In a study published in Nature, researchers led by Prof. HU Zheng from the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences, along with their collaborators, demonstrated a new model of early evolution in the transition of tumors from polyclonal to monoclonal, and elucidated the mechanisms of intercellular communication and the interaction underlying the polyclonal origin of tumors.

Colorectal cancer (CRC) is the third most common cancer worldwide, and the second leading cause of cancer-related deaths worldwide. Gaining insight into the origins and evolution of precancerous lesions is vital for preventing their progression to malignancy. 

According to the classical clonal evolution theory, tumors originate from a single cell that undergoes continuous clonal expansions. However, this study reveals that tumors arise from multiple cells, supporting a polyclonal origin model.

Researchers, utilizing a base editor-enabled DNA barcoding system, meticulously mapped the single-cell phylogenies in mouse models of intestinal tumorigenesis, triggered either by inflammation or Apc mutation. By analyzing a staggering 260,922 single cells from normal, inflamed, and neoplastic intestinal tissues, they uncovered a striking pattern: numerous independent lineages were observed undergoing parallel clonal expansions within individual lesions. 

This polyclonal origin suggested that colorectal precancers may arise from multiple distinct cellular lineages working cooperatively in the earliest stages of cancer development.

The finding was further corroborated through genomic analyses of human samples. In a study of sporadic colorectal polyps, researchers found that 29% of the samples (30 out of 102) exhibited this polyclonal origin through bulk whole-exome sequencing. The results indicated an evolutionary transition from a polyclonal phase to a monoclonal one, with monoclonal lesions representing a more advanced stage of tumorigenesis.

This study sheds light on the origins and evolution of intestinal precancerous lesions, paving the way for improved strategies to prevent the malignant transformation that can lead to colorectal cancer.

Vibrant peacock feathers illustrate the transition of tumor cells from a polyclonal to a monoclonal state. (Image by SIAT)