ECM Composition and Rheology Regulate Growth, Motility, and Response to Photodynamic Therapy in 3D Models of Pancreatic Ductal Adenocarcinoma.
ECM Composition and Rheology Regulate Growth, Motility, and Response to Photodynamic Therapy in 3D Models of Pancreatic Ductal Adenocarcinoma.
复制标题
ECM 成分和流变学调节胰腺导管腺癌 3D 模型中的生长、运动和对光动力治疗的反应。
DOI：
10.1158/1541-7786.mcr-16-0260
复制
发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Celli JP
中科院分区：
文献类型：
--
作者：
Cramer GM;Jones DP;El-Hamidi H;Celli JP
胰腺导管腺癌(PDAC)以显著的间质受累为特征，在调节肿瘤生长和治疗反应中起着复杂的作用。富含细胞外基质(ECM)的PDAC基质被认为是药物渗透的屏障，尽管基质耗竭策略在临床上取得了好坏参半的效果。目前尚不清楚与ECM的相互作用，作为表型的生物物理调节因子，不仅是药物灌流的屏障，如何调节对特定治疗的敏感性和耐药性。在此背景下，采用一种综合的方法来评估血液流变学特征的ECM的侵袭行为和运动性，以此作为化疗和光动力疗法(PDT)反应的决定因素。我们发现，在3D培养中，在细胞外基质促进侵袭进展的条件下，最活跃的细胞外基质渗透群体对PDT的反应显著增强，而同样的细胞表现出化疗耐药性。相反，产生具有增强侵袭潜力的耐药亚系，以比较相同ECM条件下的不同治疗反应，通过对基质重塑的颗粒跟踪微观流变学测量进行监测。在这两种情况下，ECM浸润性细胞群体对PDT表现出更高的敏感性，无论侵袭是由于化疗耐药的选择，还是化学耐药与侵袭行为的获得相关。然而，尽管ECM侵袭、化疗耐药细胞表现出间充质表型，但在没有ECM的单层中诱导EMT并不足以增强PDT的敏感性，但确实如预期的那样给予化疗耐药。除了包含具有更广泛适用性的平台开发，以告知微环境依赖的治疗方法，这些结果揭示了PDT针对最具侵袭性、化疗耐药、侵袭性PDAC的有效性，这些PDAC与这种疾病的悲惨结果相关。细胞外基质浸润性和化疗耐药的胰腺肿瘤群体对光动力疗法(PDT)的敏感性增加。
Pancreatic ductal adenocarcinoma (PDAC) is characterized by prominent stromal involvement, which plays complex roles in regulating tumor growth and therapeutic response. The extracellular matrix (ECM)-rich PDAC stroma has been implicated as a barrier to drug penetration, though stromal depletion strategies have had mixed clinical success. It remains less clear how interactions with ECM, acting as a biophysical regulator of phenotype, not only a barrier to drug perfusion, regulate susceptibilities and resistance to specific therapies. In this context, an integrative approach is used to evaluate invasive behavior and motility in rheologically-characterized ECM as determinants of chemotherapy and photodynamic therapy (PDT) responses. We show that in 3D cultures with ECM conditions that promote invasive progression, response to PDT is markedly enhanced in the most motile ECM-infiltrating populations while the same cells exhibit chemoresistance. Conversely, drug-resistant sublines with enhanced invasive potential were generated to compare differential treatment response in identical ECM conditions, monitored by particle tracking microrheology measurements of matrix remodeling. In both scenarios, ECM-infiltrating cell populations exhibit increased sensitivity to PDT, whether invasion is consequent to selection of chemoresistance, or whether chemoresistance is correlated with acquisition of invasive behavior. However, while ECM-invading, chemoresistant cells exhibit mesenchymal phenotype, induction of EMT in monolayers without ECM was not sufficient to enhance PDT sensitivity, yet does impart chemoresistance as expected. In addition to containing platform development with broader applicability to inform microenvironment-dependent therapeutics, these results reveal the efficacy of PDT for targeting the most aggressive, chemoresistant, invasive PDAC associated with dismal outcomes for this disease. ECM-infiltrating and chemoresistant pancreatic tumor populations exhibit increased sensitivity to photodynamic therapy (PDT).