Researchers have created the first genetically engineered model of lung cancer in naked mole rats, a species long thought to be resistant to cancer.

The findings, published in Cancer Discovery, shed light on how cancer begins in this unusual rodent and may reveal new parallels to tumour development in humans.

Naked mole rats have drawn attention for their long lifespans and apparent cancer resistance. Previous studies suggested their cells might have unique protective mechanisms. 

In this new study, researchers used CRISPR gene-editing technology to introduce a genetic change, known as the Eml4-Alk fusion, which commonly drives lung cancer in humans and mice.While this single change was enough to cause tumours in mice, it did not lead to cancer in naked mole rats.

The team discovered that tumours only formed when the EML4-ALK fusion was combined with the loss of two well-known tumour suppressor genes, p53 and Rb1. About 30% of the animals developed aggressive lung tumours that closely resembled a rare human cancer subtype called pleomorphic carcinoma.

“This study shows that naked mole rats require multiple genetic events for cancer to develop, similar to human cells,” said Joseph Kissil, Ph.D., senior author and chair of Moffitt’s Molecular Oncology Department. “This makes them a potentially more accurate model for studying how cancers begin and progress in people.”

The research also revealed that the tumours were highly diverse and infiltrated by immune cells, including T cells and macrophages. This opens the door to future studies of the tumour microenvironment in naked mole rats, which may further explain their unusual biology.

Although breeding and studying naked mole rats is more resource-intensive than using mice, the authors believe these animals could become a valuable tool for uncovering new strategies to prevent or treat cancer.

“If we want to translate comparative biology efforts into patient benefit, we need rigorous, genetically defined models,” Kissil said.

“This work took years because we had to build the tools from the ground up. But the result is a platform that can help us dissect the early steps of tumourigenesis and potentially open new therapeutic strategies, including for pleomorphic lung carcinoma, which lacks targeted options today.”

Article: An Autochthonous Model of Lung Cancer Identifies Requirements for Cellular Transformation in the Naked Mole-Rat

Source: H. Lee Moffitt Cancer Center & Research Institute