PDF(Pubmed)
Abstract：
Pancreatic ductal adenocarcinoma (PDAC) presents a formidable clinical challenge due to its intricate microenvironment characterized by desmoplasia and complex tumor-stroma interactions. Conventional models hinder studying cellular crosstalk for therapeutic development. To recapitulate key features of PDAC masses, this study creates a novel sea-and-island PDAC tumor construct (s&i PTC). The s&i PTC consists of 3D-printed islands of human PDAC cells positioned within an interstitial extracellular matrix (ECM) populated by human cancer-associated fibroblasts (CAFs). This design closely mimics the in vivo desmoplastic architecture and nutrient-poor conditions. The model enables studying dynamic tumor-stroma crosstalk and signaling reciprocity, revealing both known and yet-to-be-discovered multicellular metabolic adaptations. Using the model, we discovered the orchestrated dynamic alterations of CAFs under nutrient stress, resembling critical in vivo human tumor niches, such as the secretion of pro-tumoral inflammatory factors. Additionally, nutrient scarcity induces dynamic alterations in the ECM composition and exacerbates poor cancer cell differentiation-features well-established in PDAC progression. Proteomic analysis unveiled the enrichment of proteins associated with aggressive tumor behavior and ECM remodeling in response to poor nutritional conditions, mimicking the metabolic stresses experienced by avascular pancreatic tumor cores. Importantly, the model\'s relevance to patient outcomes is evident through an inverse correlation between biomarker expression patterns in the s&i PTCs and PDAC patient survival rates. Key findings include upregulated MMPs and key ECM proteins (such as collagen 11 and TGFβ) under nutrient-avid conditions, known to be regulated by CAFs, alongside the concomitant reduction in E-cadherin expression associated with a poorly differentiated PDAC state under nutrient deprivation. Furthermore, elevated levels of hyaluronic acid (HA) and integrins in response to nutrient deprivation underscore the model\'s fidelity to the PDAC microenvironment. We also observed increased IL-6 and reduced α-SMA expression under poor nutritional conditions, suggesting a transition of CAFs from myofibroblastic to inflammatory phenotypes under a nutrient stress akin to in vivo niches. In conclusion, the s&i PTC represents a significant advancement in engineering clinically relevant 3D models of PDAC masses. It offers a promising platform for elucidating tumor-stroma interactions and guiding future therapeutic strategies to improve patient outcomes.
摘要：
胰腺导管腺癌（PDAC）由于其复杂的微环境而表现出巨大的临床挑战，其特征在于组织增生和复杂的肿瘤-基质相互作用。常规模型阻碍了研究用于治疗开发的细胞串扰。为了概括PDAC肿块的关键特征，这项研究创造了一种新的海岛PDAC肿瘤构建体(s&iPTC)。S＆iPTC由位于由人类癌症相关成纤维细胞（CAF）填充的间质细胞外基质（ECM）内的3D打印的人类PDAC细胞岛组成。这种设计紧密地模拟了体内去纤维增生结构和营养贫乏的条件。该模型能够研究动态的肿瘤-基质串扰和信号相互作用，揭示了已知和尚未发现的多细胞代谢适应。使用该模型，我们发现了营养胁迫下CAFs的动态变化，类似于关键的体内人类肿瘤生态位，如促肿瘤炎症因子的分泌。此外,营养缺乏引起ECM组成的动态改变，并加剧了PDAC进展中公认的不良癌细胞分化特征。蛋白质组学分析揭示了与不良营养条件下侵袭性肿瘤行为和ECM重塑相关的蛋白质的富集。模拟无血管胰腺肿瘤核心经历的代谢应激。重要的是,通过S&IPTCs中生物标志物表达模式与PDAC患者生存率之间的负相关,模型与患者结局的相关性很明显.关键发现包括在营养丰富的条件下上调MMP和关键ECM蛋白（如胶原蛋白11和TGFβ）。已知受CAF监管，在营养剥夺的情况下，与低分化PDAC状态相关的E-cadherin表达伴随减少。此外，对营养剥夺的反应中透明质酸(HA)和整合素水平的升高强调了模型对PDAC微环境的保真度。我们还观察到在不良营养条件下IL-6增加和α-SMA表达减少。提示在类似于体内生态位的营养压力下，CAF从肌纤维母细胞向炎症表型的转变。总之,S&IPTC代表了PDAC质量的临床相关3D模型工程的重大进展。它为阐明肿瘤-基质相互作用和指导未来治疗策略以改善患者预后提供了一个有前途的平台。
