regulating the tumor microenvironment in low TSR pNETs to identify potential therapeutic targets. Laser capture microdissection analysis revealed that stroma-rich tumors excessively secrete apolipoprotein E (ApoE) relative to stroma-poor tumors, with the specific receptor SCARB1 predominantly located on endothelial cells (EC). Single-cell analysis revealed a greater proportion of endothelial tip cells (TipEC) in stroma-rich tumors due to transformation of other types of ECs into TipECs induced by cancer cell-derived ApoE. The TipECs played crucial roles in driving pNET progression by facilitating cancer-associated fibroblast recruitment and remodeling the TSR. Mechanistically, ApoE promoted the uptake of palmitic acid by ECs and subsequently activated the transcription factor ATF6 to upregulate the PDGF pathway. Screening of six commonly used drugs for pNETs in vivo revealed that treatment with mTOR inhibitors suppressed the secretion of ApoE by cancer cells, blocking the subsequent effects of ApoE on the stromal microenvironment. Importantly, mTOR inhibitors synergistically enhanced the antitumor effects of stroma-targeting PEGPH20 in vivo in pNETs. Overall, this study revealed that cancer cell-derived ApoE could induce TipECs to remodel the TSR and that mTOR inhibitors could increase the efficacy of stroma-targeting therapies. Secretion of ApoE by pancreatic neuroendocrine tumor cells engenders a stroma-rich microenvironment, which can be reversed with mTOR inhibitors as part of combination strategies targeting the tumor stroma.