Molecular analysis of tumor recurrence using established cancer stem cell-line and drug discovery

Area of Science:

• Oncology
• Molecular Biology
• Cancer Stem Cell Research

Background:

• Colorectal cancer (CRC) relapse, driven by minimal residual disease, remains a significant clinical challenge despite adjuvant therapies.
• The cancer stem cell (CSC) hypothesis posits that a therapy-resistant CSC subpopulation drives tumor recurrence.

Purpose of the Study:

• To investigate the role of cancer stem cells in CRC recurrence.
• To identify novel therapeutic strategies targeting CSC-driven resistance.

Main Methods:

• Development of LGR5-specific monoclonal antibodies and immunofluorescence for visualizing LGR5 in clinical tumors.
• Establishment of the PLR123 colorectal cancer cell line with robust stem cell properties.
• Utilized single-cell RNA sequencing and small molecule screening for drug discovery.

Main Results:

• Identified the RNA Polymerase I inhibitor BMH-21 as a potent suppressor of tumor recurrence.
• BMH-21 demonstrated efficacy in both in vitro and in vivo models of colorectal cancer recurrence.
• Elucidated mechanisms of CSC-driven resistance.

Conclusions:

• Targeting cancer stem cells is crucial for preventing colorectal cancer relapse.
• BMH-21 represents a promising therapeutic agent for overcoming CSC-mediated resistance and preventing tumor recurrence.