Novel Lysosomal-Associated Transmembrane Protein 4B-Positive Stem-Like Cell Subpopulation Characterizes High-Risk...

Area of Science:

• Oncology
• Genomics
• Cell Biology

Background:

• Colorectal cancer (CRC) displays significant heterogeneity due to diverse tumor stem-like cell populations.
• The molecular characteristics and clinical impact of these stem-like cells are not fully understood.
• Identifying distinct stem-like cell populations is crucial for understanding CRC progression and heterogeneity.

Purpose of the Study:

• To characterize the diversity of tumor-intrinsic stem-like cells in colorectal cancer.
• To investigate the prognostic implications of different stem-like cell populations and their ratios.
• To identify novel stem-like cell markers for improved CRC outcome prediction.

Main Methods:

• Single-cell transcriptomic profiling of 171,906 tumor epithelial cells.
• Integration with bulk transcriptomic and genomic datasets (n=1389 and n=1077, respectively).
• Functional validation using in vitro assays and multiplex immunofluorescence.

Main Results:

• Identification of a novel lysosome-associated transmembrane protein 4B-positive (LAPTM4B+) stem-like cell cluster, distinct from LGR5+ cells.
• LAPTM4B+ cells show MYC pathway activation and 8q gains, enriched in microsatellite-stable, POLE wild-type, left-sided tumors.
• Four colorectal cancer stem-like subtypes (CSS) defined by LAPTM4B+/LGR5+ ratios; CSS2 (LAPTM4B+-dominant) linked to poorest prognosis (HR=2.31).
• Combined LAPTM4B and LGR5 expression predicted CRC progression better than individual markers (AUC=0.820).

Conclusions:

• Distinct stem-like cell populations, including the novel LAPTM4B+ subtype, contribute significantly to CRC heterogeneity.
• The ratio of LAPTM4B+ to LGR5+ stem-like cells defines subtypes with differential prognostic value.
• Combined LAPTM4B and LGR5 expression offers a powerful predictive biomarker for colorectal cancer outcomes.