Thrilled to share my 1st brainchild, out today in @NatureGenet ! 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. a 🧵

@Ella_Maru @NatureGenet Thanks, Ella. We don't know yet.

@MAF_Dawson @NatureGenet Thanks mate!

@NatureGenet 11. 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 chemos

@NatureGenet 10. Q: What role do OnF cells play? 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.

@NatureGenet 9. Q: How are YAP and AP1 activated? A: RXR acts as a gatekeeper of the OnF program. Its deregulation following APC LoF activates YAP/AP1 and establishes an OnF memory, sustained by these TFs during disease progression. RXR is critical during tumor initiation but not in advCRC

@NatureGenet 8. Q: What drives the OnF program? A:YAP and AP1 cooperate but play distinct roles in driving OnF reprogramming. YAP triggers the program at tumor onset, partially by activating AP1. But Subsequent AP1 hyperactivation during disease progression breaks lineage-restrictive barriers

@NatureGenet 7. Q: Why does it occur? 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

@NatureGenet 6. Q: Is fetal-like reprogramming transient in CRC, like in injury? 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.

@NatureGenet 5. Takeaways: 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.

@NatureGenet 4. Takeaways: 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.

3. 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.

2. Longstanding Q: Why is targeting LGR5+CSCs insufficient for achieving better therapeutic outcomes? 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

Big thanks to @GuccioneLab @Nickbar36316207 @lab_marine @ggargiul_2020 @owen_sansom for the fantastic collaboration, and to @NIH @theNCI for funding this work. #EarlyStageInvestigator. Towards #BetterTherapeuticStrategies for #CRC patients #Oncofetal #CRC #PhenotypicPlasticity

RT @ItaiYanai: Half of the untold story of the scientific creative process is that it is the pain and suffering that make it your own proje…

@KarunaMDPhD @Nature @andrewrmoorman @elliebenitez11 @f_cambuli @KarunaGaneshLab @Dana_Per Congrats Karuna and team 👏

@PapapetrouMDPhD @Nature Beautiful! Congrats, Eirini and team 🍾

RT @lab_marine: 🚀 Exciting Opportunity! We're on the lookout for passionate young cancer biologists ready to take the lead in their own res…