Lou Xin, Shi Yihua, Zhao Faming, Xu Xiaowu, Wang Yan, Qin Yi, Zhang Wuhu, Ye Zeng, Wang Fei, Ding Tian, Jing Desheng, Fan Guixiong, Zhang Yue, Chen Xuemin, Chen Jie, Yu Xianjun, Xu Junfeng, Ji Shunrong
Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Cancer Res. 2025 Aug 1;85(15):2805-2819. doi: 10.1158/0008-5472.CAN-24-2528.
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.
胰腺神经内分泌肿瘤（pNET）中低肿瘤-基质比（TSR）与患者预后显著较差相关。尽管肿瘤基质是一个有吸引力的治疗靶点，但最近的临床试验并不成功。在本研究中，我们旨在剖析低TSR的pNET中调节肿瘤微环境的机制，以确定潜在的治疗靶点。激光捕获显微切割分析显示，与基质贫乏的肿瘤相比，基质丰富的肿瘤过量分泌载脂蛋白E（ApoE），其特异性受体SCARB1主要位于内皮细胞（EC）上。单细胞分析显示，由于癌细胞衍生的ApoE诱导其他类型的EC转化为内皮尖端细胞（TipEC），基质丰富的肿瘤中内皮尖端细胞（TipEC）的比例更高。TipEC通过促进癌相关成纤维细胞募集和重塑TSR在驱动pNET进展中发挥关键作用。机制上，ApoE促进EC摄取棕榈酸，随后激活转录因子ATF6以上调PDGF途径。在体内对六种常用的pNET药物进行筛选发现，用mTOR抑制剂治疗可抑制癌细胞分泌ApoE，阻断ApoE对基质微环境的后续影响。重要的是，mTOR抑制剂在体内协同增强了基质靶向药物PEGPH20对pNET的抗肿瘤作用。总体而言，本研究表明癌细胞衍生的ApoE可诱导TipEC重塑TSR，mTOR抑制剂可提高基质靶向治疗的疗效。
胰腺神经内分泌肿瘤细胞分泌ApoE产生富含基质的微环境，作为靶向肿瘤基质的联合策略的一部分，mTOR抑制剂可逆转这种微环境。
