The Role of Melanocyte Lineage Genes in Melanoma Sanna, Adriana 2020 Document Version: Publisher's PDF, also known as Version of record Link to publication Citation for published version (APA): Sanna, A. (2020). The Role of Melanocyte Lineage Genes in Melanoma. Lund University, Faculty of Medicine. 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LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 ADRIANA SANNA ADRIANA About this Thesis Melanocyteof The Role Lineage Genes Melanomain Malignant melanoma is the deadliest form of skin cancer, and the number of cases is escalating worldwide. In spite of the breakthrough in therapeutics The Role of Melanocyte made available to melanoma patients in the last decades, treatment resistance followed by tumor relapse remains the leading cause of patient death. This thesis had focused on aggressive melanoma cells that do not Lineage Genes in Melanoma respond to targeted therapies due to inactivation of the melanocyte-specific transcriptional program. The current studies aimed to unravel the role of ADRIANA SANNA the melanocyte-lineage genes, MITF and SOX10, which loss can drive novel DEPARTMENT OF CLINICAL SCIENCE, LUND | LUND UNIVERSITY undifferentiated melanoma phenotypic states. Further development of drugs that can effectively target resistant melanoma cells, or steer their state towards a drug-sensitive one, represents a powerful strategy to ultimately eradicate the tumor. Additionally, heterogeneity analyses on chronic sun-damaged (CSD) melanomas revealed that high grade CSD do not undergo further genetic changes during the progression to the advanced stages of the disease, in contrast to the low CSD melanomas. This emphasizes the importance of prevention of UV overexposure. Moreover, the biological differences among CSD subtypes can be exploited for different therapeutic approaches according to the melanoma patient groups. About the Author Adriana Sanna is a proud Sardinian who started travelling in her teens driven by an innate passion for biological studies. After attaining her Biomedical Science degree in two world leading institutions from The Netherlands and the U.S., she was granted a prestigious European fellowship to continue her research as PhD in Cancer and Molecular Biology focused on melanoma, in Sweden. During Adriana’s academic career, her beloved housekitty, MaryJane, has been loyally travelling along for the past 10 years. Division of Oncology Department of Clinical Science, Lund 199237 Lund University, Faculty of Medicine 2020:62 Doctoral Dissertation Series 2020:62 ISBN 978-91-7619-923-7 789176 ISSN 1652-8220 9 The Role of Melanocyte Lineage Genes in Melanoma Adriana Sanna DOCTORAL DISSERTATION By due permission of the Faculty of Medicine, Lund University, Sweden. To be defended on Wednesday 20th May 2020, at time 9.30 am at Medicon Village, Lund, Sweden. Faculty opponent Professor María S. 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D2 2;46;22?21 %"* /F $%#$.@ A205;<9<4F2=92A6<;<3%"* 6; &[email protected]<.5F=2?B;16332?2;A6.A21=52;<AF=2.;2D16@A6;0A96;2.42 612;[email protected];:29.;<:. #.=2?B;0<C2?21.;<C299.F2?<3?24B9.A6<;<3 &.AA52A?.;@9.A6<;.992C29)2@5<D21A5.A &6@?24B9.A21 /F A52 $!52960.@2 * * * * 9<@@ 6; :29.;<:. 92.1@ A< 120?2.@21 & .;1 ?2@B9A@ 6; 2;5.;021 :2A.@A.@6@.;1A52?.=F?2@6@A.;02;A2?2@A6;49F 6@9<0.A21<;A52*05?<:<@<:2&5B@:BA.A6<;@.3320A6;4 .@@<06.A2D6A5=<<?=?<4;<@6@6;:.92:29.;<:.=.A62;A@6:=9F6;4.;2E09B@6C2D6;1<D<3<==<?AB;6AF6; A56@42;12? #.=2?(6;[email protected]:<920B9.?32.AB?2@<3.B;6>B20<5<?A<35645.;19<D%% % :29.;<:.@ <0B@6;4<;A5292@@6;[email protected]% @B/AF=26;C62D<30.;02?=?<4?2@@6<;D23<B;1;<:BA.A6<;.916332?2;02 /2AD22;<?6;C.@6C2=5.@2@)23B?A52?</@2?C2116@@6:69.?6AF6;A5252A2?<42;26AF92C29@/2AD22;% .;1% :29.;<:.@D5605@B442@A@16@A6;4B6@5./92:<920B9.?2;[email protected]=?<4?2@@16332?2;A?<BA2@ "C2?.99D2B;?.C2921A52?<92<3:29.;<0FA2@=20636042;2@6;1236;6;416C2?@2:29.;<:.96;[email protected]@D5692 6;[email protected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he Role of Melanocyte Lineage Genes in Melanoma Adriana Sanna 3 Coverphoto by © Silvia Sanna Copyright pp 1-90 Adriana Sanna Paper 1 © by the Authors, Manuscript Paper 2 © by the Authors, Manuscript Paper 3 © by Copyright Clearance Center, Cell Reports Paper 4 © by Copyright Clearance Center, Pigment Cell & Melanoma Research Faculty of Medicine Department of Clinical Science Lund University, Faculty of Medicine Doctoral Dissertation Series 2020:62 ISBN 978-91-7619-923-7 ISSN 1652-8220 Printed in Sweden by Media-Tryck, Lund University Lund 2020 4 “ Questo è per la Gente che non posso più Scordare. Questo è per Coloro che hanno un posto nel mio Cuore. Questo è per la Gente che è Partita… Questo è per i miei Fratelli, ai miei Fratelli per la Vita. ” 5 6 Acknowledgements Choose the job you Love, and you will Work Hard anyway! But, surrounding yourself with Who does the same, it makes The complete difference for Your Life… and for Your Future… Therefore, first of all, I wish to express my deepest gratitude to my Main Supervisor Göran Jönsson, the most brilliant and enthusiastic youngest mentor I ever had the honor and pleasure to work with. I would like to recognize your reliable leadership, invaluable advice, and especially the huge patience that you had gifted my undergraduate studies with. You should be very proud and let people celebrate your great accomplishments more often! Second, I am indebted to my Co-Supervisors Bengt Phung, Katja Harbst and Christian Ingvar for the precious guidance and for sharing with me your priceless knowledge, together with tips & tricks to help me to persevere through PhD students’ dilemmas. In particular, Bengt Phung had to cope with me the most in the Lab, and I am grateful for your constructive criticisms, professional commitment and tireless creativity that prompted my scientific thinking outside the box.