Slim Mzoughi
@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
https://profiles.mountsinai.org/slim-mzoughi
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.
February 12, 2025 at 6:28 PM
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.
Key takeaways can be found in this thread:
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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. www.nature.com/articles/s41... (rdcu.be/d9iSN) a 🧵
February 11, 2025 at 3:26 PM
Key takeaways can be found in this thread:
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Reposted by Slim Mzoughi
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. www.nature.com/articles/s41... (rdcu.be/d9iSN) a 🧵
February 11, 2025 at 3:25 PM
Thank you, Chris, for all your support!
February 10, 2025 at 4:13 PM
Thank you, Chris, for all your support!
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.
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.
February 10, 2025 at 3:35 PM
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.
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.
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.
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.
February 10, 2025 at 3:35 PM
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.
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.
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
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
February 10, 2025 at 3:35 PM
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
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
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.
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.
February 10, 2025 at 3:34 PM
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.
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.
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.
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.
February 10, 2025 at 3:34 PM
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.
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.
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.
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.
February 10, 2025 at 3:34 PM
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.
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.
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.
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.
February 10, 2025 at 3:33 PM
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.
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.
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.
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.
February 10, 2025 at 3:32 PM
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.
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.
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.
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.
February 10, 2025 at 3:31 PM
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.
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.
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.
February 10, 2025 at 3:31 PM
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.
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.
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
@owensansom 4 the fantastic collaboration. NIH funding #EarlyStageInvestigator. Towards #BetterTherapeuticStrategies 4 #CRC patients #Oncofetal #CRC #IntratumoralHeterogeneity #PhenotypicPlasticity
February 10, 2025 at 3:18 PM
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
@owensansom 4 the fantastic collaboration. NIH funding #EarlyStageInvestigator. Towards #BetterTherapeuticStrategies 4 #CRC patients #Oncofetal #CRC #IntratumoralHeterogeneity #PhenotypicPlasticity