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Novel cell states in melanoma progression and residual disease

Using zebrafish models to visualise cells at the site of melanoma residual disease with the potential to drive melanoma recurrence: October 2019

Zebrafish MITF-low melanoma models human MITF-low melanoma. While the bulk of the tumor is dependent on MITF activity, MITF-independent cells pre-exist and arise de novo in residual disease.
Zebrafish MITF-low melanoma models human MITF-low melanoma. While the bulk of the tumor is dependent on MITF activity, MITF-independent cells pre-exist and arise de novo in residual disease.

Melanoma is the deadliest type of skin cancer with over 15,000 new cases every year in the UK.  If removed early, most people are cured of the disease. However, for those with malignant metastatic melanoma the outcomes are poor. Understanding how cancers develop and why they resist therapy is critical for the development of new treatments. Importantly, while many melanomas can initially respond to therapy, ultimately some surviving cancer cells ("residual disease") allow the melanoma to return, often resistant to further therapy.

It is well established that genetic mutations contribute to melanoma progression (so-called "driver mutations"), but researchers at the MRC Human Genetics Unit and Cancer Research UK Edinburgh Centre now show that gene expression changes can also promote melanoma and act as "driver cell states". Gene expression is the process by which the instructions in our DNA are converted into a functional product, such as a protein. These altered cell states provide new therapeutic opportunities.

Gene expression studies classify patient melanomas into three groups with distinct survival prognosis. One of these is the 'MITF-low' gene expression signature and is associated with poor outcomes for patients. MITF is a transcription factor essential for melanocyte development and survival. Little is known about the biological significance of the MITF-low classification and if it is relevant to melanoma progression.

Using zebrafish, the IGMM researchers have established that the MITF-low gene expression state is a "driver cell state" and that it is highly similar to human MITF-low melanomas. Further, they show that while the bulk of the tumour depends on MITF for survival, they discover a subpopulation of cells that are resistant to loss of MITF activity following tumour regression (called MITF-independent cells). Critically, they discover that MITF-independent residual disease cell states are already in the primary tumour and in recurring disease, suggesting they may be critical new drug targets.

Through this work we have identified cell states caused by something additional to DNA mutation that can drive melanoma, identify residual disease, and potentialy reveal new drug targets

Professor Liz PattonMRC Human Genetics Unit, University of Edinburgh

This study is notable because it uses state-of-the-art high-resolution imaging combined with single cell gene expression analysis to understand these new cell states for the first time in a complex living system. This discovery highlights that MITF-independent subpopulations may be an important therapeutic target to achieve long-term survival improvements for melanoma patients.

Links

Original article https://doi.org/10.1158/0008-5472.CAN-19-0037

Patton research group

CRUK information on melanoma: https://www.cancerresearchuk.org/about-cancer/melanoma

Funding acknowledgements: Medical Research Council, European Research Council, and L’Oreal-Melanoma Research Alliance