Study reveals polyclonal origins of tumors and evolutionary transition to monoclonality

A team led by Prof. HU Zheng from the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences (CAS), in collaboration with international researchers, has unveiled a groundbreaking model of early tumor evolution. Their study sheds light on the transition of tumors from a polyclonal to a monoclonal state and reveals the intricate mechanisms of intercellular communication driving the polyclonal origins of tumors.

The research was published in Nature on October 30.

Colorectal Cancer Origins: A Paradigm Shift

Colorectal cancer (CRC), the third most common cancer worldwide and the second leading cause of cancer-related deaths, poses a critical challenge to global health. Understanding the origins and evolution of precancerous lesions is essential for developing strategies to prevent their progression to malignancy. However, knowledge in this area has been limited—until now.

Traditionally, the clonal evolution theory has dominated the field, positing that tumors originate from a single cell undergoing continuous clonal expansion. This new study challenges that notion, presenting robust evidence that tumors can emerge from multiple cells, supporting a polyclonal origin model.

Innovative Methodology: Tracking Single-Cell Evolution

The researchers employed a cutting-edge DNA barcoding system, enabled by base editors, to map single-cell phylogenies in mouse models of intestinal tumorigenesis. These models were induced either by inflammation or mutations in the *Apc* gene. By analyzing an extraordinary dataset of 260,922 single cells from normal, inflamed, and neoplastic intestinal tissues, the team identified a striking pattern: multiple independent cellular lineages underwent parallel clonal expansions within individual lesions.

This discovery highlights the cooperative dynamics between distinct cellular lineages in the earliest stages of colorectal tumorigenesis. 

Human Data Validation: Polyclonal Origins Confirmed

To validate their findings, the researchers conducted genomic analyses of human colorectal samples. Among sporadic colorectal polyps, 29% (30 out of 102) exhibited polyclonal origins based on bulk whole-exome sequencing. This figure rose to 60% (3 out of 5) when single-gland whole-genome sequencing was applied. These results not only confirm the polyclonal origin of precancerous lesions but also demonstrate an evolutionary transition to monoclonality as the tumors progress, with monoclonal lesions representing more advanced stages of tumorigenesis.

Implications for Cancer Prevention

This study offers transformative insights into the origins and evolutionary trajectories of intestinal precancerous lesions. By elucidating the polyclonal origins and subsequent monoclonal transitions, the findings pave the way for innovative strategies to prevent the malignant transformation of precancerous lesions into colorectal cancer.