In a study of RAS gene mutations in squamous cell carcinoma, researchers have found that a single mutated gene in an otherwise healthy stem cell can trigger a feedback loop of miscommunication between the cancerous stem cell and its surrounding tissue, fueling the development of a malignant tumour.
The findings, published in Nature, suggest that many of the mutations in cancer may be amplifying errors that originate in a tumour stem cell’s aberrant chemical dialogue with its surroundings.
“It’s not just that cancer moulds the microenvironment, or that the environment affects the tumour,” said the study’s first author Shaopeng Yuan in a press release. “Our study shows that there is crosstalk between the microenvironment and the stem cells in tumours. They communicate with each other and create a loop of tumour-promoting factors.”
Yuan is a graduate student in the laboratory of Elaine Fuchs, PhD, at The Rockefeller University in New York City.
Yuan and his colleagues induced mutant HRAS—the member of the RAS family of genes most common in skin cancers—into individual skin stem cells and monitored how the cancerous stem cells interact with the surrounding tissue.
“Over time, the dialogue between the cancer stem cell and its microenvironment became more and more aberrant,” Dr. Fuchs said in the release. “As we deciphered the dialogue, we realized that the miscommunication between the stem cell and its microenvironment resulted in the activation of much the same pathway that is active in the corresponding human cancers that harbour a high mutational burden.”
The findings suggest that cancer mutations on their own do not set the course of the disease, the authors write. Instead, the mutations “lock in” a malignant progression determined by faulty crosstalk between a cancer stem cell and its environment.
Researchers found that invasive cancer stem cells were unexpectedly expressing the leptin receptor, Lepr. Malignant tumours expressing this receptor grew more aggressively in a leptin-rich environment.
Further, Lepr signalling within the cancer stem cells stimulated many pathways known to be hyperactivated in cancers, including the PI3-kinase, AKT and mTOR pathways.
The team is now investigating ways to block the leptin receptors in tumours to see if doing so will inhibit cancer growth.
“The leptin receptor/leptin crosstalk between cancer stem cells and the microenvironment drives a positive feedback loop that fuels malignancy,” Yuan said. “If we block this loop, which is a major pathway driving tumour progression, perhaps we can block tumour progression.”