胰腺癌转移异质性:靶向干预的机制和机会。

Ravikanth Maddipati
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摘要

胰腺导管腺癌(PDAC)仍然是最致命的癌症之一,转移是死亡率的主要驱动因素。尽管各种恶性肿瘤的转移机制是相同的,但由于存在广泛的肿瘤异质性、结缔组织增生和免疫抑制,PDAC转移带来了独特的治疗挑战,这些特征使得多种迁移行为和治疗耐药性成为可能。最近的进展表明,PDAC的转移进展源于肿瘤细胞内在因素和微环境因素之间的动态相互作用,在转移级联过程中,每种因素都适应不断变化的应激源。在原发肿瘤中,基因组不稳定性和表观遗传重编程产生具有更高侵袭潜力的亚克隆,而密集的基质反应和髓细胞主导的免疫抑制促进了逃逸。在循环过程中,PDAC细胞通过同型聚类和与血液成分的异型相互作用采用独特的生存策略。在远处,PDAC细胞通过上下文相关的代谢和免疫调节来适应器官特异性微环境,导致与原发肿瘤不同的表型。在这篇综述中,我们研究了肿瘤-基质串扰机制如何影响PDAC的转移进展,提供了一个框架来理解为什么传统疗法经常不能治疗转移性疾病,并强调了针对这些独特适应性的阶段和部位特异性治疗干预的新机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Metastatic heterogeneity in pancreatic cancer: mechanisms and opportunities for targeted intervention.
Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal cancers, with metastasis as the primary driver of mortality. While metastatic mechanisms are shared across malignancies, PDAC metastasis poses unique therapeutic challenges due to the presence of extensive tumor heterogeneity, desmoplasia, and immunosuppression - features that enable diverse migratory behaviors and therapeutic resistance. Recent advances have shown that metastatic progression in PDAC emerges from dynamic interactions between tumor cell-intrinsic and microenvironmental factors, each adapting to evolving stressors throughout the metastatic cascade. In the primary tumor, genomic instability and epigenetic reprogramming generate subclones with heightened invasive potential, while dense stromal reactions and myeloid-dominated immune suppression facilitate escape. During circulation, PDAC cells employ distinctive survival strategies through homotypic clustering and heterotypic interactions with blood components. At distant sites, PDAC cells adapt to organ-specific microenvironments through context-dependent metabolic and immune modulation, resulting in phenotypes that diverge from the primary tumor. In this Review, we examine how tumor-stroma crosstalk mechanisms shape metastatic progression in PDAC, provide a framework for understanding why conventional therapies often fail against metastatic disease, and highlight emerging opportunities for stage- and site-specific therapeutic interventions that target these unique adaptations.
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