Baiskhanova Dinara, Menzel Maike, Geismann Claudia, Röcken Christoph, Beitz Eric, Sebens Susanne, Trauzold Anna, Schäfer Heiner
Institute of Experimental Cancer Research, UKSH Campus Kiel, Arnold-Heller-Str. 3, Bldg. U30, 24105 Kiel, Germany.
Department of Pharmacy, Christian-Albrechts-University Kiel, 24118 Kiel, Germany.
Int J Mol Sci. 2025 Jun 4;26(11):5398. doi: 10.3390/ijms26115398.
Tumor cell heterogeneity, e.g., in stroma-rich pancreatic ductal adenocarcinoma (PDAC), includes a differential metabolism of lactate. While being secreted as waste product by most cancer cells characterized by the glycolytic Warburg metabolism, it is utilized by a subset of highly malignant cancer cells running the reverse Warburg metabolism. Key drivers of lactate transport are the carrier proteins SLC16A1 (import/export) and SLC16A3 (export). Expression and function of both carriers are controlled by the chaperone Basigin (BSG), which itself is functionally controlled by the transmembrane protease serine 11B (TMPRSS11B). In this study we explored the impact of TMPRSS11B on the phenotype of PDAC cells under reverse Warburg conditions. Amongst a panel of PDAC cell lines, Panc1 and BxPc3 cells were identified to express TMPRSS11B at a high level, whilst other cell lines such as T3M4 did not. ShRNA-mediated TMPRSS11B knock-down in Panc1 and BxPc3 cells enhanced lactate import through SLC16A1, as shown by GFP/iLACCO1 lactate uptake assay, whereas TMPRSS1B overexpression in T3M4 dampened SLC16A1-driven lactate uptake. Moreover, knock-down and overexpression of TMPRSS11B differentially impacted proliferation and chemoresistance under reverse Warburg conditions in Panc1 or BxPc3 and T3M4 cells, respectively, as well as their stemness properties indicated by altered colony formation rates and expression of the stem cell markers Nanog, Sox2, KLF4 and Oct4. These effects of TMPRSS11B depended on both SLC16A1 and BSG as shown by gene silencing. Immunohistochemical analysis revealed a reciprocal expression of TMPRSS11B and BSG together with SLC16A1 in some areas of tumor tissues from PDAC patients. Those regions exhibiting low or no TMPRSS11B expression but concomitant high expression of SLC16A1 and BSG revealed greater amounts of KLF4. In contrast, other tumor areas exhibiting high expression of TMPRSS11B together with BSG and SLC16A1 were largely negative for KLF4 expression. Thus, the differential expression of TMPRSS11B adds to metabolic heterogeneity in PDAC and its absence supports the reverse Warburg metabolism in PDAC cells by the enhancement of BSG-supported lactate uptake through SLC16A1 and subsequent phenotype alterations towards greater stemness.
肿瘤细胞异质性，例如在富含基质的胰腺导管腺癌（PDAC）中，包括乳酸代谢的差异。大多数以糖酵解型瓦伯格代谢为特征的癌细胞将乳酸作为废物分泌，而一小部分进行反向瓦伯格代谢的高恶性癌细胞则利用乳酸。乳酸转运的关键驱动因子是载体蛋白SLC16A1（输入/输出）和SLC16A3（输出）。这两种载体的表达和功能受伴侣蛋白基底膜联蛋白（BSG）控制，而BSG本身又受跨膜蛋白酶丝氨酸11B（TMPRSS11B）的功能调控。在本研究中，我们探讨了TMPRSS11B在反向瓦伯格条件下对PDAC细胞表型的影响。在一组PDAC细胞系中，Panc1和BxPc3细胞被鉴定为高水平表达TMPRSS11B，而其他细胞系如T3M4则不表达。GFP/iLACCO1乳酸摄取试验表明，shRNA介导的Panc1和BxPc3细胞中TMPRSS11B敲低增强了通过SLC16A1的乳酸摄取，而T3M4中TMPRSS1B过表达则抑制了SLC16A1驱动的乳酸摄取。此外，TMPRSS11B的敲低和过表达分别对Panc1或BxPc3以及T3M4细胞在反向瓦伯格条件下的增殖和化疗耐药性产生不同影响，以及对其干性特性产生影响，这通过集落形成率的改变以及干细胞标志物Nanog、Sox2、KLF4和Oct4的表达来表明。基因沉默表明，TMPRSS11B的这些作用依赖于SLC16A1和BSG。免疫组织化学分析显示，在PDAC患者肿瘤组织的某些区域，TMPRSS11B与BSG以及SLC16A1相互表达。那些TMPRSS11B表达低或无表达但SLC16A1和BSG同时高表达的区域显示出更多的KLF4。相反，其他TMPRSS11B与BSG以及SLC16A1同时高表达的肿瘤区域KLF4表达基本为阴性。因此，TMPRSS11B的差异表达增加了PDAC中的代谢异质性，其缺失通过增强BSG支持的SLC16A1乳酸摄取以及随后向更高干性的表型改变，支持了PDAC细胞中的反向瓦伯格代谢。
