sleemmz.bsky.social
Assistant Professor, Tish Cancer Institute @Mount Sinai. Colorectal Cancer. Oncofetal reprogramming. Views are my own. "By land and by sea, Carthage will rise again"
https://profiles.mountsinai.org/slim-mzoughi
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#dreamteam
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About the cover: The mutant intestinal epithelium (jar) generates diverse CSC flavors (gummies): canonical LGR5+(orange), non-canonical oncofetal (blue), and a spectrum of intermediate states. This CSC heterogeneity fuels CRC progression and underpins its ability to evade therapy.
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Key takeaways can be found in this thread:
bsky.app/profile/slee...
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❗Don't miss the Research Briefing❗
⬇️
www.nature.com/articles/s41...
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Thanks, Chris.
More info in this thread:
bsky.app/profile/slee...
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Thank you, Chris, for all your support!
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10b)
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.
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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.
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9) Q: How are YAP and AP-1 activated?
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
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8) Q: What drives the OnF program?
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.
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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.
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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.
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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.
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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.
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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.
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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.
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1) Huge thanks to @guccionelab.bsky.social @nickbarker @marinelab.bsky.social @ggargiul.bsky.social
@owensansom 4 the fantastic collaboration. NIH funding #EarlyStageInvestigator. Towards #BetterTherapeuticStrategies 4 #CRC patients #Oncofetal #CRC #IntratumoralHeterogeneity #PhenotypicPlasticity
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could you pls add me. Thanks.
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I'd love to join. Thanks.
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I'd love to join. Thanks.
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would love to join.
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I'd love to join. Thanks!
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🤚
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I'd like to join. Thanks.
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Duncan, i'd love to join.
thanks.
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i'd love to join. Thanks!
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✋️
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Thanks Ankur :)
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i'd love to be added. Thanks.
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Johanna, can you please add me? thanks.
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✋️
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i'd like to join. Thanks.
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I'd love to join. thanks.
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✋️
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✋️
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I'd like to join. Thanks.