Progressive plasticity during colorectal cancer metastasis

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.