Cancer in lymph nodes: What happens and treatment
Mouse Model Sheds Light On How Lung Adenocarcinoma Can Transform Into A More Aggressive Type Of Lung Cancer
Initial treatments for lung adenocarcinomas may be effective at first, but sometimes these tumors can respond by turning into small cell lung cancer (SCLC), a more aggressive and difficult-to-treat disease.
Lung adenocarcinoma is the most common type of lung cancer, accounting for 40% of cases. It's a form of non-small cell lung cancer (NSCLC) that can occur in people with or without a history of smoking. Epidermal growth factor receptor (EGFR) mutations are the most common oncogenes in NSCLC, which drive cancer growth.
Initial treatments for lung adenocarcinomas may be effective at first, but sometimes these tumors can respond by turning into small cell lung cancer (SCLC), a more aggressive and difficult-to-treat disease.
Now, researchers at Weill Cornell Medicine have developed a mouse model that sheds light on the processes behind this transformation. Their findings, published in Science, may help identify potential targets for new, more effective treatments.
"Broadly, this study reinforces that not all oncogenes can transform any cell type into a cancer. Here, we use lung cancer as a model system and explore a phenomenon termed 'histological transformation,' Eric E. Gardner, Pharm.D., Ph.D., lead author of the study and a postdoctoral fellow at the Varmus laboratory at Meyer Cancer Center in Weill Cornell Medicine, told Managed Healthcare Executive.
Gardner explained that their study focused on histological transformation of EGFR-driven lung adenocarcinoma (LUAD) into small-cell lung cancer. "SCLC is an aggressive, recalcitrant cancer that spreads quickly. Currently, there are limited therapeutic options to treat and control SCLC. This may be – in part – due to a lack of a basic understanding as to how this cancer is fundamentally driven," he said.
The researchers observed that during the transition from lung adenocarcinoma to SCLC, the mutated cells underwent a change in cell identity through an intermediate, stem cell-like state. This shift facilitated the transformation and highlighted the role of specific genes, such as Myc, in driving the process.
"Specifically, this study demonstrates that the oncogenes that drive these two different types of lung cancer are not only different but incompatible (i.E., toxic) when placed into the other type of cell," Gardner stated.
"We use something called 'lineage tracing' where we have designed genetically engineered mice to activate different oncogenes (human or mouse) in different cell types in a very controlled manner. We can use these tools to study the impact certain oncogenes have on cell behavior in a completely intact (whole animal) system," he explained.
"For example, we show that the oncogene Myc is sufficient to transform the pulmonary neuroendocrine cell (PNEC) lineage; however, when we express oncogenic Myc in the alveolar type II cell (the predominant cell of origin for LUAD), we do not observe transformation, but rather toxicity to this cell type – the cells die," Gardner said.
These findings reveal new insights into the role of oncogenes and highlight the importance of considering cell type when developing targeted therapies. The researchers plan to further investigate the adenocarcinoma-SCLC transition and explore how the immune system responds to this transformation. Ultimately, their work could lead to more effective treatments targeting lung cancer.
One Type Of Lung Cancer Can Turn Into Another, Study Finds
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Lung tumors called adenocarcinomas sometimes respond to initially effective treatments by transforming into a much more aggressive small cell lung cancer (SCLC) that spreads rapidly and has few options for treatment. Researchers at Weill Cornell Medicine have developed a mouse model that illuminates this problematic process, known as histological transformation. The findings advance the understanding of how mutated genes can trigger cancer evolution and suggest targets for more effective treatments.
The researchers, whose results were published Feb. 8 in Science, discovered that during the transition from lung adenocarcinoma to small cell lung cancer (SCLC), the mutated cells appeared to undergo a change in cell identity through an intermediate, stem cell-like state, which facilitated the transformation.
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Subscribe for FREE"It is very difficult to study this process in human patients. So my aim was to uncover the mechanism underlying the transformation of lung adenocarcinoma to small cell lung cancer in a mouse model," said study lead Dr. Eric Gardner, a postdoctoral fellow in the laboratory of Dr. Harold Varmus, the Lewis Thomas University Professor of Medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. The complex mouse model took several years to develop and characterize but has allowed the researchers to crack this difficult problem.
This study was in collaboration with Dr. Ashley Laughney, assistant professor of physiology and biophysics and a member of the Meyer Cancer Center at Weill Cornell Medicine and Ethan Earlie, a graduate student in the Laughney lab and part of the Tri-Institutional Computational Biology and Medicine program.
"It is well known that cancer cells continue to evolve, especially to escape the pressure of effective treatments," said Dr. Varmus. "This study shows how new technologies—including the detection of molecular features of single cancer cells, combined with computer-based analysis of the data—can portray dramatic, complex events in the evolution of lethal cancers, exposing new targets for therapeutic attack."
Catching Transformation in the ActSCLC most commonly occurs in heavy smokers, but this type of tumor also develops in a significant number of patients with lung adenocarcinomas, particularly after treatment with therapies that target a protein called Epidermal Growth Factor Receptor (EGFR), which promotes tumor growth. The new SCLC-type tumors are resistant to anti-EGFR therapy because their growth is fueled by a new cancer driver, high levels of Myc protein.
To unravel the interplay of these cancer pathways, the researchers engineered mice to develop a common form of lung adenocarcinoma, in which lung epithelial cells are driven by a mutated version of the EGFR gene. They then turned the adenocarcinoma tumors into SCLC-type tumors, which generally arise from neuroendocrine cells. They did this by shutting off EGFR in the presence of several other changes including losses of the tumor suppressor genes Rb1 and Trp53 as well as turning up the production of Myc, a known driver of SCLC.
