Anatomic position determines oncogenic specificity in melanoma

Joshua M. Weiss, Miranda V. Hunter, Nelly M. Cruz, Arianna Baggiolini, Mohita Tagore, Yilun Ma, Sandra Misale, Michelangelo Marasco, Theresa Simon-Vermot, Nathaniel R. Campbell, Felicity Newell, James S. Wilmott, Peter A. Johansson, John F. Thompson, Georgina V. Long, John V. Pearson, Graham J. Mann, Richard A. Scolyer, Nicola Waddell, Emily D. Montal, Ting-Hsiang Huang, Philip Jonsson, Mark T. A. Donoghue, Christopher C. Harris, Barry S. Taylor, Tianhao Xu, Ronan Chaligné, Pavel V. Shliaha, Ronald Hendrickson, Achim A. Jungbluth, Cecilia Lezcano, Richard Koche, Lorenz Studer, Charlotte E. Ariyan, David B. Solit, Jedd D. Wolchok, Taha Merghoub, Neal Rosen, Nicholas K. Hayward and Richard M. White ()
Additional contact information
Joshua M. Weiss: Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program
Miranda V. Hunter: Memorial Sloan Kettering Cancer Center
Nelly M. Cruz: Memorial Sloan Kettering Cancer Center
Arianna Baggiolini: Memorial Sloan Kettering Cancer Center
Mohita Tagore: Memorial Sloan Kettering Cancer Center
Yilun Ma: Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program
Sandra Misale: Memorial Sloan Kettering Cancer Center
Michelangelo Marasco: Memorial Sloan Kettering Cancer Center
Theresa Simon-Vermot: Memorial Sloan Kettering Cancer Center
Nathaniel R. Campbell: Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program
Felicity Newell: QIMR Berghofer Medical Research Institute
James S. Wilmott: The University of Sydney
Peter A. Johansson: QIMR Berghofer Medical Research Institute
John F. Thompson: The University of Sydney
Georgina V. Long: The University of Sydney
John V. Pearson: QIMR Berghofer Medical Research Institute
Graham J. Mann: The University of Sydney
Richard A. Scolyer: The University of Sydney
Nicola Waddell: QIMR Berghofer Medical Research Institute
Emily D. Montal: Memorial Sloan Kettering Cancer Center
Ting-Hsiang Huang: Memorial Sloan Kettering Cancer Center
Philip Jonsson: Memorial Sloan Kettering Cancer Center
Mark T. A. Donoghue: Memorial Sloan Kettering Cancer Center
Christopher C. Harris: Memorial Sloan Kettering Cancer Center
Barry S. Taylor: Memorial Sloan Kettering Cancer Center
Tianhao Xu: Memorial Sloan Kettering Cancer Center
Ronan Chaligné: Memorial Sloan Kettering Cancer Center
Pavel V. Shliaha: University of Southern Denmark
Ronald Hendrickson: Memorial Sloan Kettering Cancer Center
Achim A. Jungbluth: Memorial Sloan Kettering Cancer Center
Cecilia Lezcano: Memorial Sloan Kettering Cancer Center
Richard Koche: Memorial Sloan Kettering Cancer Center
Lorenz Studer: Memorial Sloan Kettering Cancer Center
Charlotte E. Ariyan: Memorial Sloan Kettering Cancer Center
David B. Solit: Memorial Sloan Kettering Cancer Center
Jedd D. Wolchok: Memorial Sloan Kettering Cancer Center
Taha Merghoub: Weill Cornell Medicine
Neal Rosen: Memorial Sloan Kettering Cancer Center
Nicholas K. Hayward: QIMR Berghofer Medical Research Institute
Richard M. White: Memorial Sloan Kettering Cancer Center

Nature, 2022, vol. 604, issue 7905, 354-361

Abstract: Abstract Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13 genes. This positional gene programme synergized with CRKL to amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

Date: 2022
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DOI: 10.1038/s41586-022-04584-6

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