SOX10 ablation arrests cell cycle, induces senescence, and suppresses melanomagenesis.

The transcription factor SOX10 is essential for survival and proper differentiation of neural crest cell lineages, where it plays an important role in the generation and maintenance of melanocytes. SOX10 is also highly expressed in melanoma tumors, but a role in disease progression has not been established. Here, we report that melanoma tumor cell lines require wild-type SOX10 expression for proliferation and SOX10 haploinsufficiency reduces melanoma initiation in the metabotropic glutamate receptor 1 (Grm1(Tg)) transgenic mouse model. Stable SOX10 knockdown in human melanoma cells arrested cell growth, altered cellular morphology, and induced senescence. Melanoma cells with stable loss of SOX10 were arrested in the G1 phase of the cell cycle, with reduced expression of the melanocyte determining factor microphthalmia-associated transcription factor, elevated expression of p21WAF1 and p27KIP2, hypophosphorylated RB, and reduced levels of its binding partner E2F1. As cell-cycle dysregulation is a core event in neoplastic transformation, the role for SOX10 in maintaining cell-cycle control in melanocytes suggests a rational new direction for targeted treatment or prevention of melanoma.

Aldara activates TLR7-independent immune defence.

Aldara is a cream used for topical treatment of non-melanoma skin cancer, and is thought to act through stimulation of anti-tumour immunity. The active ingredient, imiquimod, has been shown to stimulate toll-like receptor 7. Aldara also induces psoriasis-like lesions when applied to naive murine skin, and as such is used as a mouse model for psoriasis. Here we find that in naive murine skin, Aldara induces inflammation largely independently of toll-like receptor 7. Surprisingly, inflammasome activation, keratinocyte death and interleukin 1 release also occur in response to the vehicle cream in the absence of imiquimod. We show that isostearic acid, a major component of the vehicle, promotes inflammasome activation in cultured keratinocytes, and so may contribute to the observed effects of Aldara on murine skin. Aldara therefore stimulates at least two immune pathways independently, and both imiquimod and vehicle are required for a full inflammatory response. Although it remains to be tested, it is possible that imiquimod-independent effects also contribute to the therapeutic efficacy of Aldara.

Cutaneous drug eruptions associated with the use of new oncological drugs.

There is a variety of adverse effects and toxicities of newer and older chemotherapeutic agents which emerge in the skin, mucosa and adnexa. Common skin reactions while undergoing chemotherapy include alopecia, changes in skin pigmentation, palmoplantar erythrodysesthesia, nail dystrophies and stomatitis. Extravasation injuries or hypersensitivity reactions may be severe. New oncologic agents have led to the development of different, class-specific cutaneous side effects. Epidermal growth factor receptor (EGFR) inhibitors induce papulopustular rashes in a high percentage of patients as well as, to a smaller degree, xerosis cutis, hair and nail changes, hyper pigmentation and enhancement of radiation dermatitis. Multikinase inhibitors will often cause hand-foot syndrome, but may also induce facial erythema, subungual splinter hemorrhages and other less frequent skin changes. BRAF inhibitors can lead to rash and development of cutaneous keratinocytic neoplasias for which patients should be closely monitored. Finally, MEK/ERK inhibitors induce similar skin toxicities to EGFR inhibitors such as papulopustular rashes, xerosis cutis and paronychia. Our chapter will focus on the clinical picture, histopathology and treatment options of these new class-specific cutaneous side effects.