From moles to melanoma

USCF team pinpoints how benign moles become cancerous and recreate the process with CRISPR

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Non-melanoma skin cancer is the most common type of cancer, beating out even lung cancer. Of the different types of skin cancer, melanoma comprises only 1 percent of all cases, and yet is responsible for nearly three times as many deaths as other types of skin cancer, due to being highly metastatic.
While melanoma’s lethality has been well known for years, the exact process by which benign moles turn into cancerous melanomas is not as clear. But thanks to scientists from the University of California, San Francisco (UCSF), that process is being brought to light. As detailed in two companion Cancer Cell papers, the research team pinpointed the genetic changes that cause moles to become malignant and, through the use of CRISPR gene editing, have recreated the process in vitro with human skin cells.
At present, potential cancerous skin growths are monitored visually, with changes in shape and size being the most common alterations patients are advised to keep an eye on. Suspicious moles or growths are biopsied for diagnosis. But Dr. Boris Bastian, a UCSF Health skin cancer pathologist who directs the Clinical Cancer Genomics Laboratory for the UCSF Helen Diller Comprehensive Cancer Center and one of the leaders of this work, noted that “It’s a very crude assessment of the progression state of a tumor to measure it with a ruler. We’d prefer to be able to measure a mole’s genetic state to assess its risk of turning malignant, but the biology of this transformation has not been fully understood.”
The first of the two published studies was led by Bastian and cancer geneticist Dr. Hunter Shain, also of UCSF. The team worked with a dataset of surgically removed tissue samples from 82 melanoma patients, which featured samples of both the tumors and the moles the cancer originated from. Some patient samples also included matched samples of metastatic tumors and the primary melanomas in the skin that produced the metastatic cells. All told, the dataset provided the team with 230 tissue samples.
Tumor DNA and RNA was sequenced to look for gene mutations at different stages of the cancer and how the mutations were reflected by gene activity, as noted in press release penned by USCF Senior Public Information Representative Nicholas Weiller.
The key fact of note, according to the first paper—titled “Genomic and Transcriptomic Analysis Reveals Incremental Disruption of Key Signaling Pathways during Melanoma Evolution”—is that the process of benign skin moles going cancerous is indeed a multifaceted process. As reported in the abstract, “Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas. UV radiation-induced point mutations steadily increased until melanoma invasion, at which point copy-number alterations also became prevalent.”
Of these changes, mutations in the SWI/SNF gene cohort were a consistent culprit with regards to cells turning malignant, which could point to a possible biomarker.
According to Shain, “The field has a tendency to oversimplify how cancers evolve, as if there were just a switch that gets flipped on. Now we see that this pathway is turned on just a little early on, then ramped up over the course of tumor evolution. We think this may allow cancers to avoid cellular alarm bells until enough genetic changes have accumulated that the alarms no longer function.”
The second study, “Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation,” was led by Dr. Robert Judson, a UCSF melanoma geneticist. In this work, CRISPR/Cas9 was used to recreate melanoma's evolution by inserting the sequence of mutations noted in the first study into healthy human skin cells, per Weiller's press release.
While it had been known that losing the CDKN2A tumor suppressor often results in the spread of melanoma, the authors noted in their abstract, the exact mechanism of action behind this had not been identified. As per the authors, with the edited skin cells, “[W]e discovered that a lineage-restricted transcription factor, BRN2, is downstream of CDKN2A and directly regulated by E2F1. In a cohort of melanocytic tumors that capture distinct progression stages, we observed that CDKN2A loss coincides with both the onset of invasive behavior and increased BRN2 expression. Loss of the CDKN2A protein product p16INK4A permitted metastatic dissemination of human melanoma lines in mice, a phenotype rescued by inhibition of BRN2. These results demonstrate a mechanism by which CDKN2A suppresses the initiation of melanoma invasion through inhibition of BRN2.”
“Previous studies have typically used cell lines derived from advanced-stage cancers, where there is so much going wrong at the genetic level that it’s hard to know what’s causing what,” Judson commented in a press release. “Here we’re looking at otherwise healthy skin cells with specific mutations engineered in. It’s much clearer what each mutation does.”
SOURCE: UCSF press release

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