Genetics of melanoma chemoresistance

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."

Melanomas can develop anywhere on your body, but they most often develop in areas that have had exposure to the sun, such as your back, legs, arms and face. Melanomas can also occur in areas that don't receive much sun exposure, such as the soles of your feet, palms of your hands and on fingernail beds. These hidden melanomas are more common in people with darker skin.

The first melanoma symptoms often are:

* A change in an existing mole
* The development of a new, unusual-looking growth on your skin

Melanoma doesn't always begin as a mole. It can also occur on otherwise normal-appearing skin.

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Contact: Heather Cosel
[email protected]
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.