CITED1 is a potential therapeutic target for metastatic melanoma
Cancer kills over 8 million people every year. What makes it so deadly is its ability to spread from the organ where it originates to the rest of the body, a process known as metastasis. Even though science is making huge progress in improving the treatment and survival of patients, we still understand relatively little about how metastasis works. We do, however, know that cancer cells need to acquire several important properties in order to metastasise successfully. For instance, they need to be able to move very quickly, which they normally achieve by contracting and deforming the neighbouring tissue. These are what we call contractile cancer cells. Once cells have invaded the tissue surrounding the original tumour, they usually find a way to enter blood vessels located near the original tumour. They are then transported all over the body by the blood flow, until they find a way to exit the stream and grow again in a completely different part of the body to form a secondary tumour. For example, skin cancer cells can make their way to the lungs or the liver. The aim of this study was to identify molecular pathways that drive the conversion of cancer cells into their highly metastatic form. We chose to work in melanoma – the deadliest form of skin cancer – because it is highly metastatic: nonetheless, all of our findings have the potential to be applicable in other types of cancer.
We have found that a molecule known as TGFβ induces the conversion of melanoma cancer cells into their highly metastatic form, that is able to move fast a be contractile. TGFβ is produced by both cancer cells and other cell types that are present around the tumour and that are not malignant. While these cells are not part of the cancer itself, it is possible that their TGFβ production might be hijacked by cancer cells to increase metastatic potential. We have subsequently focused on the mechanism through which TGFβ changes cancer cells: we have discovered that it does so switching “on” a specific set of genes. Healthy and cancer cells alike are driven by what genes within their DNA are switched “on” and “off”. All cells in the body have the same DNA, which is unique for each individual. However, different cells in different organs switch “on” or “off” different parts of that DNA (which are known as “genes”) to allow them to fulfil specific functions. For example, a muscle cell and a skin cell look and act very differently because different genes within their DNA are switched “on”. TGFβ stimulation switches “on” a set of genes within the DNA of cancer cells, which changes their basic blueprint and makes them more contractile and therefore more metastatic. We have found that this process is dependent on a molecule called CITED1, which switches genes “on” after the cell has been activated with TGFβ.
Interestingly, we have found that melanoma patients that produce a lot of CITED1 have a lower chance of survival than patients who do not. This suggests that the effect of TGFβ on cancer cells plays a crucial role in how melanomas metastasise and therefore on the chances of patients to survive. Studies that increase our understanding of the disease are very important for developing new cancer therapies. For example, we think that a drug that stops CITED1 from switching genes “on” would be very effective in stopping melanomas from spreading throughout the body and forming metastases.
Gaia Cantelli and Victoria Sanz-Moreno
Randall Division of Cell and Molecular Biophysics
King’s College London
TGF-β-Induced Transcription Sustains Amoeboid Melanoma Migration and Dissemination.
Cantelli G, Orgaz JL, Rodriguez-Hernandez I, Karagiannis P, Maiques O, Matias-Guiu X, Nestle FO, Marti RM, Karagiannis SN, Sanz-Moreno V
Curr Biol. 2015 Nov 16
|California has changed social norms, dramatically reducing… The rapid rise in the dependency on cigarette smoking in the United States occurred in the first half of the 20th century fueled by large mass media marketing campaigns and…|
|Turning on neuronal gene programs in prostate cancer cells Cancer of the prostate gland is a common malignancy afflicting males worldwide. This cancer is the second deadliest amongst male in United States, with most of the mortality resulting from…|
|Mesenchymal stem cells for treating knee osteoarthritis Cartilage in the knee does not heal very well nor very quickly, so continued use of the leg when walking for example can result in further damage, bony projections (osteophytes),…|
|Eavesdropping on cell communications to treat cancer with… An estimated 19.3 million new cancer cases and almost 10 million cancer deaths occurred worldwide in 2020. It’s estimated that one in three individuals will be diagnosed with some kind…|
|Arming macrophages to stop cancer progression Macrophages are a type of immune cells that fight infection and support tissue remodeling. They are best known as phagocytes which engulf bacteria and damaged cells stimulating other immune cells.…|
|Metformin improves pancreatic cancer and lymphoma outcomes… Type 2 diabetics are at increased risk of cancer in part because of increased insulin in the blood from insulin resistance. Insulin and its related growth factor IGF-1 can stimulate…|
Leave a Reply
You must be logged in to post a comment.