Summary
Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programs 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 has a unique tropism for the limbs, specifically the hands and feet3. 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 but CRKL amplifications in acral melanoma. We modeled these changes in transgenic zebrafish models and found that CRKL-driven tumors predominantly formed 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/limb melanocytes, compared to body melanocytes, revealed a positional identity gene program typified by posterior HOX13 genes. This positional gene program synergized with CRKL to drive tumors at acral sites. Abrogation of this CRKL-driven program 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.
Competing Interest Statement
S.M. consulted for Boehringer-Ingelheim. J.F.T. has received honoraria for advisory board participation from BMS Australia, MSD Australia, GSK and Provectus Inc, and travel support from GSK and Provectus Inc. R.A.S. has received fees for professional services from Qbiotics, Novartis, MSD Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. J.V.P. and N.W. are equity holders and Board members of genomiQa PTY LTD. P.J. is currently employed by Celsius Therapeutics. B.S.T. reports receiving Honoria and research funding from Genentech and Illumina and advisory board activities for Boehringer Ingelheim and Loxo Oncology, a wholly owned subsidiary of Eli Lilly. B.S.T. is currently employed by Loxo Oncology. D.B.S. has consulted with/received honoraria from Pfizer, Loxo Oncology, Lilly Oncology, Vivideon Therapeutics, Q.E.D. Therapeutics, and Illumina. J.D.W. is a consultant for Amgen; Apricity; Arsenal; Ascentage Pharma; Astellas; Boehringer Ingelheim; Bristol Myers Squibb; Eli Lilly; F Star; Georgiamune; Imvaq; Kyowa Hakko Kirin; Merck; Neon Therapeutics; Polynoma; Psioxus, Recepta; Trieza; Truvax; Sellas. J.D.W. has grant and research support from Bristol Meyers Squibb and Sephora. J.D.W. has equity in Tizona Pharmaceuticals; Imvaq; Beigene; Linneaus, Apricity, Arsenal IO; Georgiamune. T.M. is a consultant for Leap Therapeutics, Immunos Therapeutics and Pfizer, and co-founder of Imvaq therapeutics. T.M. has equity in Imvaq therapeutics. T.M. reports grants from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmeceuticals, Adaptive Biotechnologies, Leap Therapeutics and Aprea. T.M. is inventor on patent applications related to work on oncolytic viral therapy, alphavirus-based vaccines, neo-antigen modeling, CD40, GITR, OX40, PD-1 and CTLA-4. N.R. is on the SAB and receives research funding from Chugai, on the SAB and owns equity in Beigene, and Fortress. N.R. is also on the SAB of Daiichi-Sankyo, Astra-Zeneca-MedImmune, and F-Prime, and is a past SAB member of Millenium-Takeda, Kadmon, Kura, and Araxes. N.R. is a consultant to Novartis, Boehringer Ingelheim, Tarveda, and Foresight and consulted in the last three years with Eli Lilly, Merrimack, Kura Oncology, Araxes, and Kadman. N.R. owns equity in ZaiLab, Kura Oncology, Araxes, and Kadman. N.R. also collaborates with Plexxikon. R.M.W. is a paid consultant to N-of-One Therapeutics, a subsidiary of Qiagen. R.M.W. is on the Scientific Advisory Board of Consano but receives no income for this. R.M.W. receives royalty payments for the use of the casper line from Carolina Biologicals.
Footnotes
↵24 Lead Contact
