Scholarlink

<p>Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment, yet resistance mechanisms to LGR5<sup>+</sup> 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<sup>+</sup> states in isolation is constrained by their functional redundancy. Although the canonical LGR5<sup>+</sup> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月10日

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

摘要

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.