Tumor-derived Apolipoprotein E induces Tip endothelial cell to remodel tumor stroma ratio and promote pancreatic neuroendocrine tumor progression

A low tumor stroma ratio (TSR) in patients with pancreatic neuroendocrine tumors (pNETs) is associated with a significantly poorer tumor prognosis. However, current clinical trials have shown that administration of a single drug targeting a matrix component does not improve tumor prognosis. The investigation of treatments targeting matrix components in combination with other therapies is crucial for effectively managing the TSR in pNETs. LCM analysis revealed that stroma-rich tumors excessively secrete APOE relative to stroma-poor tumors, with the specific receptor SCARB1 predominantly located on ECs. Single-cell analysis revealed a greater proportion of endothelial tip cells (TipECs) in stroma-rich tumors, because tumor-derived APOE could induce the transformation of other types of ECs into TipECs. These TipECs played crucial roles in driving pNETs progression by facilitating cancer-associated fibroblasts (CAFs) recruitment and remodeling the TSR. Mechanistically, APOE promoted the uptake of palmitic acid by ECs, and subsequently activated the transcription factor ATF6 to promote the PDGF pathway in vitro. Clinically, screening of 6 commonly used drugs for pNETs in vivo revealed that treatment with mTOR inhibitors suppressed the secretion of APOE by tumor cells and the subsequent effects of APOE on the stromal microenvironment, including the proportions of TipECs and CAFs. Importantly, mTOR inhibitors synergistically enhanced the effects of stroma-targeting PEGPH20 in vivo in pNETs. Overall, our study revealed that tumor-derived APOE could induce TipECs to remodel the TSR, and that mTOR inhibitors could increase the efficacy of the stroma-targeting drug PEGPH20.