Slim Mzoughi

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 ...

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!

📢 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!

#dreamteam

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.

🔈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...

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

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....

❗Don't miss the Research Briefing❗

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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...

📢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...

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

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...

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...

Thank you, Chris, for all your support!

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

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.

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.

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

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.

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.

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.

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.

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.

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.

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

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

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 🧵

could you pls add me. Thanks.

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I'd love to join. Thanks!