What stimulates tumor growth? Is it a few rogue cells imposing their will on healthy tissue, or diseased tissue bringing out the worst in otherwise peaceful cells? Or is it a back and forth, a dialogue between the two? According to a new study, it could be the latter, at least when it comes to the progression of a common skin cancer.
Researchers have found that a single mutated gene in an otherwise healthy stem cell can trigger an increasingly deviant feedback loop of miscommunication between the cancer stem cell and its surrounding tissues, fueling the development of a malignant tumor. The results suggest that many of cancer’s mutations could simply set in stone a path already set by the tumor stem cell’s aberrant dialogue with its environment. If these results, published in Natureprove broadly applicable, the findings could pave the way for new approaches to treating a range of cancers.
“It’s not just that the cancer shapes the microenvironment or that the environment affects the tumor,” says first author Shaopeng Yuan, a graduate student in Elaine Fuchs’ lab at Rockefeller University. “Our study shows that there is crosstalk between the microenvironment and stem cells in tumors. They communicate with each other and create a loop of tumor-promoting factors.”
Spotlight on squamous cell carcinoma
At the heart of almost every tumor is a small subset of cancer stem cells. Resistant to chemotherapy and immunotherapy, these malignant seeds are the cells responsible for keeping tumors alive and are key players in the process that transforms benign tumors into metastatic diseases. And behind many cancer stem cells, including those in skin, pancreatic, lung, and colorectal cancers, is a RAS gene that, when mutated, allows tissue stem cells to ignore normal environmental cues. and deviate from their natural course, controlling tissue growth.
To better understand the intricacies of this interaction, Yuan and his colleagues turned their attention to squamous cell carcinoma, a skin cancer linked to RAS mutations. The team started by inducing mutant HRAS (the most common RAS family member in skin cancers) in individual skin stem cells and monitoring the cancer stem cells’ interaction with surrounding tissue. “Over time, the dialogue between the cancer stem cell and its microenvironment has become more and more aberrant,” says Fuchs. “By deciphering the dialogue, we realized that miscommunication between the stem cell and its microenvironment results in the activation of much of the same pathway that is active in corresponding human cancers that harbor a high mutational load.”
This observation raised an intriguing possibility. Perhaps many cancer mutations do not fix the course of a disease but lock it in, asserting a malignant progression already determined by aberrant crosstalk between a cancer stem cell and its microenvironment.
A surprising role for leptin signaling
By further investigating how the cancer stem cell changed in the face of this new self-imposed malignant tumor microenvironment, the team realized that the invasive cancer stem cells had unexpectedly begun to express the leptin receptor, Lepr . A hormone produced by fat cells and linked to obesity, leptin appeared misplaced in non-obese mice with non-fat tumors. Lepr is not expressed in normal epithelium and rarely seen in benign tumor cells. Here it appeared unexpectedly in cancer stem cells from the advanced stage of the tumour, known as squamous cell carcinoma (SCC).
Yuan used CRISPR technology to show that Lepr receptor and leptin signaling was essential for progression from benign to malignant. But where did leptin come from? There was no apparent increase in fat cells that would explain leptin, and neither the benign growths, nor the advanced tumor cells, nor the tumor microenvironment appeared to express the leptin gene. Yet the malignant tumor expressing the leptin receptor benefited greatly from the presence of leptin – the more leptin there is, the faster it grows.
The team began to wonder if the leptin that normally circulates in the bloodstream arrives at the tumor via blood vessels that deliver nutrients and other factors to the tumor. Through a series of experiments, they provided compelling evidence that this was the case. Additionally, they went on to demonstrate that Lepr/leptin signaling in cancer stem cells stimulates many pathways known to be overactivated in cancers, including the PI3-kinase, AKT, and mTOR pathways. Taken together, the researchers discovered how a single oncogene could trigger a series of miscommunications between the stem cell and its environment leading to malignancy.
The team is now investigating ways to block leptin receptors in tumors because doing so could throw a molecular wrench into the vicious loop and derail cancer. “Leptin/leptin receptor 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 for tumor progression, we may be able to block tumor progression.”
Squamous cell carcinomas affect not only the skin, but also the esophagus, head and neck, lungs and other epithelial tissues and together are the sixth most common cancer in the world. But the implications of the findings extend beyond this particular cancer. Cancer biologists generally assume that the changes in gene expression that drive tumor progression are the result of many mutations accumulating in a cell, but from the perspective of a stem cell biologist, this work shows how a single oncogenic mutation can trigger events that will lead to cancer. by aberrant exchange with the tumor microenvironment, independently of subsequent mutations.
“Our study shows that one oncogenic mutation can hijack a pathway and achieve the same as many cumulative mutations,” Yuan says. “We are always looking for mutations, but we must not forget to think about how to stop the signaling pathways that drive tumor growth.”