Oncogenes, such as EGFR and Myc, are mutated forms of genes that normally control cell growth. They are known for their roles in driving the growth and spread of cancer. Tumor suppressor genes, on the other hand, normally inhibit cell proliferation and tumor development.
Context MattersSurprisingly, this study showed that oncogenes act in a context-dependent manner. While most lung cells are resistant to becoming cancerous by Myc, neuroendocrine cells, are very sensitive to the oncogenic effects of Myc. Conversely, epithelial cells, which line the air sacs of the lungs and are the precursors to lung adenocarcinomas, grow excessively in response to mutated EGFR.
"This shows that an 'oncogene' in the wrong cell type doesn't act like an oncogene anymore," Dr. Laughney said. "So, it fundamentally changes how we think about oncogenes."
The researchers also discovered a stem cell-like intermediate that was neither adenocarcinoma nor SCLC. Cells in this transitional state became neuroendocrine in nature only when mutations in the tumor suppressor genes RB1 and TP53 were present. They observed that loss of another tumor suppressor called Pten accelerated this process. At that stage, oncogenic Myc could drive these intermediate stem-like cells to form SCLC-type tumors.
This study further supports efforts seeking therapeutics that target Myc proteins, which are implicated in many types of cancers. The researchers now plan to use their new mouse model to further explore the adenocarcinoma-SCLC transition, detailing, for example, how the immune system normally responds to this transition.
Reference: Gardner EE, Earlie EM, Li K, et al. Lineage-specific intolerance to oncogenic drivers restricts histological transformation. Science. 2024;383(6683):eadj1415. Doi: 10.1126/science.Adj1415
This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.
Lung Cancer Symptoms: What You Should Know
Most of the time, lung cancer has no symptoms in its early stages. Your lungs don't have many nerve endings, so a tumor can start to grow there without causing pain. You may not notice the signs until your cancer has begun to spread.
When signs of the disease start to appear, they can include:
These problems usually happen because of blocked breathing passages or because the cancer has spread farther into the lung, nearby areas, or other parts of the body.
Early-stage lung cancer often has few symptoms. When it's caught early, it's usually because the patient had a screening. (Photo Credit: E+/Getty Images)
Stage I lung cancer symptoms
This early stage of lung cancer often doesn't cause any symptoms. Stage I lung cancer is more likely to be caught because you had a screening, not because you noticed anything wrong. If you do have symptoms, they may include:
Stage IV lung cancer symptoms
When your cancer reaches this stage, it has begun to spread to more spots in your lungs, the fluid around your lungs, or other places in your body. In addition to respiratory symptoms such as coughing and wheezing, you may have:
Less common lung cancer symptoms
Some symptoms affect parts of your body that don't seem related to to your lungs. Those signs include:
Lung cancer symptoms on the skin
In addition to sweating issues caused by Horner syndrome, lung cancer can cause other issues with your skin. They include:
Lung cancer is the leading cause of cancer deaths among all genders. Lung cancer rates are falling across the board, but the decline hasn't been as big for younger women. Experts aren't sure why this is happening. Genetic mutations may play a role. Lung cancer has traditionally been associated with older men who have a history of smoking, so doctors may not suspect lung cancer at first when a nonsmoking young woman comes in with general symptoms such as cough or frequent respiratory infections.
There are two main types of lung cancer: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). NSCLC is more common and makes up about 85% of all lung cancer cases. Within NSCLC, there are three subtypes:
There are two types of SCLC, mainly based on the type of cells involved and how they look under a microscope: small-cell carcinoma and mixed small-cell/large-cell cancer. It's sometimes called combined small-cell lung cancer. SCLC is strongly linked to cigarette smoking.
Both SCLC and NSCLC have many symptoms in common: cough, chest pain, wheezing, and hoarseness, for instance.
Non-small-cell lung cancer symptoms
NSCLC is more likely than SCLC to cause Horner syndrome, the collection of symptoms that affects your pupil, eyelid, and sweating on one side of your face.
Small-cell lung cancer symptoms
This type tends to grow and spread more quickly to other parts of your body. That means it's more likely to produce symptoms, such as:
SCLC is more likely than NSCLC to cause hypercalcemia and interfere with your adrenal glands.
If you have any of these symptoms of lung disease, especially an ongoing cough, blood-streaked mucus, wheezing, hoarseness, or a lung infection that keeps coming back, see your doctor. You'll get a thorough checkup, and you may also get X-rays or other tests.
Go immediately to the emergency room if you have any of the following:
In its early stages, lung cancer often has no symptoms. If you're coughing up mucus (especially if it's streaked with blood), have wheezing, hoarseness, chest pain, or frequent cases of bronchitis or pneumonia, these can be signs of lung cancer. Many of the symptoms of SCLS and NSCLC are the same. Those symptoms can also be signs of other illnesses. It's important to talk to your doctor if you have concerns.
How long can you have lung cancer without knowing?
Lung cancer can grow in your body for years before you start to notice symptoms.
Is cancer in the lungs curable?
Experts generally don't use the word "cured" when it comes to lung cancer. They're more likely to say you're in "remission" or that your body shows "no evidence of disease" (NED). At 5 years or more of remission or NED, your doctor might consider you cured. The earlier your cancer is found and you begin treatment, the better your outcome is likely to be. That's why experts have begun to encourage lung cancer screening for certain people at higher risk. You may want to look into the benefits of screening if you meet these requirements:
How long can you live with lung cancer?
How long you'll live depends on many factors, including:
The survival rates for lung cancer have been increasing with the development of new treatments.
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