phaidra.vetmeduni.ac.at o:1350 DOI 10.1038/s41467-022-34899-x Decoding molecular programs in melanoma brain metastases Melanoma brain metastases (MBM) variably respond to therapeutic interventions; thus determining patient's prognosis. However, the mechanisms that govern therapy response are poorly understood. Here, we use a multi-OMICS approach and targeted sequencing (TargetSeq) to unravel the programs that potentially control the development of progressive intracranial disease. Molecularly, the expression of E-cadherin (Ecad) or NGFR, the BRAF mutation state and level of immune cell infiltration subdivides tumors into proliferative/pigmented and invasive/stem-like/therapy-resistant irrespective of the intracranial location. The analysis of MAPK inhibitor-naive and refractory MBM reveals switching from Ecad-associated into NGFR-associated programs during progression. NGFR-associated programs control cell migration and proliferation via downstream transcription factors such as SOX4. Moreover, global methylome profiling uncovers 46 differentially methylated regions that discriminate BRAFmut and wildtype MBM. In summary, we propose that the expression of Ecad and NGFR sub- classifies MBM and suggest that the Ecad-to-NGFR phenotype switch is a rate-limiting process which potentially indicates drug-response and intracranial progression states in melanoma patients. eng 2023-07-21T09:21:57.726Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Radke;Josefine; FN:Josefine Radke X-ORCID:https://orcid.org/0000-0001-9860-2007 END:VCARD BEGIN:VCARD VERSION:3.0 N:Schumann;Elisa; FN:Elisa Schumann END:VCARD BEGIN:VCARD VERSION:3.0 N:Onken;Julia; FN:Julia Onken END:VCARD BEGIN:VCARD VERSION:3.0 N:Koll;Randi; FN:Randi Koll END:VCARD BEGIN:VCARD VERSION:3.0 N:Acker;Güliz; FN:Güliz Acker END:VCARD BEGIN:VCARD VERSION:3.0 N:Bodnar;Bohdan; FN:Bohdan Bodnar END:VCARD BEGIN:VCARD VERSION:3.0 N:Senger;Carolin; FN:Carolin Senger END:VCARD BEGIN:VCARD VERSION:3.0 N:Tierling;Sascha; FN:Sascha Tierling END:VCARD BEGIN:VCARD VERSION:3.0 N:Möbs;Markus; FN:Markus Möbs X-ORCID:https://orcid.org/0000-0002-1502-3032 END:VCARD BEGIN:VCARD VERSION:3.0 N:Vajkoczy;Peter; FN:Peter Vajkoczy END:VCARD BEGIN:VCARD VERSION:3.0 N:Vidal;Anna; FN:Anna Vidal X-ORCID:https://orcid.org/0000-0001-6172-0130 END:VCARD BEGIN:VCARD VERSION:3.0 N:Högler;Sandra; FN:Sandra Högler X-ORCID:https://orcid.org/0000-0002-6899-5273 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kodajova;Petra; FN:Petra Kodajova END:VCARD BEGIN:VCARD VERSION:3.0 N:Westphal;Dana; FN:Dana Westphal END:VCARD BEGIN:VCARD VERSION:3.0 N:Meier;Friedegund; FN:Friedegund Meier END:VCARD BEGIN:VCARD VERSION:3.0 N:Heppner;Frank; FN:Frank Heppner X-ORCID:https://orcid.org/0000-0001-9816-8917 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kreuzer-Redmer;Susanne; FN:Susanne Kreuzer-Redmer X-ORCID:https://orcid.org/0000-0001-9425-3356 END:VCARD BEGIN:VCARD VERSION:3.0 N:Grebien;Florian; FN:Florian Grebien X-ORCID:https://orcid.org/0000-0003-4289-2281 END:VCARD BEGIN:VCARD VERSION:3.0 N:Jürchott;Karsten; FN:Karsten Jürchott END:VCARD BEGIN:VCARD VERSION:3.0 N:Redmer;Torben; FN:Torben Redmer X-ORCID:https://orcid.org/0000-0002-0050-9478 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 4534137 https://phaidra.vetmeduni.ac.at/o:1350 https://phaidra.vetmeduni.ac.at/api/object/o:1350/thumbnail LOMv1.0 discipline