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Published on: June 7, 2019
Melanoma-Derived BRAF(V600E) Mutation in Peritumoral Stromal Cells: Implications for in Vivo Cell Fusion
Zsuzsanna Kurgyis1, Lajos V Kemény2, Tünde Buknicz3
1Department of Dermatology and Allergology, University of Szeged, Szeged 6720, Hungary. kurgyis.zsuzsanna@med.u-szeged.hu.
Abstract:
Melanoma often recurs in patients after the removal of the primary tumor, suggesting the presence of recurrent tumor-initiating cells that are undetectable using standard diagnostic methods. As cell fusion has been implicated to facilitate the alteration of a cell's phenotype, we hypothesized that cells in the peritumoral stroma having a stromal phenotype that initiate recurrent tumors might originate from the fusion of tumor and stromal cells. Here, we show that in patients with BRAF(V600E) melanoma, melanoma antigen recognized by T-cells (MART1)-negative peritumoral stromal cells express BRAF(V600E) protein. To confirm the presence of the oncogene at the genetic level, peritumoral stromal cells were microdissected and screened for the presence of BRAF(V600E) with a mutation-specific polymerase chain reaction. Interestingly, cells carrying the BRAF(V600E) mutation were not only found among cells surrounding the primary tumor but were also present in the stroma of melanoma metastases as well as in a histologically tumor-free re-excision sample from a patient who subsequently developed a local recurrence. We did not detect any BRAF(V600E) mutation or protein in the peritumoral stroma of BRAF(WT) melanoma. Therefore, our results suggest that peritumoral stromal cells contain melanoma-derived oncogenic information, potentially as a result of cell fusion. These hybrid cells display the phenotype of stromal cells and are therefore undetectable using routine histological assessments. Our results highlight the importance of genetic analyses and the application of mutation-specific antibodies in the identification of potentially recurrent-tumor-initiating cells, which may help better predict patient survival and disease outcome.
Insights
Recurrent melanoma may originate from fusion between tumor and stromal cells. BRAF(V600E) mutations were found in peritumoral stromal cells, suggesting they harbor oncogenic information and may initiate new tumors.
Area of Science:
- Oncology
- Cell Biology
- Cancer Genetics
Background:
- Melanoma recurrence after primary tumor removal suggests the presence of undetectable tumor-initiating cells.
- Cell fusion is a known mechanism for altering cellular phenotype.
- The origin of recurrent melanoma-initiating cells remains unclear.
Purpose of the Study:
- To investigate the hypothesis that peritumoral stromal cells, exhibiting a stromal phenotype, may initiate recurrent tumors.
- To determine if melanoma and stromal cell fusion contributes to melanoma recurrence.
- To identify novel markers for detecting recurrent tumor-initiating cells.
Main Methods:
- Microdissection of peritumoral stromal cells from melanoma patients.
- Screening for BRAF(V600E) mutation using mutation-specific polymerase chain reaction.
- Detection of BRAF(V600E) protein using mutation-specific antibodies.
- Analysis of stromal cells in primary tumors, metastases, and re-excision samples.
Main Results:
- BRAF(V600E) protein and mutation were detected in melanoma antigen recognized by T-cells (MART1)-negative peritumoral stromal cells from BRAF(V600E) melanoma patients.
- The BRAF(V600E) mutation was found in stromal cells surrounding primary tumors, in metastatic lesions, and in tumor-free re-excision samples from patients with local recurrence.
- No BRAF(V600E) mutation or protein was detected in the peritumoral stroma of BRAF wild-type (WT) melanoma.
- These BRAF(V600E)-positive stromal cells displayed a stromal phenotype, making them undetectable by standard histological methods.
Conclusions:
- Peritumoral stromal cells can acquire melanoma-derived oncogenic information, potentially through cell fusion.
- These hybrid cells, expressing stromal phenotypes, may represent a source of recurrent melanoma.
- Genetic analyses and mutation-specific antibodies are crucial for identifying these otherwise undetectable recurrent tumor-initiating cells.
- Identifying these cells could improve patient survival and disease outcome prediction.
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