Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer

Area of Science:

• Oncology
• Cancer Biology
• Stem Cell Research

Background:

• Colorectal cancer stem cells (CSCs), identified by Lgr5 expression, are believed to initiate metastatic disease due to their self-renewal and multipotency.
• Understanding the cellular origins of metastases is critical for developing effective cancer therapies.

Purpose of the Study:

• To investigate the cell type responsible for seeding distant metastases in colorectal cancer.
• To explore the plasticity of colorectal cancer cells in the context of metastasis formation.

Main Methods:

• Utilized a mouse model of colorectal cancer (CRC).
• Analyzed human tumor xenografts.
• Tracked disseminated colorectal cancer cells in circulation and at metastatic sites.

Main Results:

• The majority of circulating colorectal cancer cells involved in seeding metastases were Lgr5-negative.
• Lgr5-positive CSCs emerged within established distant metastases.
• Cellular plasticity, enabling Lgr5-negative cells to become Lgr5-positive CSCs, was essential for metastatic outgrowth but not initial establishment.
• This plasticity was independent of microenvironmental factors that induce stemness.

Conclusions:

• Colorectal cancer metastases are predominantly seeded by Lgr5-negative cells.
• These Lgr5-negative cells possess an intrinsic ability to transition into CSCs in a niche-independent manner.
• The plasticity of these cells is vital for the progression of metastatic disease and the re-establishment of tumor hierarchies.