Slim Mzoughi’s Post

Thrilled to share my 1st brainchild, out today in @Nature Genetics. 🚀 Been hearing a lot about fetal-like states lately? Here, we uncover the molecular mechanisms, functional significance and clinical relevance of #oncofetal reprogramming in CRC.  We lay the foundation for more effective durable therapeutic strategies for CRC patients. https://lnkd.in/dqF3BtDn https://rdcu.be/d9iSN  Huge thanks to Ernesto Guccione Nick Barker Jean-Chris Marine Gaetano Gargiulo Owen Sansom Alex Tsankov for the fantastic collaboration, and to National Cancer Institute (NCI) for funding me to continue this work. #EarlyStageInvestigator. Grateful to a fantastic team of scientists too Megan Schwarz Kevin Mohammed Habiba Zorgati Denis Torre Deniz Demircioğlu Xuedi Wang Gulay Bengu Ulukaya Lewis Tomalin Marc Leushacke, PhD Bruno Giotti Panagiotis Karras, PhD. Towards #BetterTherapeuticStrategies for #CRC patients #Oncofetal #CRC #IntratumoralHeterogeneity #PhenotypicPlasticity. Longstanding Question: Why is targeting LGR5+ CSCs insufficient for achieving better therapeutic outcomes? A: 1. OnF CSCs can sustain tumor growth in absence of the LGR5+ CSCs. 2. The LGR5+ state is sensitive to current therapies. Resistance is primarily driven by the OnF program. Takeaways: 1.   OnF reprogramming of mutant LGR5+ SCs triggers phenotypic (intratumoral) heterogeneity during tumor initiation and drives lineage plasticity in advanced CRC. 2.   While YAP initiates the OnF program, subsequent AP-1 hyperactivation drives lineage plasticity. 3.   RXR acts as a gatekeeper of OnF reprogramming and operates downstream of APC. 4.   Early RXR deregulation is sufficient to establish an OnF memory.   5.   Crucial during tumor initiation, RXR’s role becomes irrelevant in advanced CRC. 6.   Diverse flavors/states of CSCs exist in CRC. 7.   The OnF state is inherently resistant to therapies and is co-opted by some LGR5+ CSCs to survive treatment. 8.   The success and durability of current CRC therapies hinges on effective targeting of the OnF program. A detailed dive can be found at: @sleemmz.bsky.social‬ https://x.com/Sleemmzz