Genetics of melanoma chemoresistance

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Malignant melanoma is a highly aggressive and notoriously chemoresistant form of cancer. In this paper, Ohanna et al. reveal that anti-melanoma drugs may, paradoxically, induce a senescence-associated secretory profile ("secretome") that can ultimately promote metastasis and contribute to melanoma relapse.

While cellular senescence has been thought of as a natural mechanism to combat uncontrolled cell growth, or cancer, recent studies have shown that some cell types express a secretome during senescence that alters the tumor microenvironment and affects the cell’s response to chemotherapeutic drugs. Ohanna et al. confirm that senescent melanoma cells do, in fact, express an inflammatory secretome, and have delineated the genetic pathways involved: Depletion of the MITF transcription factor, or exposure to anti-melanoma drugs, activates the DNA damage response and triggers senescence. Senescent melanoma cells express a PARP-1 and NF-kB—associated secretome, which contains high levels of the chemokine CCL2. CCL2, in turn, leads to a loss of E-cadherin expression and an invasive phenotype.

In fact, Ohanna et al. show that culturing melanoma cells with exogenous CCL2 enhances their survival and invasiveness. 

This finding suggests that blocking CCL2, or its upstream effectors, may represent a novel therapeutic pathway. As Dr. Bertolotto explains, “Our data disclose a part of the mechanisms contributory to failure of anti-melanoma chemotherapies and we gain valuable insight for the identification of new candidates, namely PARP-1, NF-kB or CCL2, for therapeutic intervention in view to overcome drug resistance.”

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Contact: Heather Cosel

Cold Spring Harbor Laboratory

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As information:
Melanoma facts

* Melanoma is a skin cancer that begins in cells called melanocytes.

* Melanocytes can grow together to form benign (not cancerous) moles.

* A change in size, shape, or color of a mole can be a sign of melanoma. Other symptoms of a malignant (cancerous) mole include itching, bleeding, and scaliness.

* Melanoma can be cured if detected early before spread (metastasis) to other areas of the body.

* Diagnosis of melanoma is confirmed with a biopsy of the abnormal skin.

* To determine the stage of the melanoma, the doctor will need to determine the thickness of the melanoma and check if the melanoma has spread.

* Treatment of melanoma depends on the extent of disease and the patient’s age and general health.

* The prognosis of melanoma depends upon a melanoma’s thickness, the depth of penetration of the skin, the extent to which it has spread, and certain characteristics of the tumor such as its mitotic rate and the presence of ulceration.

* Sun exposure can cause skin damage that can lead to melanoma.

What is melanoma?

Melanoma is a type of skin cancer. It begins in cells in the skin called melanocytes. To understand melanoma, it is helpful to know about the skin and about melanocytes—what they do, how they grow, and what happens when they become cancerous.

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