Using Deep Learning to Decipher the Impact of Telomerase Promoter Mutations on the Morpholome

Melanoma showcases a complex interplay of genetic alterations and cellular morphologicalchanges during metastatic transformation. While pivotal, the role of specific mutations in dictatingthese changes still needs to be fully elucidated. Telomerase promoter mutations (TPMs)significantly influence melanoma’s progression, invasiveness, and resistance to various emergingtreatments, including chemical inhibitors, telomerase inhibitors, targeted therapy, andimmunotherapies. We aim to understand the morphological and phenotypic implications of thetwo dominant monoallelic TPMs, C228T and C250T, enriched in melanoma metastasis. Wedeveloped isogenic clonal cell lines containing the TPMs and utilized dual-color expressionreporters steered by the endogenous Telomerase promoter, giving us allelic resolution. Thisapproach allowed us to monitor morpholomic variations induced by these mutations. TPM-bearingcells exhibited significant morpholome differences from their wild-type counterparts, withincreased allele expression patterns, augmented wound-healing rates, and unique spatiotemporaldynamics. Notably, the C250T mutation exerted more pronounced changes in the morpholomethan C228T, suggesting a differential role in metastatic potential. Our findings underscore thedistinct influence of TPMs on melanoma's cellular architecture and behavior. The C250T mutationmay offer a unique morpholomic and systems-driven advantage for metastasis. These insightsprovide a foundational understanding of how a non-coding mutation in melanoma metastasisaffects the system, manifesting in cellular morpholome.