BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease that can develop therapy resistance over time. The dense stroma in PDAC plays a critical role in tumor progression and resistance. How this stroma interacts with the tumor cells and how this is influenced by chemotherapy remain poorly understood. METHODS: The backbone of this study is the parallel transcriptome analysis of human tumor and mouse stroma in two molecular and clinical representative patient-derived tumor xenografts models. Mice (8 animals per group) were treated for 4 weeks with gemcitabine or control. We studied tumor growth, RNA expression in the stroma, tumor-associated macrophages (TAMs) with immunofluorescence, and cytokines in the serum. RESULTS: A method for parallel transcriptome analysis was optimized. We found that the tumor (differentiation, gene expression) determines the infiltration of macrophages into the stroma. In aggressive PDAC (epithelial-to-mesenchymal transition high), we find more M2 polarized TAMs and the activation of cytokines and growth factors (TNFα, TGFβ1, and IL6). There are increased stromal glycolysis, reduced fatty acid oxidation, and reduced mitochondrial oxidation (tricarboxylic acid cycle and oxidative phosphorylation). Treatment with gemcitabine results in a shift of innate immune cells, especially additional infiltration of protumoral M2 TAMs (P < .001) and metabolic reprogramming. CONCLUSIONS: Gemcitabine treatment of PDAC xenografts stimulates a protumoral macrophage phenotype, and this, in combination with a shift of the tumor cells to a mesenchymal phenotype that we reported previously, contributes to tumor progression and therapeutic resistance. Targeting M2-polarized TAMs may benefit PDAC patients at risk to become refractory to current anticancer regimens.

背景：胰腺导管腺癌（PDAC）是一种非常致命的疾病，随着时间的推移会发展出治疗耐药性。PDAC中的致密基质在肿瘤进展和耐药中起关键作用。这种基质如何与肿瘤细胞相互作用以及如何受到化学疗法影响仍然知之甚少。方法：本研究的主要内容是在两种分子和临床代表性患者来源的肿瘤异种移植模型中对人类肿瘤和小鼠基质进行平行转录组分析。用吉西他滨或对照将小鼠（每组8只动物）治疗4周。我们研究了肿瘤的生长，基质中的RNA表达，具有免疫荧光的肿瘤相关巨噬细胞（TAM）和血清中的细胞因子。结果：优化了平行转录组分析的方法。我们发现肿瘤（分化，基因表达）决定了巨噬细胞向基质的浸润。在侵袭性的PDAC（上皮向间充质高转变）中，我们发现了更多的M2极化的TAM以及细胞因子和生长因子（TNFα，TGFβ1和IL6）的激活。基质糖酵解增加，脂肪酸氧化减少，线粒体氧化减少（三羧酸循环和氧化磷酸化）。吉西他滨治疗导致先天免疫细胞转移，尤其是肿瘤M2 TAM的额外浸润（P <.001）和代谢重编程。结论：吉西他滨对PDAC异种移植物的治疗刺激了肿瘤巨噬细胞表型，这与我们先前报道的肿瘤细胞向间充质表型的转变相结合，有助于肿瘤进展和治疗耐药性。靶向M2极化的TAM可能使处于危险中的PDAC患者受益于目前的抗癌方案。