The therapeutic potential of targeting minimal residual disease in melanoma

Patel, Riyaben P.; Somasundram, Pretashini M; Smith, Lorey; Sheppard, Karen E.; McArthur, Grant A.

doi:10.1002/ctm2.1197

Cited by 4 publications

(2 citation statements)

References 102 publications

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“…Phenotype switching has been linked to drug resistance, with the undifferentiated/invasive cell state recently found to be drug tolerant 8,13,72 .This finding has important clinical relevance, as drug tolerant persister cells are a major contributor to relapse in patients 73 . Based on this, we examined how the confined, invasive state affects response to therapy.…”

Section: Resultsmentioning

confidence: 99%

Mechanical confinement governs phenotypic plasticity in melanoma

Hunter,

Montal,

et al. 2024

Preprint

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Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes - proliferative versus invasive states. While it has long been hypothesised that such switching is triggered by external cues, the identity of these cues has remained elusive. Here, we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumor cells at the interface between the tumor and surrounding microenvironment. Morphological analysis of these rare cells showed flattened, elliptical nuclei suggestive of mechanical confinement by adjacent tissue. Spatial and single-cell transcriptomics demonstrated that the interface cells adopted a gene program of neuronal invasion, including acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favor the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2hightumor cells are less proliferative but more drug resistant. Our results implicate the mechanical microenvironment as a mechanism driving phenotype switching in melanoma.

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Section: Resultsmentioning

confidence: 99%

Mechanical confinement governs phenotypic plasticity in melanoma

Hunter,

Montal,

et al. 2024

Preprint

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“…As a common skin tumor, cutaneous melanoma (SKCM) has a poor prognosis and are more likely to present with aggressive clinical manifestations such as ulcers 1 . Recent clinical trials have shown that immune checkpoint inhibitors and BRAF/MEK inhibitors significantly improve overall survival in patients with advanced melanoma, but there are still melanoma patients who could not benefit from these methods since poor immune response to tumors and low rates of BRAF gene mutations 2–4 . It is still of great significance to find specific tumor markers and therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

m6A‐ and m5C‐ modified lncRNAs orchestrate the prognosis in cutaneous melanoma and m6A‐ modified LINC00893 regulates cutaneous melanoma cell metastasis

Shi,

Tian,

et al. 2024

Skin Research and Technology

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BackgroundAs the most important modifications on the RNA level, N6‐methyladenosine (m6A‐) and 5‐methylcytosine (m5C‐) modification could have a direct influence on the RNAs. Long non‐coding RNAs (lncRNAs) could also be modified by methylcytosine modification. Compared with mRNAs, the function of lncRNAs could be more potent to some extent in biological processes like tumorigenesis. Until now, rare reports have been done associated with cutaneous melanoma. Herein, we wonder if the m6A‐ and m5C‐ modified lncRNAs could influence the immune landscape and prognosis in melanoma, and we also want to find some lncRNAs which could directly affect the malignant behaviors of melanoma.MethodsSystematically, we explored the expression pattern of m6A‐ and m5C‐ modified lncRNAs in melanoma from datasets including UCSC Xena and NCBI GEO, and the prognostic lncRNAs were selected. Then, according to the expression pattern of lncRNAs, melanoma samples from these datasets were divided into several subtypes. Prognostic model, nomogram survival model, drug sensitivity, GO, and KEGG pathway analysis were performed. Furthermore, among several selected lncRNAs, we identified one lncRNA named LINC00893 and investigated its expression pattern and its biological function in melanoma cell lines.ResultsWe identified 27 m6A‐ and m5C‐ related lncRNAs which were significantly associated with survival, and we made a subtype analysis of melanoma samples based on these 27 lncRNAs. Among the two subtypes, we found differences of immune cells infiltration between these two subtypes. Then, LASSO algorithm was used to screen the optimized lncRNAs combination including ZNF252P‐AS1, MIAT, FAM13A‐AS1, LINC‐PINT, LINC00893, AGAP2‐AS1, OIP5‐AS1, and SEMA6A‐AS1. We also found that there was a significant correlation between the different risk groups predicted based on RS model and the actual prognosis. The nomogram survival model based on independent survival prognostic factors was also constructed. Besides, sensitivity to chemotherapeutic agents, GO and KEGG analysis were performed. In different risk groups, a total of 14 drug molecules with different distributions were obtained, which included AZD6482, AZD7762, AZD8055, camptothecin, dasatinib, erlotinib, gefitinib, gemcitabine, GSK269962A, nilotinib, rapamycin, and sorafenib. A total of 55 significantly related biological processes and 17 KEGG signaling pathways were screened. At last, we noticed that LINC00893 had a relatively lower expression in melanoma tissue and cell lines compared with adjacent tissues and epidermal melanocyte, and down‐regulation of LINC00893 could promote the malignant behavior of melanoma cells in A875 and MV3. In these two melanoma cell lines, down‐regulation of m6A‐related molecules like YTHDF3 and METTL3 could promote the expression of LINC00893.ConclusionWe made an analysis of m6A‐ and m5C‐ related lncRNAs in melanoma samples and a prediction of these lncRNAs’ role in prognosis, tumor microenvironment, immune infiltration, and clinicopathological features. We also found that LINC00893, which is potentially regulated by m6A modification, could serve as a tumor‐suppressor in melanoma and play an inhibitory role in melanoma metastasis.

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Liquid biopsy for diagnostic and prognostic evaluation of melanoma

Slusher,

Jones,

Nonaka

2024

Front. Cell Dev. Biol.

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Melanoma is the most aggressive form of skin cancer, and the majority of cases are associated with chronic or intermittent sun exposure. The incidence of melanoma has grown exponentially over the last 50 years, especially in populations of fairer skin, at lower altitudes and in geriatric populations. The gold standard for diagnosis of melanoma is performing an excisional biopsy with full resection or an incisional tissue biopsy. However, due to their invasiveness, conventional biopsy techniques are not suitable for continuous disease monitoring. Utilization of liquid biopsy techniques represent substantial promise in early detection of melanoma. Through this procedure, tumor-specific components shed into circulation can be analyzed for not only diagnosis but also treatment selection and risk assessment. Additionally, liquid biopsy is significantly less invasive than tissue biopsy and offers a novel way to monitor the treatment response and disease relapse, predicting metastasis.

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The therapeutic potential of targeting minimal residual disease in melanoma

Cited by 4 publications

References 102 publications

Mechanical confinement governs phenotypic plasticity in melanoma

Mechanical confinement governs phenotypic plasticity in melanoma

m6A‐ and m5C‐ modified lncRNAs orchestrate the prognosis in cutaneous melanoma and m6A‐ modified LINC00893 regulates cutaneous melanoma cell metastasis

Liquid biopsy for diagnostic and prognostic evaluation of melanoma

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