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Progressive plasticity during colorectal cancer metastasis.

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Metastatic colorectal cancer cells exhibit plasticity, reprogramming from intestinal stem-like states into a fetal progenitor state. This facilitates non-canonical differentiation, therapy resistance, and poor survival, with PROX1 downregulation enabling this reprogramming.

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Area of Science:

  • Cancer Biology
  • Cellular Plasticity
  • Tumorigenesis

Background:

  • Metastatic tumors are more aggressive and therapy-resistant than primary tumors.
  • Non-genetic phenotypic plasticity plays a crucial role in cancer progression and treatment resistance.
  • Understanding metastatic cell states and their transition mechanisms is critical.

Purpose of the Study:

  • To investigate the phenotypic plasticity of colorectal cancer cells during metastasis.
  • To elucidate the mechanisms driving cancer cell state transitions and therapy resistance.
  • To identify key regulators of metastatic cell reprogramming.

Main Methods:

  • Analysis of matched normal colon, primary, and metastatic colorectal cancer biospecimen trios.
  • Utilizing patient-derived organoids to assess cell-autonomous differentiation potential.
  • Investigating the role of PROX1 in regulating cell lineage plasticity.

Main Results:

  • Metastases exhibit progressive plasticity, losing intestinal identity and entering a conserved fetal progenitor state.
  • Cancer cells undergo non-canonical differentiation into squamous and neuroendocrine-like states, exacerbated by metastasis and chemotherapy.
  • PROX1 downregulation was identified as a key event enabling non-canonical reprogramming and lineage plasticity.

Conclusions:

  • Metastatic colorectal cancer cells display significant phenotypic plasticity, reprogramming into a fetal progenitor state.
  • This reprogramming facilitates non-canonical differentiation, contributing to therapy resistance and poor patient survival.
  • Targeting PROX1 may offer therapeutic strategies to inhibit metastatic progression and reprogramming.