The Role of Melanocyte Lineage Genes in Melanoma
Sanna, Adriana LU
(2020)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- Malignant melanoma accounts for the highest number of deaths among all skin cancer types, and its incidence has increased dramatically over the past decades. Despite the tremendous therapeutic advances, treatment resistant cells emerge in the vast heterogeneity of melanoma, driving tumor relapse and poor patient outcome. The aims of the studies conducted in this thesis were to contribute to the knowledge with regards to therapy-resistant melanomas, and to explore tumor heterogeneity in relation to cancer progression among the chronic sun-damaged (CSD) melanomas.
Therapy resistant cells have lost the melanocyte lineage-specific transcriptional program, which is mainly driven by the master-melanocyte regulator MITF. Paper I validated the... (More) - Malignant melanoma accounts for the highest number of deaths among all skin cancer types, and its incidence has increased dramatically over the past decades. Despite the tremendous therapeutic advances, treatment resistant cells emerge in the vast heterogeneity of melanoma, driving tumor relapse and poor patient outcome. The aims of the studies conducted in this thesis were to contribute to the knowledge with regards to therapy-resistant melanomas, and to explore tumor heterogeneity in relation to cancer progression among the chronic sun-damaged (CSD) melanomas.
Therapy resistant cells have lost the melanocyte lineage-specific transcriptional program, which is mainly driven by the master-melanocyte regulator MITF. Paper I validated the MITF-negative (MITFNeg) melanomas to be highly aggressive and associated with inferior patient survival compared with the MITF-high (MITFHigh) cases. We herein discovered an even more undifferentiated melanoma subtype that lacks the MITF upstream marker SOX10 (MITFNegSOX10Neg), characterized by superior metastatic potential and resistance to targeted therapy. Importantly, we found gene methylation explaining the silencing of both MITF and SOX10 in these melanomas. To discriminate the role of SOX10 in MITFNeg cells, in Paper II we engineered SOX10KO by CRISPR-Cas9 technology. Depletion of SOX10 in MITFNeg cells lead to a hyper-undifferentiated phenotype: a new distinct lineage identity state in melanoma. Paper III uncovered a novel layer of regulation of MITF at the translational level. We showed that MITF is regulated by the RNA-helicase DDX3X. DDX3X loss in melanoma leads to decreased MITF, and results in enhanced metastasis and therapy resistance. Interestingly, DDX3X is located on the X-chromosome. Thus, mutations affecting DDX3X associate with poor prognosis in male melanoma patients, implying an exclusive window of opportunity in this gender. Paper IV investigated the molecular features of a unique cohort of high and low CSD (CSDhigh, CSDlow) melanomas. Focusing on the less investigated CSDhigh subtype in view of cancer progression, we found no mutational difference between in situ or invasive phases. We further observed dissimilarity in the heterogeneity levels between CSDhigh and CSDlow melanomas, which suggests distinguishable molecular entities that progress via different routes.
Overall, we unraveled the role of melanocyte-specific genes in defining diverse melanoma lineage states, while investigating novel biological mechanisms behind their regulation. Our findings further highlighted the variable heterogeneity in CSD melanoma subtypes, which should be taken into consideration for an improved diagnosis, and when choosing the best treatment options for melanoma patients. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/339a0f60-16f8-4089-8581-0c91d4b03ab5
- author
- Sanna, Adriana
LU
- supervisor
-
- Göran B Jönsson LU
- Christian Ingvar LU
- Bengt Phung LU
- Katja Harbst LU
- opponent
-
- Dr. Soengas, María S., Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- organization
- publishing date
- 2020
- type
- Thesis
- publication status
- published
- subject
- keywords
- Melanoma, Genetic, Epigenetic, Heterogeneity, MITF, SOX10, CSD
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2020:62
- pages
- 90 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Föreläsningssal E24, Medicon Village, Scheleevägen 2, Byggnad 404, Lund
- defense date
- 2020-05-20 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-7619-923-7
- language
- English
- LU publication?
- yes
- id
- 339a0f60-16f8-4089-8581-0c91d4b03ab5
- date added to LUP
- 2020-04-27 17:02:47
- date last changed
- 2022-09-07 16:46:01
@phdthesis{339a0f60-16f8-4089-8581-0c91d4b03ab5,
abstract = {{Malignant melanoma accounts for the highest number of deaths among all skin cancer types, and its incidence has increased dramatically over the past decades. Despite the tremendous therapeutic advances, treatment resistant cells emerge in the vast heterogeneity of melanoma, driving tumor relapse and poor patient outcome. The aims of the studies conducted in this thesis were to contribute to the knowledge with regards to therapy-resistant melanomas, and to explore tumor heterogeneity in relation to cancer progression among the chronic sun-damaged (CSD) melanomas.<br/>Therapy resistant cells have lost the melanocyte lineage-specific transcriptional program, which is mainly driven by the master-melanocyte regulator MITF. Paper I validated the MITF-negative (MITFNeg) melanomas to be highly aggressive and associated with inferior patient survival compared with the MITF-high (MITFHigh) cases. We herein discovered an even more undifferentiated melanoma subtype that lacks the MITF upstream marker SOX10 (MITFNegSOX10Neg), characterized by superior metastatic potential and resistance to targeted therapy. Importantly, we found gene methylation explaining the silencing of both MITF and SOX10 in these melanomas. To discriminate the role of SOX10 in MITFNeg cells, in Paper II we engineered SOX10KO by CRISPR-Cas9 technology. Depletion of SOX10 in MITFNeg cells lead to a hyper-undifferentiated phenotype: a new distinct lineage identity state in melanoma. Paper III uncovered a novel layer of regulation of MITF at the translational level. We showed that MITF is regulated by the RNA-helicase DDX3X. DDX3X loss in melanoma leads to decreased MITF, and results in enhanced metastasis and therapy resistance. Interestingly, DDX3X is located on the X-chromosome. Thus, mutations affecting DDX3X associate with poor prognosis in male melanoma patients, implying an exclusive window of opportunity in this gender. Paper IV investigated the molecular features of a unique cohort of high and low CSD (CSDhigh, CSDlow) melanomas. Focusing on the less investigated CSDhigh subtype in view of cancer progression, we found no mutational difference between in situ or invasive phases. We further observed dissimilarity in the heterogeneity levels between CSDhigh and CSDlow melanomas, which suggests distinguishable molecular entities that progress via different routes.<br/>Overall, we unraveled the role of melanocyte-specific genes in defining diverse melanoma lineage states, while investigating novel biological mechanisms behind their regulation. Our findings further highlighted the variable heterogeneity in CSD melanoma subtypes, which should be taken into consideration for an improved diagnosis, and when choosing the best treatment options for melanoma patients.}},
author = {{Sanna, Adriana}},
isbn = {{978-91-7619-923-7}},
issn = {{1652-8220}},
keywords = {{Melanoma; Genetic; Epigenetic; Heterogeneity; MITF; SOX10; CSD}},
language = {{eng}},
number = {{2020:62}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{The Role of Melanocyte Lineage Genes in Melanoma}},
url = {{https://lup.lub.lu.se/search/files/78917487/AS_kappa_200520.pdf}},
year = {{2020}},
}