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Slim Mzoughi @sleemmz.bsky.social · Jul 1

I have two open positions (wet and dry lab) to work on phenotypic plasticity and therapy resistance. Come join a vibrant team in a vibrant city!

Are you passionate about phenotypic plasticity and therapy resistance? | Slim Mzoughi

Are you passionate about phenotypic plasticity and therapy resistance? Curious about the epigenetic mechanisms driving these processes? Excited to make transformative discoveries and take your career ...

www.linkedin.com

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Slim Mzoughi @sleemmz.bsky.social · Jun 25

📢 Exciting news: The Mzoughi Lab will launch in January 2026 at the Icahn School of Medicine at Mount Sinai in NYC! Young talents and cell plasticity enthusiasts—stay tuned for upcoming opportunities!

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Slim Mzoughi @sleemmz.bsky.social · Feb 13

#dreamteam

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Slim Mzoughi @sleemmz.bsky.social · Feb 12

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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Slim Mzoughi @sleemmz.bsky.social · Feb 12

🔈We've got the cover of the 2nd NG issue for 2025🙌
Read about the cover: In the comment👇
Also check out our research briefing🚨 (link below):
nature.com/articles/s41...
nature.com/articles/s41...

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Slim Mzoughi @sleemmz.bsky.social · Feb 11

Key takeaways can be found in this thread:
bsky.app/profile/slee...

Slim Mzoughi @sleemmz.bsky.social · Feb 10

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 🧵

Reposted by Slim Mzoughi

Nature Genetics @natgenet.nature.com · Feb 11

❗Don't miss the Research Briefing❗

⬇️

www.nature.com/articles/s41...

Oncofetal reprogramming induces phenotypic heterogeneity in colorectal cancer - Nature Genetics

Phenotypic plasticity of cancer cells is increasingly recognized as a mechanism of tumor escape from targeted therapies. Yet, the phenotypic heterogeneity of colorectal cancer remains poorly explored....

www.nature.com

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Reposted by Slim Mzoughi

Nature Genetics @natgenet.nature.com · Feb 11

📢ONLINE @naturegenet.bsky.social

📰Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer.

By @sleemmz.bsky.social, @guccionelab.bsky.social and colleagues.

⬇️

www.nature.com/articles/s41...

Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer - Nature Genetics

Oncofetal (OnF) reprogramming, driven by YAP and AP-1, induces phenotypic plasticity and therapy resistance in WNT-dependent colorectal cancer (CRC). Targeting the OnF state in combination with chemot...

www.nature.com

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Slim Mzoughi @sleemmz.bsky.social · Feb 11

Thanks, Chris.
More info in this thread:
bsky.app/profile/slee...

Slim Mzoughi @sleemmz.bsky.social · Feb 10

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 🧵

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Reposted by Slim Mzoughi

Chris Tape @christophertape.bsky.social · Feb 11

Nice paper from @sleemmz.bsky.social et al underscoring the importance of stem cell transdetermination in CRC. RXR, YAP, and AP1 signalling collectively control access to revival stem cells and inhibition of these nodes limits plasticity to improve chemosensitivity.

www.nature.com/articles/s41...

Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer - Nature Genetics

Oncofetal (OnF) reprogramming, driven by YAP and AP-1, induces phenotypic plasticity and therapy resistance in WNT-dependent colorectal cancer (CRC). Targeting the OnF state in combination with chemot...

www.nature.com

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Slim Mzoughi @sleemmz.bsky.social · Feb 10

Thank you, Chris, for all your support!

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Reposted by Slim Mzoughi

Chris Marine Lab @marinelab.bsky.social · Feb 10

So happy to see this live, Slim! Congratulations to you, Ernesto and the whole team for your resilience, vision and creativity!

Slim Mzoughi @sleemmz.bsky.social · Feb 10

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 🧵

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Slim Mzoughi @sleemmz.bsky.social · Feb 10

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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Slim Mzoughi @sleemmz.bsky.social · Feb 10

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.

Slim Mzoughi @sleemmz.bsky.social · Feb 10

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

Slim Mzoughi @sleemmz.bsky.social · Feb 10

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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Slim Mzoughi @sleemmz.bsky.social · Feb 10

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.

Slim Mzoughi @sleemmz.bsky.social · Feb 10

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.

Slim Mzoughi @sleemmz.bsky.social · Feb 10

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.

Slim Mzoughi @sleemmz.bsky.social · Feb 10

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.

Slim Mzoughi @sleemmz.bsky.social · Feb 10

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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Slim Mzoughi @sleemmz.bsky.social · Feb 10

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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Reposted by Slim Mzoughi

Mark Hartmann @mphartmann.bsky.social · Feb 10

Out now @naturegenet.bsky.social:

**Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer**

www.nature.com/articles/s41...

Interesting story about #oncofetal #reprogramming and phenotypic #plasticity in #colorectal #cancer.

#science
#epigenetics
#OncoSky

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Slim Mzoughi @sleemmz.bsky.social · Feb 10

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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Slim Mzoughi @sleemmz.bsky.social · Feb 10

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 🧵

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