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Updated: Jun 21, 2025
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance
Ryan H Boe1, Catherine G Triandafillou2, Rossana Lazcano3,4
1Genetics and Epigenetics Program, Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Abstract:
Resistance to cancer therapy is driven by both cell-intrinsic and microenvironmental factors. Previous work has revealed that multiple resistant cell fates emerge in melanoma following treatment with targeted therapy and that, in vitro, these resistant fates are determined by the transcriptional state of individual cells prior to exposure to treatment. What remains unclear is whether these resistant fates are shared across different genetic backgrounds and how, if at all, these resistant fates interact with the tumor microenvironment. Through spatial transcriptomics and single-cell RNA sequencing, we uncovered distinct resistance programs in melanoma cells shaped by both intrinsic cellular states and the tumor microenvironment. Consensus non-negative matrix factorization revealed shared intrinsic resistance programs across different cell lines, highlighting the presence of universal and unique resistance pathways. In patient samples, we demonstrated that these resistance programs coexist within individual tumors and associate with diverse immune signatures, suggesting that the tumor microenvironment and distribution of resistant fates are closely connected. Single-cell resolution spatial transcriptomics in xenograft models revealed both intrinsically determined and extrinsically influenced resistant fates. Overall, this work demonstrates that each therapy resistant fate coexists with a distinct immune microenvironment in tumors and that, in vivo, tissue features, such as regions of necrosis, can influence which resistant fate is adopted.
Insights
Cancer therapy resistance involves cell-intrinsic and microenvironmental factors. This study reveals shared resistance programs across melanoma cell lines and patient tumors, linked to distinct immune microenvironments and influenced by tissue features.
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Cancer therapy resistance is a complex challenge driven by intrinsic cellular states and the tumor microenvironment.
- Previous research identified multiple resistant cell fates in melanoma post-targeted therapy, determined by pre-treatment transcriptional states.
- The interplay between genetic backgrounds, resistant cell fates, and the tumor microenvironment remains incompletely understood.
Purpose of the Study:
- To investigate whether melanoma resistant cell fates are shared across different genetic backgrounds.
- To explore the interaction between melanoma resistant cell fates and the tumor microenvironment.
- To elucidate the mechanisms underlying therapy resistance in melanoma.
Main Methods:
- Spatial transcriptomics and single-cell RNA sequencing were employed to analyze melanoma cells.
- Consensus non-negative matrix factorization was used to identify shared resistance programs.
- Analysis of patient samples and xenograft models provided in vivo insights.
Main Results:
- Distinct melanoma resistance programs were uncovered, shaped by both intrinsic cellular states and the tumor microenvironment.
- Shared intrinsic resistance programs were identified across different cell lines, indicating universal and unique resistance pathways.
- In patient samples, resistance programs coexisted within tumors and associated with diverse immune signatures, highlighting a close connection between the microenvironment and resistant cell fate distribution.
Conclusions:
- Melanoma therapy resistance is influenced by both intrinsic cellular programs and the tumor microenvironment.
- Resistant cell fates are conserved across different genetic backgrounds and interact dynamically with immune signatures.
- In vivo, tissue features such as necrosis can dictate the adoption of specific resistant fates, underscoring the importance of the tumor ecosystem in therapeutic outcomes.
