What drives tumor growth? Is it a few rogue cells imposing their will upon healthy tissue, or diseased tissue bringing out the worst in otherwise peaceable cells? Or is it a back-and-forth, a dialogue between the two? According to a new study, it may be the latter, at least when it comes to the progression of one common skin cancer.
Researchers found that a single mutated gene in an otherwise healthy stem cell can kick off an increasingly deviant feedback loop of miscommunication between the cancerous stem cell and its surrounding tissue, fueling the development of a malignant tumor. The findings suggest that many of the mutations in cancer may simply be setting in stone a path already forged by the tumor stem cell’s aberrant dialogue with its surroundings. If these results, published in Nature, prove broadly applicable, the findings could pave the way for novel approaches to treating a range of cancers.
“It’s not just that cancer molds the microenvironment, or that the environment affects the tumor,” says the first author. “Our study shows that there is crosstalk between the microenvironment and the stem cells in tumors. They communicate with each other and create a loop of tumor-promoting factors.”
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 the tumor alive and are key players in the process that turns benign growths into metastatic disease. And behind many cancer stem cells, including those of skin, pancreatic, lung, and colorectal cancers, is a RAS gene that, when mutated, allows tissue stem cells to ignore normal environmental signals and deviate from their natural course, promoting out-of-control tissue growth.
To better understand the finer points of that interaction, the researchers turned their attention to squamous cell carcinoma, a skin cancer linked to RAS mutations. The team started off by inducing mutant HRAS (the member of the RAS family most common in skin cancers) in individual skin stem cells, and monitoring how the cancerous stem cells interacted with the surrounding tissue. “Over time, the dialogue between the cancer stem cell and its microenvironment became more and more aberrant,” the senior author says. “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 harbor a high mutational burden.”
This observation raised an intriguing possibility. Perhaps many cancer mutations do not set the course of a disease so much as lock it in place, affirming a malignant progression already determined by aberrant crosstalk between a cancer stem cell and its microenvironment.
Further investigating how the cancer stem cell changed as it confronted 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 seemed out of place in non-obese mice carrying non-fatty tumors. Lepr is not expressed in normal epithelium and rarely seen in benign tumor cells. Here it showed up unexpectedly in the cancer stem cells of the advanced stage of the tumor, known as squamous cell carcinoma (SCC).
The authors used CRISPR technology to show that Lepr and leptin receptor signaling was essential for progression from the benign to malignant state. But where was the leptin coming from? There was no apparent increase in fat cells that would explain the leptin and neither the benign growths, the advanced tumor cells, or the tumor microenvironment seemed to express the leptin gene. Yet, the malignant tumor expressing the leptin receptor greatly benefited from the presence of leptin—the more leptin, the faster it grew.
The team began to wonder whether leptin that normally circulates in the bloodstream was arriving at the tumor via the blood vessels that bring nutrients and other factors to the tumor. Through a series of experiments, they provided compelling evidence that this was the case. Moreover, they went on to demonstrate that Lepr/leptin signaling within the cancer stem cells stimulated many of the pathways known to be hyperactivated in cancers, including the PI3-kinase, AKT and mTOR pathways. Taken together, the researchers unraveled how a single oncogene could trigger a self-perpetuating series of miscommunications between the stem cell and its environment leading to malignancy.
The team is now investigating ways to block the leptin receptors in tumors as in doing so, it could throw a molecular monkey wrench into the vicious loop and derail the cancer. “The leptin receptor/leptin crosstalk between cancer stem cells and the microenvironment drives a positive feedback loop that fuels malignancy,” the first author says. “If we block this loop, which is a major pathway driving tumor progression, perhaps we can block tumor progression.”
Squamous cell carcinomas affect not only skin, but also esophagus, head and neck, lung and other epithelial tissues and, together, comprise the sixth most common cancer world-wide. 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 accumulating mutations within a cell, but from a stem cell biologist’s view, this work shows how a single oncogenic mutation can set events in motion that will drive cancer forward by aberrant exchange with the tumor microenvironment, independent of subsequent mutations.
“Our study shows that one oncogenic mutation can hijack a pathway and achieve the same thing as many cumulative mutations,” the author says. “We are always looking for mutations, but we must not forget to think about how to stop signaling pathways that drive tumor growth.”
https://www.nature.com/articles/s41586-022-05475-6
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fras-drives-malignancy&filter=22
Stem cell crosstalk with the microenvironment drives Ras malignancy
- 1,256 views
- Added
Edited
Latest News
Immune cells identified as…
By newseditor
Posted 28 Mar
TB blood test which could d…
By newseditor
Posted 27 Mar
Propionate supplementation…
By newseditor
Posted 27 Mar
Role of human Kallistatin i…
By newseditor
Posted 26 Mar
Addressing both flu and COV…
By newseditor
Posted 26 Mar
Other Top Stories
Llama-derived antibodies provide universal flu protection
Read more
Gut bacteria may control movement
Read more
Immigration to the United States changes a person's microbiome
Read more
How gut microbiota recovers after antibiotic exposure
Read more
What triggers cell division?
Read more
Protocols
All-optical presynaptic pla…
By newseditor
Posted 23 Mar
Epigenomic tomography for p…
By newseditor
Posted 20 Mar
A mouse DRG genetic toolkit…
By newseditor
Posted 17 Mar
An optogenetic method for t…
By newseditor
Posted 13 Mar
Profiling native pulmonary…
By newseditor
Posted 08 Mar
Publications
BHLHE40/41 regulate microgl…
By newseditor
Posted 28 Mar
Balancing neuronal activity…
By newseditor
Posted 28 Mar
OSBP-mediated PI(4)P-choles…
By newseditor
Posted 28 Mar
Integrated plasma proteomic…
By newseditor
Posted 27 Mar
APP antisense oligonucleoti…
By newseditor
Posted 27 Mar
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar