美国西奈山伊坎医学院Ernesto Guccione课题组宣布他们的最新研究提出了癌胎重编程驱动WNT依赖性结直肠癌的表型可塑性。该研究于2025年2月10日发表于国际一流学术期刊《自然—遗传学》杂志上。

在本研究中，课题组人员揭示了突变肠干细胞（SCs）偏离其规范身份，穿越动态表型谱。这种增强的可塑性是由癌胎（OnF）重编程启动的，由YAP和AP-1驱动，随后AP-1过度激活促进谱系不忠。在大肠腺瘤性息肉病（APC）功能丧失后，类视黄酮X受体作为OnF重编程及其解除管制的守门者，建立了由YAP和AP-1维持的OnF“记忆”。

值得注意的是，OnF和LGR5⁺状态的临床意义受到其功能冗余的限制。虽然典型的LGR5⁺状态对FOLFIRI方案敏感，但活跃的OnF程序与耐药性相关，支持其在驱动耐药状态中的作用。结合当前的护理标准，针对这一计划是实现有效和持久的结直肠癌治疗的关键。

据介绍，靶向癌症干细胞（CSCs）对于有效的癌症治疗至关重要，但在wnt驱动的结直肠癌（CRC）中，LGR5⁺ CSC耗竭的耐药机制仍不清楚。

附：英文原文

Title: Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer

Author: Mzoughi, Slim, Schwarz, Megan, Wang, Xuedi, Demircioglu, Deniz, Ulukaya, Gulay, Mohammed, Kevin, Zorgati, Habiba, Torre, Denis, Tomalin, Lewis E., Di Tullio, Federico, Company, Carlos, Dramaretska, Yuliia, Leushacke, Marc, Giotti, Bruno, Lannagan, Tamsin RM, Lozano-Ojalvo, Daniel, Karras, Panagiotis, Vermeulen, Peter B., Hasson, Dan, Sebra, Robert, Tsankov, Alexander M., Sansom, Owen J., Marine, Jean-Christophe, Barker, Nick, Gargiulo, Gaetano, Guccione, Ernesto

Issue&Volume: 2025-02-10

Abstract: Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment, yet resistance mechanisms to LGR5⁺ CSC depletion in WNT-driven colorectal cancer (CRC) remain elusive. In the present study, we revealed that mutant intestinal stem cells (SCs) depart from their canonical identity, traversing a dynamic phenotypic spectrum. This enhanced plasticity is initiated by oncofetal (OnF) reprogramming, driven by YAP and AP-1, with subsequent AP-1 hyperactivation promoting lineage infidelity. The retinoid X receptor serves as a gatekeeper of OnF reprogramming and its deregulation after adenomatous polyposis coli (APC) loss of function establishes an OnF ‘memory’ sustained by YAP and AP-1. Notably, the clinical significance of OnF and LGR5⁺ states in isolation is constrained by their functional redundancy. Although the canonical LGR5⁺ state is sensitive to the FOLFIRI regimen, an active OnF program correlates with resistance, supporting its role in driving drug-tolerant states. Targeting this program in combination with the current standard of care is pivotal for achieving effective and durable CRC treatment.

DOI: 10.1038/s41588-024-02058-1

Source: https://www.nature.com/articles/s41588-024-02058-1