Biology subjects

Brown, G. S.

Publications and source records attributed to Brown, G. S..

4 recordsLinked to original sources

bioRxiv2026

Single-cell lineage tracing maps clonal and transcriptional dynamics in melanoma metastasis

Melanoma metastasis is driven by extensive intratumoral heterogeneity and phenotypic plasticity, yet how clonal identity relates to transcriptional programs during metastasis remains unclear. Here, we applied MeRLin, a single-cell lineage tracing platform, to dissect the clonal and transcriptional heterogeneity of metastatic melanoma in a patient-derived spontaneous metastasis model. Clonal analyses revealed hierarchical structures during tumor progression, with a subset of lineages from primary tumors consistently enriched across metastatic sites, supporting a model of polyclonal seeding followed by selective expansion of pre-existing highly metastatic subpopulations. Single-cell transcriptomic profiling identified two major metastatic subpopulations of distinct transcriptional programs, characterized by neural crest stem cell-like and lipid metabolism signatures. Both programs were enriched for invasion-associated genes and maintained across organs through distinct regulatory networks. Spatial mapping by barcode RNA-FISH linked these transcriptional states to their tissue context and showed that OLFML3 expression partially co-localized with a dominant subpopulation at the tumor-liver interface, marking the invasive fronts of metastatic growth. Together, these findings establish a framework in which clonal identity, transcriptional state, and spatial organization jointly shape metastatic melanoma progression.

cancer biology↗

bioRxiv2025

Clonal dynamics shaped by diverse drug-tolerant persister states in melanoma resistance

Most advanced melanomas initially respond to targeted therapy but eventually relapse. Rather than acquiring new mutations, resistance is driven by drug-tolerant persister cells that enter a reversible drug-refractory state. We developed MeRLin, a high-resolution lineage tracing platform integrating cellular barcoding, single-cell transcriptomics, RNA fluorescence in situ hybridization (FISH), and computational analyses to track clonal and transcriptional dynamics in patient-derived melanoma models during prolonged therapy. Clonal dynamics revealed that persister subpopulations first responded to treatment but persisted and expanded during minimal residual disease, ultimately leading to tumor recurrence. Pre-treatment melanoma populations diversified into four conserved persister states characterized by stress-like, lipid metabolism, PI3K signaling, and extracellular matrix remodeling programs associated with adaptive resistance. Spatial transcriptomics showed the organization of these adaptive programs and a complex signaling network of autocrine and paracrine interactions among persister subpopulations. Barcoded RNA-FISH enabled spatial mapping of clonal identity and gene expression, revealing in situ co-localization of a dominant resistant clone with SLC2A1 expression. MeRLin provides a robust framework for dissecting cancer heterogeneity and identifying vulnerabilities in persister populations.

cancer biology↗

bioRxiv2023

Dasatinib Resensitizes MAPK Inhibitor Efficacy in Standard-of-Care Relapsed Melanomas

Resistance to combination BRAF/MEK inhibitor (BRAFi/MEKi) therapy arises in nearly every patient with BRAFV600E/K melanoma, despite promising initial responses. Achieving cures in this expanding BRAFi/MEKi-resistant cohort represents one of the greatest challenges to the field; few experience additional durable benefit from immunotherapy and no alternative therapies exist. To better personalize therapy in cancer patients to address therapy relapse, umbrella trials have been initiated whereby genomic sequencing of a panel of potentially actionable targets guide therapy selection for patients; however, the superior efficacy of such approaches remains to be seen. We here test the robustness of the umbrella trial rationale by analyzing relationships between genomic status of a gene and the downstream consequences at the protein level of related pathway, which find poor relationships between mutations, copy number amplification, and protein level. To profile candidate therapeutic strategies that may offer clinical benefit in the context of acquired BRAFi/MEKi resistance, we established a repository of patient-derived xenograft models from heavily pretreated patients with resistance to BRAFi/MEKi and/or immunotherapy (R-PDX). With these R-PDXs, we executed in vivo compound repurposing screens using 11 FDA-approved agents from an NCI-portfolio with pan-RTK, non-RTK and/or PI3K-mTOR specificity. We identify dasatinib as capable of restoring BRAFi/MEKi antitumor efficacy in [~]70% of R-PDX tested. A systems-biology analysis indicates elevated baseline protein expression of canonical drivers of therapy resistance (e.g., AXL, YAP, HSP70, phospho-AKT) as predictive of MAPKi/dasatinib sensitivity. We therefore propose that dasatinib-based MAPKi therapy may restore antitumor efficacy in patients that have relapsed to standard-of-care therapy by broadly targeting proteins critical in melanoma therapy escape. Further, we submit that this experimental PDX paradigm could potentially improve preclinical evaluation of therapeutic modalities and augment our ability to identify biomarker-defined patient subsets that may respond to a given clinical trial. SINGLE SENTENCE SUMMARYBroad target inhibition effective as a salvage strategy in BRAF/MEK inhibitor-acquired resistance PDX

cancer biology↗

bioRxiv2019

No evidence for disruption of global patterns of nest predation in shorebirds

Kubelka et al. (Science, 9 November 2018, p. 680-683) claim that climate change has disrupted patterns of nest predation in shorebirds. They report that predation rates have increased since the 1950s, especially in the Arctic. We describe methodological problems with their analyses and argue that there is no solid statistical support for their claims.

ecology↗