A significantly increased risk of metastasis is noted in patients with early AJCC stage melanoma with the mixed loss of the autophagy-regulatory protein AMBRA1 and the terminal differentiation marker loricrin in the peritumoural epidermis.

A study evaluated the potential role of melanoma paracrine TGFβ signaling in the loss of AMBRA1 in the epidermis overlying the primary tumor and breach in epidermal integrity.

Immunohistochemistry analysis was done in- 

• 109 all AJCC stage melanomas for AMBRA1 and TGFβ2 
• 30 AJCC stage I melanomas for TGFβ2 
• 42 AJCC stage I melanomas for claudin-1with AMBRA1 and loricrin (AMLo) expression. 

Also, 42 melanomas underwent investigation for pre-ulceration, with TGFβ2 signaling evaluated in primary keratinocytes.

The following observations were made-

• Increased tumoural TGFβ2 was found to cause loss of peritumoural AMBRA1, ulceration, AMLo high-risk status and metastasis. 
• Keratinocytes, when treated for TGFβ2 caused downregulation of AMBRA1, loricrin and claudin-1. 
• AMBRA1 knockdown resulted in decreased expression of claudin-1 and increased proliferation of keratinocytes. 
• Loss of AMBRA1 in the peritumoural epidermis caused decreased claudin- 1 expression, parakeratosis and cleft formation in the dermal-epidermal junction.

The obtained data indicate a paracrine mechanism where TGFβ2 causes loss of AMBRA1 overlying high-risk early AJCC stage melanomas and decreased epidermal integrity, resulting in erosion of the epidermis and tumor ulceration.

Source- BJD, November 2021. https://doi.org/10.1111/bjd.20889