Early-stage melanomas at risk of spreading secrete the TGFβ2 growth factor, which causes the downregulation of the AMBRA1 and Loricrin proteins.
Researchers at Newcastle University have developed a novel test that reliably predicts the spread or return of melanoma, according to a press release.1
The test, called AMBLor, could help reassure patients who are diagnosed with early stage melanoma and who are concerned about the risk of spread. By applying the test to the standard biopsy of the primary melanoma on its removal, clinicians could be able to identify patients who are at a low risk of the disease reoccurring or spreading, according to the study authors.1
The rate of melanoma is increasing worldwide, with more than 96,000 diagnoses in the United States annually. In the new research, the authors explained that early-stage melanomas at risk of spreading secrete the TGFβ2 growth factor, which causes the downregulation of the AMBRA1 and Loricrin proteins. Both proteins are found in the skin overlaying the tumor, and TGFβ2 also causes the loss of claudin-1, which negatively impacts the integrity of the skin and facilitates ulceration, according to the study.1
“Like mortar and bricks holding together a wall, AMBRA1, Loricrin, and Claudin 1 are all proteins key to maintaining the integrity of the upper layer of the skin,” said senior author Penny Lovat, a professor of cellular dermatology and oncology at Newcastle University, in the press release. “When these proteins are lost, gaps develop—like the mortar crumbling away in the wall. This allows the tumor to spread and ultimately ulcerate, which we know is a process associated with higher risk tumors.”1
In a study evaluating the role of TGFβ2 in the epidermis, researchers used immunohistochemistry to analyze AMBRA1 and TGFβ2 in a cohort of 109 patients with all-stage melanoma. Furthermore, TGFβ2 was analyzed in a cohort of 30 stage 1 melanomas, and claudin-1 was analyzed in a cohort of 42 stage I melanomas.2
Increased tumoral TGFβ2 was significantly associated with a loss of peritumoral AMBRA1, ulceration, AMLo high-risk status, and metastasis. TGFβ2 treatment of keratinocytes resulted in downregulation of AMBRA1, loricrin, and claudin-1, whereas knockdown of AMBRA1 was associated with decreased expression of claudin-1 and increased proliferation of keratinocytes.2
Importantly, the researchers found that loss of AMBRA1 in the peritumoral epidermis was associated with decreased claudin-1 expression, parakeratosis, and cleft formation in the dermoepidermal junction. Collectively, these findings suggest that TGFβ2 causes loss of AMBRA1 overlying high-risk early-stage melanomas and reduced epidermal integrity, which causes skin erosion and tumor ulceration.2
“Our test offers a personalized prognosis as it more accurately predicts if your skin cancer is unlikely to spread,” Lovat said in the press release. “This test will aid clinicians to identify genuinely low risk patients diagnosed with an early-stage melanoma and to reduce the number of follow-up appointments for those identified as low risk, saving the [National Health Service] time and money.”
1. First melanoma test to offer reassurance of low risk of cancer spread. News release. EurekAlert; January 13, 2022. Accessed January 17, 2022. https://www.eurekalert.org/news-releases/939808
2. Cosgarea I, McConnell AT, Ewen T, Tang D, et al. Melanoma secretion of transforming growth factor-β2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumor ulceration. British Journal of Dermatology. November 13, 2021. doi:10.1111.bjd.20889. Accessed January 17, 2022.