Melanoma cell plasticity: ALDH1A3 as a regulator of heterogeneity and therapeutic target

Abstract

Melanoma is the most lethal form of skin cancer. Melanoma heterogeneity not only roots from the genetic mutations, but also the distinct phenotypes driven by their special transcriptional state. Such plasticity allows the tumour to adapt throughout disease progression and more importantly, give rise to drug tolerant persister cells (DTPs) when undergoing treatment. Intriguingly, some melanoma cells including the DTPs share the lineage developmental stem cell transcription program, also referred to as the neural crest stem cell (NCSC) signature. This phenomenon of cancer cells to express stem cell-like markers and to have tumour-initiating capacity has been linked to the drug resistance formation.

High levels of aldehyde dehydrogenase 1 (ALDH1) activity also mark a stem-cell like melanoma subpopulation. However, it is unknown whether or how ALDH1 regulates cell plasticity and DTP state of melanoma. In this study, I hypothesized that ALDH1 regulates melanoma cell states and is a potential target for DTPs. I used human melanoma cell lines, zebrafish melanoma models, as well as bioinformatic analysis to:

1. Profile the transcription signatures of ALDH1High melanoma subpopulation; 2. Investigate the mechanism how ALDH1A3 regulates the cell state of melanoma; and 3. Target ALDH1High cells using a published pro-drug compound Nifuroxazide (NAZ) in combination with the melanoma targeted therapy drug, BRAFV600E inhibitor.

To each end, 1. I discovered a novel ALDH1A3-TFAP2B (transcription factor AP-2 beta)-NCSC transcription signature enriched in ALDHHigh melanoma; 2. I found ALDH1A3 to have novel functions regulating the central carbon metabolism as well as histone H3 acetylation, which in turn established the ALDH1A3-TFAP2B-NCSC state; and 3. in zebrafish melanoma models, I used NAZ to successfully target ALDH1High DTPs after the tumours regressed on BRAFV600E inhibitor, which prolonged zebrafish tumour progression-free survival and delayed the drug-resistant regrowth; Moreover, I found NAZ changed tumour infiltrating lymphocyte (TIL) profiles when combined with BRAFV600E inhibitor.

In summary, my work demonstrates novel functions of ALDH1A3 to regulate the transcriptional, metabolic, and epigenetic states of melanoma cells, which is central to melanoma plasticity and a valuable target to tackle melanoma drug resistance.