Thrilled to share my 1st brainchild, out today @naturegenet.bsky.social 🚀 Been hearing a lot about fetal-like states lately? We uncover the molecular mechanisms, functional significance and clinical relevance of #oncofetal reprogramming in CRC. https://www.nature.com/articles/s41588-024-02058-1 (https://rdcu.be/d9iSN) a 🧵
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A2. Resistance. The OnF state is inherently resistant to FOLFIRI. We believe LGR5+ cells must activate this program to survive treatment.
Targeting the OnF state (genetically) or its drivers (pharmacologically) improves the effectiveness and durability of current chemotherapies.
A1: Tumor growth. The canonical LGR5+ and non-canonical OnF CSCs work in tandem to drive tumor growth. Targeting either state alone is insufficient- they are functionally redundant in this context.
A: RXR acts as a gatekeeper of the OnF program. Its deregulation following APC LoF activates YAP/AP-1 and establishes an OnF memory, sustained by these TFs during disease progression. RXR is critical during tumor initiation but not in advanced CRC
A: YAP and AP-1 cooperate but play distinct roles in driving OnF reprogramming. YAP triggers the program at tumor onset, partially by activating AP-1. But Subsequent AP-1 hyperactivation during disease progression breaks lineage-restrictive barriers.
A: OnF reprogramming of mutant LGR5+ SCs creates a continuum of phenotypes delimited by the canonical LGR5+ and non-canonical OnF states–a phenotypic heterogeneity key to primary resistance.
Cells at the extreme OnF end exhibit lineage infidelity/plasticity.
A: Oncofetal (OnF) reprogramming of intestinal stem cells (ISCs) is triggered by APC LoF during tumor initiation and persists in advanced tumors. KRASG12D and p53 LoF favor the OnF and LGR5+ states, respectively.
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.
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.
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.
A: 1. The OnF state 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.
@owensansom 4 the fantastic collaboration. NIH funding #EarlyStageInvestigator. Towards #BetterTherapeuticStrategies 4 #CRC patients #Oncofetal #CRC #IntratumoralHeterogeneity #PhenotypicPlasticity