Sharma Pinky, Michaels Yale S, Pearson Joel D
Department of Pharmacology & Therapeutics, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.
Paul Albrechtsen Research Institute CancerCare Manitoba, Winnipeg, MB, Canada.
Biochem J. 2025 May 28;482(11):741-61. doi: 10.1042/BCJ20253077.
Cancers have traditionally been classified based on their tissue of origin. However, with advances in sophisticated genome sequencing techniques and progression toward an era of precision medicine, it has become increasingly clear that classifying tumors based on unifying molecular features instead of tissue of origin may hold the key to improving patient outcomes. Various efforts have been undertaken to address this critical aspect of cancer biology, but it is still unclear as to the best approach to stratify tumors into different molecular classes. One approach is to define many small subclasses based on complex molecular signatures, while another option is to divide cancers into larger groups based on higher-order features of cancer behavior. This latter approach holds appeal as it may provide opportunities to identify broadly relevant therapeutics. However, our understanding of these fundamental 'rules' of cancer biology and how they can be used to better classify and treat cancers is in its infancy. We recently demonstrated that cancers can be functionally stratified into binary YAPon and YAPoff super-classes with unique therapeutic vulnerabilities based on distinct expression and function of the transcriptional coactivators, YAP and TAZ. In YAPon cancers, YAP and TAZ drive oncogenesis, whereas in YAPoff cancers, YAP and TAZ are instead tumor suppressors. In this review, we discuss our understanding of these distinct cancer classes with a focus on the mechanisms that underlie the opposite function of YAP/TAZ in YAPon and YAPoff cancers, as well as the potential therapeutic implications of these findings.
传统上，癌症是根据其起源组织进行分类的。然而，随着先进的基因组测序技术的发展以及向精准医学时代的迈进，越来越明显的是，基于统一的分子特征而非起源组织对肿瘤进行分类可能是改善患者预后的关键。人们已经做出了各种努力来解决癌症生物学的这一关键问题，但对于将肿瘤分层为不同分子类别的最佳方法仍不清楚。一种方法是基于复杂的分子特征定义许多小的亚类，而另一种选择是根据癌症行为的高阶特征将癌症分为更大的组。后一种方法具有吸引力，因为它可能提供识别广泛相关治疗方法的机会。然而，我们对癌症生物学的这些基本“规则”以及如何利用它们更好地对癌症进行分类和治疗的理解仍处于起步阶段。我们最近证明，基于转录共激活因子YAP和TAZ的不同表达和功能，癌症可以在功能上分层为具有独特治疗脆弱性的二元YAPon和YAPoff超类。在YAPon癌症中，YAP和TAZ驱动肿瘤发生，而在YAPoff癌症中，YAP和TAZ则是肿瘤抑制因子。在这篇综述中，我们讨论了我们对这些不同癌症类别的理解，重点关注YAP/TAZ在YAPon和YAPoff癌症中相反功能的潜在机制，以及这些发现的潜在治疗意义。
