University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
Section of Developmental Biology, Dept. of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
PLoS One. 2024 Apr 10;19(4):e0298808. doi: 10.1371/journal.pone.0298808. eCollection 2024.
Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level.
胰腺导管腺癌 (PDAC) 在晚期出现，并且对大多数治疗方法都具有抗性。Wnt 信号激活在增殖和化学抗性中起着关键作用。通过对七种源自胰腺肿瘤类器官文库 (PTOL) 的患者来源类器官 (PDO) 的 Wnt 抑制来确定最小培养基条件、生长因子依赖性和 Wnt 依赖性。在体内使用患者来源的异种移植物评估在体外有反应的类器官。为每个类器官确定了 Wnt(+)和 Wnt(-)基因特征。与单独使用化疗或 ETC-159 相比，用 ETC-159 联合紫杉醇或吉西他滨治疗时，Panc269 的类器官生长呈下降趋势。与吉西他滨相比，Panc320 在 ETC-159 和紫杉醇的联合治疗中表现出更明显的抗增殖作用，但与吉西他滨无明显作用。将 Panc269 和 Panc320 植入裸鼠中，并分别用 ETC-159、紫杉醇和吉西他滨以及联合治疗。ETC-159 和紫杉醇的联合治疗显示出比单独使用 ETC-159 更强的抗肿瘤作用。在 Panc320 异种移植物中观察到联合治疗效果的程度较小。Panc269 和 320 的 Wnt(+)和 Wnt(-)基因特征与表型一致。通过 RT-PCR 评估的几个关键 Wnt 基因的表达在体内治疗后表现出明显的倍数变化。每个胰腺类器官的生长分析显示，在体外联合使用 Wnt 抑制剂和标准化疗后，对各种生态位因子的依赖性各不相同，为靶向治疗提供了途径。迄今为止，这种联合治疗模式在我们的患者来源的异种移植物模型中得到了支持，这些模型用 Wnt 抑制剂加紫杉醇或吉西他滨治疗。基因表达分析表明，存在关键的 Wnt 基因，这些基因对胰腺肿瘤的 Wnt(+)和 Wnt(-)表型有贡献，为 Wnt(+)和 Wnt(-)依赖性以及在基因型水平上对治疗的敏感性或抗性提供了合理的机制解释。
