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

Melanoma showcases a complex interplay of genetic alterations and cellular morphological
changes during metastatic transformation. While pivotal, the role of specific mutations in dictating
these changes still needs to be fully elucidated. Telomerase promoter mutations (TPMs)
significantly influence melanoma’s 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 TPMs, C228T and C250T, enriched in melanoma metastasis. We
developed isogenic clonal cell lines containing the TPMs 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. TPM-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 TPMs on melanoma's 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.