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Updated: Jul 8, 2025

Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres
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A Mutation-driven oncofetal regression fuels phenotypic plasticity in colorectal cancer

Slim Mzoughi, Megan Schwarz, Xuedi Wang

    Biorxiv : the Preprint Server for Biology
    |December 18, 2023
    PubMed

    Insights

    Colorectal cancer (CRC) resistance involves an oncofetal (OnF) cell state that co-evolves with LGR5+ stem cells (SCs). Targeting both OnF and SC states is essential for sustained tumor regression in CRC.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Cancer Stem Cell Research

    Background:

    • Targeting cancer stem cells (CSCs) is vital for effective cancer treatment.
    • Mechanisms of resistance to LGR5+ CSC depletion in colorectal cancer (CRC) are not fully understood.

    Purpose of the Study:

    • To identify novel cellular states contributing to CRC progression and drug resistance.
    • To elucidate the molecular mechanisms driving resistance in LGR5+ CSCs.
    • To explore combination therapies targeting multiple cellular states in CRC.

    Main Methods:

    • Investigated a primitive cell state termed the oncofetal (OnF) state.
    • Utilized genetic deletion of APC and assessed Retinoid X Receptor (RXR) activity.
    • Analyzed epigenetic circuitry involving YAP and AP1.
    • Performed phenotypic tracing and ablation experiments in vivo.

    Main Results:

    • Discovered the OnF state, which collaborates with LGR5+ stem cells (SCs) in CRC tumor evolution.
    • OnF reprogramming is triggered by APC deletion and diminished RXR activity, involving YAP/AP1.
    • The OnF state confers resistance to chemotherapy and enables LGR5+ CSCs to enter a drug-tolerant state.
    • Demonstrated functional redundancy between OnF and SC states, necessitating dual targeting for tumor regression.

    Conclusions:

    • Established the oncofetal state as a key driver of CRC progression and therapeutic resistance.
    • Uncovered a novel RXR-YAP-AP1 axis regulating OnF cell plasticity.
    • Highlighted the necessity of targeting both OnF and LGR5+ SCs for sustained CRC tumor regression.

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