Single-cell transcriptomic analysis deciphers heterogenous cancer stem-like cells in colorectal cancer and their...

Area of Science:

• Oncology
• Cancer Biology
• Molecular Biology

Background:

• Metastasis is the primary cause of cancer mortality.
• Understanding the heterogeneity of cancer cells and their metastatic pathways is crucial but largely undiscovered.

Purpose of the Study:

• To identify the specific cancer cell types driving metastasis in colorectal cancer (CRC).
• To elucidate the mechanisms of organ-specific metastasis to the liver and ovary.

Main Methods:

• Single-cell RNA sequencing and spatial transcriptomic analysis of primary CRC and its metastases (liver and ovary).
• Immunofluorescence staining and functional experiments to investigate metastatic mechanisms.

Main Results:

• A stem-like cell cluster expressing high levels of protein tyrosine phosphatase receptor type O (PTPRO) and achaete scute-like 2 (ASCL2) was identified as the metastatic culprit.
• Distinct subpopulations within this cluster exhibited preferences for liver or ovarian metastasis.
• Population 1 (P1) cells, high in delta-like ligand 4 (DLL4) and MAF bZIP transcription factor A (MAFA), were enriched in primary CRC and ovarian metastases (oCRC).
• Population 3 (P3) cells, resembling cholangiocytes, were found in primary CRC and liver metastases (lCRC), suggesting a role in liver metastasis.
• Stem-like cells utilized the DLL4-NOTCH signaling pathway for metastasis to the ovary, interacting with cancer-associated fibroblasts and endothelial cells.
• In the oCRC microenvironment, myofibroblasts facilitated cancer cell colonization and development through metabolic reprogramming via glutamine.

Conclusions:

• A mechanism for organ-specific colorectal cancer metastasis has been uncovered.
• Stem-like cancer cells with distinct molecular profiles drive metastasis to specific organs.