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Updated: Aug 26, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Lineage-coupled clonal capture identifies clonal evolution mechanisms and vulnerabilities of BRAFV600E inhibition

Ze-Yan Zhang1,2, Yingwen Ding3,4, Ravesanker Ezhilarasan3,4

  • 1Department of Radiation Oncology, New York University (NYU) Grossman School of Medicine, New York, NY, USA. zeyan.zhang@nyulangone.org.

Cell Discovery
|October 6, 2022
PubMed

Insights

We developed CAPTURE, a single-cell barcoding method, to track cancer cell evolution and resistance. This approach identified new resistance mechanisms and therapeutic targets for BRAF V600E melanoma.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Targeted cancer therapies show promise but face limitations due to treatment resistance.
  • Tumor clonal evolution is a key driver of acquired resistance to cancer therapies.
  • Understanding resistance mechanisms is crucial for developing effective, long-term cancer treatments.

Purpose of the Study:

  • To develop a novel single-cell barcoding approach (CAPTURE) for tracing clonal dynamics and capturing resistant cancer cells.
  • To investigate the mechanisms of vemurafenib resistance in BRAF V600E melanoma.
  • To identify novel therapeutic vulnerabilities in resistant melanoma clones.

Main Methods:

  • Single-cell barcoding (CAPTURE) for lineage tracing.
  • Multi-omics analysis of captured resistant cells.
  • Functional studies to validate resistance mechanisms and therapeutic targets.

Main Results:

  • Demonstrated that heterogeneous clones, both pre-existing and emerging, drive vemurafenib resistance in BRAF V600E melanoma.
  • Uncovered a novel resistance mechanism involving chromosome 18q21 gain, conferring sensitivity to BCL2 inhibitors.
  • Identified targetable dependencies in resistant clones, including oxidative phosphorylation and E2F pathways.

Conclusions:

  • The CAPTURE platform enables comprehensive analysis of clonal evolution and resistance mechanisms in cancer.
  • Identified a new therapeutic strategy targeting BCL2 for melanoma patients with chromosome 18q21 gain.
  • Discovered actionable vulnerabilities in resistant melanoma, offering new avenues for combination therapies and improved patient outcomes.

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