癌症研究所Axel Behrens研究小组近日取得一项新成果。经过不懈努力，他们报道了SPP1是维持胰腺癌间充质细胞命运所必需的。相关论文于2025年9月24日发表在《自然》杂志上。

课题组研究人员之前的研究表明，间质PDAC细胞分泌的BMP拮抗剂GREM1对BMP活性的持续抑制对于维持上皮PDAC细胞的命运至关重要。

在这里，课题组发现SPP1（也称为骨桥蛋白）4是胰腺癌间充质细胞命运的关键调节因子。PDAC患者血浆的蛋白质组学分析显示，SPP1在晚期疾病中显著上调。SPP1的失活导致单主题PDAC模型的肿瘤发生延迟，并消除转移形成。SPP1在上皮性PDAC细胞中表达，SPP1失活导致间质PDAC细胞向上皮性PDAC细胞转化。机制上，SPP1结合间质PDAC细胞上的CD61受体诱导Bmp2和Grem1表达，而上皮细胞中SPP1表达BMP信号需要Grem1抑制，从而形成细胞间调控环。同时，Grem1的失活使SPP1基因敲除后的上皮表型恢复为完全间质PDAC。相反，Grem1杂合性结合SPP1敲除导致野生型PDAC组织学，这一结果证实了这些因子的直接拮抗功能。因此，间充质和上皮PDAC细胞的命运是由可溶性因子GREM1和SPP1的相互旁分泌调节决定的。

据介绍，阐明肿瘤细胞之间复杂的通讯网络对于理解细胞命运决定和胰腺导管腺癌（PDAC）的进展至关重要。

附：英文原文

Title: SPP1 is required for maintaining mesenchymal cell fate in pancreatic cancer

Author: Li, Huafu, Lan, Linxiang, Chen, Hengxing, Zaw Thin, May, Ps, Hari, Nelson, Jessica K., Evans, Ian M., Ruiz, E. Josue, Cheng, Rongjie, Tran, Li, Allen, Mark, Ma, Jian, Yi, Tingzhuang, Wang, Chunming, He, Yulong, Guppy, Naomi, Sadanandam, Anguraj, Lin, Shao-Zhen, Zhang, Changhua, Behrens, Axel

Issue&Volume: 2025-09-24

Abstract: Elucidating the complex network of communication between tumour cells is central to understanding cell fate decisions and progression of pancreatic ductal adenocarcinoma (PDAC)1,2. We previously showed that constant suppression of BMP activity by the BMP antagonist GREM1 secreted by mesenchymal PDAC cells is essential for maintaining the fate of epithelial PDAC cells3. Here we identify SPP1 (also known as osteopontin)4 as a key regulator of mesenchymal cell fate in pancreatic cancer. Proteomic analysis of plasma from patients with PDAC showed that SPP1 is substantially upregulated in late-stage disease. Inactivation of Spp1 led to a delay in tumorigenesis in mouse PDAC models and abolished metastasis formation. Spp1 was expressed in epithelial PDAC cells, and Spp1 inactivation resulted in a conversion of mesenchymal to epithelial PDAC cells. Mechanistically, SPP1 bound the CD61 receptor on mesenchymal PDAC cells to induce Bmp2 and Grem1 expression, and GREM1 inhibition of BMP signalling was required for Spp1 expression in epithelial cells, thereby forming an intercellular regulatory loop. Concomitant inactivation of Grem1 reverted the epithelial phenotype of Spp1 knockout to fully mesenchymal PDAC. Conversely, Grem1 heterozygosity combined with Spp1 knockout resulted in wild-type PDAC histology, a result that confirmed the direct antagonistic functions of these factors. Hence, mesenchymal and epithelial PDAC cell fates are determined by the reciprocal paracrine regulation of the soluble factors GREM1 and SPP1.

DOI: 10.1038/s41586-025-09574-y

Source: https://www.nature.com/articles/s41586-025-09574-y