Alver Tine Norman, Bergholtz Helga, Holm Maia Blomhoff, Dorg Linda Trobe, Skrede Martina Landschoof, Kure Elin Hegland, Verbeke Caroline Sophie
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norway.
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norway.
Mod Pathol. 2025 Jun;38(6):100726. doi: 10.1016/j.modpat.2025.100726. Epub 2025 Jan 29.
Intratumor heterogeneity is considered a major cause of treatment failure in pancreatic ductal adenocarcinoma (PDAC). In recent years, marked heterogeneity at the genomic and transcriptional level has been revealed, but the spatial distribution of the heterogeneous cell populations has not been considered. Yet, it is assumed that cancer cells at the invasive front are endowed with enhanced migratory and invasive properties, although evidence is scanty, and cancer-associated fibroblasts (CAFs) in this location have not been characterized. In this study, digital spatial profiling was used to compare the transcriptional profiles of cancer cells and CAFs in the tumor center versus the invasive front of human PDAC. Four well-differentiated PDACs with conventional morphology were investigated with the GeoMx system (Nanostring). Regions of interest were analyzed in the tumor center and at the invasive front using a whole transcriptome assay in the cancer cell and CAF segments separately. Three of the PDACs harbored mutated KRAS, whereas the fourth case was confirmed wild-type KRAS. Substantial inter-regional heterogeneity was identified, with increased activity of pathways associated with cellular stress (including TNFα-signaling via NFκB, hypoxia, P53 pathway), proliferation (MYC targets, mitotic spindle), glycolysis, and epithelial-mesenchymal transition (EMT) at the invasive front in both the cancer cell and CAF segments compared with the center of the tumor. Immunohistochemical validation on 17 PDACs of well, moderate, and poor differentiation confirmed significant inter-regional heterogeneity in the expression level of markers of EMT and glycolysis. The results of this study show that in PDAC, transcriptional profiles of both cancer cells and CAFs differ between the center of the tumor and the invasive front.
肿瘤内异质性被认为是胰腺导管腺癌（PDAC）治疗失败的主要原因。近年来，已揭示出基因组和转录水平上的显著异质性，但尚未考虑异质细胞群体的空间分布。然而，尽管证据不足，但推测侵袭前沿的癌细胞具有增强的迁移和侵袭特性，并且该位置的癌症相关成纤维细胞（CAF）尚未得到表征。在本研究中，使用数字空间分析来比较人类PDAC肿瘤中心与侵袭前沿的癌细胞和CAF的转录谱。使用GeoMx系统（Nanostring）对四个具有传统形态的高分化PDAC进行了研究。分别在癌细胞和CAF片段中使用全转录组分析，对肿瘤中心和侵袭前沿的感兴趣区域进行了分析。其中三个PDAC携带KRAS突变，而第四例被确认为野生型KRAS。确定了显著的区域间异质性，与肿瘤中心相比，侵袭前沿的癌细胞和CAF片段中与细胞应激（包括通过NFκB的TNFα信号传导、缺氧、P53途径）、增殖（MYC靶点、有丝分裂纺锤体）、糖酵解和上皮-间质转化（EMT）相关的信号通路活性增加。对17个高分化、中分化和低分化PDAC进行免疫组织化学验证，证实了EMT和糖酵解标志物表达水平存在显著的区域间异质性。本研究结果表明，在PDAC中，肿瘤中心和侵袭前沿的癌细胞和CAF的转录谱均存在差异。
