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PhD Public Seminar: ARCHIT GHOSH

When & Where

February 6, 2025
2:00 PM - 3:00 PM
UTHH MD Anderson Cancer Center, 4SCR1.110 ( View in Google Map)

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Event Description

Disentangling Hierarchical Chromatin Loops in Melanoma Metastasis

Archit Kumar Ghosh, BS (Advisory Professor: Kunal Rai, PhD)

Functional states of the genome are dictated by chromosomal interactions through 3D genome folding. While its role in tumorigenesis is becoming clearer, its contribution to metastasis has yet to be explored. In this thesis, I investigate how chromatin architecture influences melanoma progression, given its aggressive metastatic behavior. The transition to metastasis requires cellular plasticity, including changes in cell state such as epithelial-to-mesenchymal transition, suggesting a role for epigenomic remodeling. However, whether chromosome looping directly influences metastatic cell fate decisions is unclear. Mammalian genomes are organized into Topologically Associating Domains (TADs), insulated regions maintained by CTCF and cohesin that regulate enhancer-promoter (E-P) interactions. Disruption of these domains and loops alters gene expression and contributes to cancer progression. Here, I identify significant alterations in chromatin looping between primary and metastatic melanoma, implicating 3D genome remodeling in metastatic potential.

One of the central discoveries of this thesis is the role of super-enhancer looping in mediating inflammatory signaling and immune evasion in disseminated tumor cells. The mechanisms underlying organotropic colonization during metastasis remain poorly understood. I hypothesized that three-dimensional chromatin organization mediates this process through epigenomic reprogramming. Using a newly developed murine melanoma metastasis model, I demonstrate that subtle chromatin reorganization contributes to immune evasion of disseminated tumor cells, facilitating survival and growth within the lung metastatic niche. Specifically, this study provides evidence for two de novo long-range super-enhancer loops that regulate a subset of interferon-gamma response genes and metastatic interface regulators, promoting immune evasion and pulmonary colonization. Epigenetic editing of these metastasis-specific loops silences target genes, enhances susceptibility to CD8+ T-cell cytotoxicity and improves host survival. These adaptations involve chromatin hyperacetylation, AP-1 transcription factor enrichment, and altered intrachromosomal interactions within contact domains. Collectively, this study reveals that tumor cell-intrinsic chromatin looping contributes to melanoma lung colonization partly through immune evasion implicating three-dimensional genome reorganization as a regulatory mechanism for fitness of disseminated tumor cells, partly through immune evasion.

To further define higher order chromatin organization in the context of melanoma progression, I performed an unbiased comparative analysis of loop domains across a cohort of patient-matched primary and metastatic melanomas. This resulted in identification of conserved metastatic TAD disruptions (splits) that epigenetically dysregulated the expression of clustered protocadherins (cPCDH) via CTCF rewiring. Epigenetic silencing of these CTCF sites resulted in alterations in adhesion-migration dynamics of melanoma cells.

This thesis is the first to describe the contribution of chromosomal looping in the context of melanoma metastasis. By integrating chromatin conformation capture techniques with functional epigenetic perturbation studies, I show that spatial genome reorganization supports metastatic fitness through features such as immune evasion and transcriptional control. These findings provide a framework for understanding how chromatin architecture influences metastasis and illuminate alternative therapeutic modalities for metastatic melanoma.

Advisory Committee:

  • Kunal Rai, PhD, Chair
  • Mark Bedford, PhD
  • Jeffrey Chang, PhD
  • Kyle Eagen, PhD
  • Nicholas Navin, PhD

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