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While pivotal, the role of specific mutations in dictating these changes still needs to be fully elucidated. Telomerase promoter mutations (TERTp mutations) significantly influence melanoma\u2019s progression, invasiveness, and resistance to various emerging treatments, including chemical inhibitors, telomerase inhibitors, targeted therapy, and immunotherapies. We aim to understand the morphological and phenotypic implications of the two dominant monoallelic TERTp mutations, C228T and C250T, enriched in melanoma metastasis. We developed isogenic clonal cell lines containing the TERTp mutations and utilized dual-color expression reporters steered by the endogenous Telomerase promoter, giving us allelic resolution. This approach allowed us to monitor morpholomic variations induced by these mutations. TERTp mutation-bearing cells exhibited significant morpholome differences from their wild-type counterparts, with increased allele expression patterns, augmented wound-healing rates, and unique spatiotemporal dynamics. Notably, the C250T mutation exerted more pronounced changes in the morpholome than C228T, suggesting a differential role in metastatic potential. Our findings underscore the distinct influence of TERTp mutations on melanoma\u2019s cellular architecture and behavior. The C250T mutation may offer a unique morpholomic and systems-driven advantage for metastasis. These insights provide a foundational understanding of how a non-coding mutation in melanoma metastasis affects the system, manifesting in cellular morpholome.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012271","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T17:22:22Z","timestamp":1722360142000},"page":"e1012271","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Using deep learning to decipher the impact of telomerase promoter mutations on the dynamic metastatic morpholome"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8337-6454","authenticated-orcid":true,"given":"Andres J.","family":"Nevarez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anusorn","family":"Mudla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina A.","family":"Diaz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Hao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,7,30]]},"reference":[{"key":"pcbi.1012271.ref001","first-page":"6300329","article-title":"TERT Promoter Mutations and Telomerase in Melanoma","volume":"2022","author":"Y Guo","year":"2022","journal-title":"J Oncol"},{"issue":"16","key":"pcbi.1012271.ref002","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.18632\/oncotarget.26688","article-title":"TERT promoter mutations in melanoma survival","volume":"10","author":"E Nagore","year":"2019","journal-title":"Oncotarget"},{"issue":"1","key":"pcbi.1012271.ref003","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/bjc.2017.384","article-title":"Prognostic impact and concordance of TERT promoter mutation and protein expression in matched primary and metastatic cutaneous melanoma","volume":"118","author":"E Hugdahl","year":"2018","journal-title":"Br J Cancer"},{"issue":"2","key":"pcbi.1012271.ref004","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.jid.2019.06.149","article-title":"Classifying Melanoma by TERT Promoter Mutational Status","volume":"140","author":"M Shaughnessy","year":"2020","journal-title":"Journal of Investigative Dermatology"},{"issue":"9","key":"pcbi.1012271.ref005","doi-asserted-by":"crossref","DOI":"10.1093\/jnci\/dju246","article-title":"TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma","volume":"106","author":"KG Griewank","year":"2014","journal-title":"J Natl Cancer Inst"},{"issue":"2","key":"pcbi.1012271.ref006","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.cell.2012.06.024","article-title":"A landscape of driver mutations in melanoma","volume":"150","author":"E Hodis","year":"2012","journal-title":"Cell"},{"issue":"2","key":"pcbi.1012271.ref007","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41419-017-0059-7","article-title":"Cell death-based treatments of melanoma:conventional treatments and new therapeutic strategies","volume":"9","author":"G Mattia","year":"2018","journal-title":"Cell Death & Disease"},{"key":"pcbi.1012271.ref008","unstructured":"Sundararajan S, Thida AM, Yadlapati S, Koya S. 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