MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Stem Cell Research

Background:

• Colorectal cancer (CRC) metastasis is a major cause of mortality, often initiated by colon cancer stem cells (CSCs).
• Metastasis-associated in colon cancer 1 (MACC1) is a prognostic biomarker for CRC progression, but its role in human CSCs is unclear.
• Understanding MACC1's function in CSCs is crucial for developing targeted therapies against metastasis.

Purpose of the Study:

• To investigate the molecular mechanisms by which MACC1 regulates stemness and the invasive phenotype in human colorectal cancer.
• To explore the relationship between MACC1 expression and CSC markers in patient-derived models and cell lines.
• To identify MACC1 as a potential therapeutic target for preventing CRC metastasis.

Main Methods:

• Utilized patient-derived tumor organoids (PDOs) and patient-derived xenografts (PDXs) from colorectal cancer patients.
• Performed RNA sequencing on CSC-enriched populations (CD44+, ALDH1+).
• Investigated MACC1's transcriptional activity on the LGR5 gene promoter.

Main Results:

• MACC1 expression correlated positively with CSC markers (CD44, LGR5, NANOG) and stemness in PDOs and cell lines.
• MACC1 enhanced stem cell gene expression, clonogenicity, and sphere formation.
• MACC1 directly binds to the LGR5 promoter, identifying LGR5 as a novel mediator of MACC1-induced CSC properties.

Conclusions:

• MACC1 is a key regulator of cancer stemness and metastasis in colorectal cancer, acting through LGR5.
• MACC1 functions as a CSC-associated marker in human CRC.
• Targeting MACC1 presents a promising strategy for eradicating CSCs and preventing CRC recurrence and metastasis.