MLL1 regulates cytokine-driven cell migration and metastasis

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Cell migration is a key driver of metastasis, a process traditionally linked to immune cell cytokine production.
• The role of intrinsic cancer cell cytokine production in migration and metastasis remains less understood.

Purpose of the Study:

• To investigate the role of the histone methyltransferase Mixed-Lineage Leukemia 1 (MLL1) in regulating cancer cell migration and metastasis.
• To elucidate the molecular mechanisms by which MLL1 controls cell migration and proliferation.

Main Methods:

• Utilized MLL1 depletion in orthotopic tumor models in mice.
• Analyzed cytokine secretion (IL-6, IL-8, TGF-β1) and downstream signaling pathways (e.g., pSTAT3, Gli2, ROCK1/2, pMLC2).
• Assessed actin filament assembly, myosin contractility, and dynamic protrusion generation.

Main Results:

• MLL1 controls 3D cell migration through secreted cytokines IL-6, IL-8, and TGF-β1, acting via specific molecular axes.
• MLL1 regulates actin dynamics and myosin contractility, essential for cell migration and protrusion formation.
• MLL1 depletion in tumors reduced lung metastatic burden and improved survival, independent of primary tumor growth rates.
• Combination therapy with an MLL1-Menin inhibitor and paclitaxel effectively reduced tumor growth and eradicated existing metastasis.

Conclusions:

• MLL1 is a critical regulator of cancer cell migration and metastasis, acting through intrinsic cytokine production and cytoskeletal control.
• Targeting MLL1, particularly in combination therapy, presents a promising strategy for treating metastatic cancers.