Cited by 4,944Single-cell and spatial transcriptomicsCancer Immunotherapy and BiomarkersCutaneous Melanoma Detection and Management

Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

Open access
Tirosh, Itay, Izar, Benjamin, Prakadan, Sanjay M., Wadsworth, Marc H., Treacy, Daniel, Trombetta, John J., Rotem, Asaf, Rodman, Christopher +29 more·2016·Science

Abstract

Single-cell expression profiles of melanoma: Tumors harbor multiple cell types that are thought to play a role in the development of resistance to drug treatments. Tirosh et al. used single-cell sequencing to investigate the distribution of these differing genetic profiles within melanomas. Many cells harbored heterogeneous genetic programs that reflected two different states of genetic expression, one of which was linked to resistance development. Following drug treatment, the resistance-linked expression state was found at a much higher level. Furthermore, the environment of the melanoma cells affected their gene expression programs. Science , this issue p. 189

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Crossref · 10.1126/science.aad0501

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  • SALL4-regulated genes showed significant enrichment and positive correlation with published invasiveness signatures, while significantly anti-correlated with their corresponding proliferation signatures.

    “SALL4-regulated genes showed a significant enrichment and positive correlation with published invasiveness signatures40–42, while they significantly anti-correlated with their corresponding proliferation signatures40–42”

    From Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4 (2021) · cites this paper as [42]

    In “Heterogeneity in the abundance of a dormant, drug-resistant melanoma subpopulation” (page unavailable), the source defines opposing MITF-high and AXL-high melanoma gene programs, supporting its citation as a source of published signatures. Our copy does not explicitly identify those programs as invasiveness and proliferation signatures. The SALL4 enrichment and correlation results are the citing authors’ own analysis, not findings attributed to this source. (LLM, conf=0.74)

    Experimental — accuracy not yet measured
  • Among SALL4-HDAC2 targets upregulated upon SALL4 knockdown were integrins (ITGB1, ITGA6, ITGA4), N-cadherin (CDH2), TGFBR2, VEGFR-1, PDGFC, LOXL2, MAPK8, and others associated with invasive melanoma phenotypes.

    “among the SALL4-HDAC2 targets upregulated upon SALL4 knockdown, we found integrins (ITGB1, ITGA6, ITGA4), N-cadherin (CDH2), TGFBR2, VEGFR-1, PDGFC, LOXL2, MAPK8, and many others which are associated with invasive melanoma phenotypes40–42”

    From Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4 (2021) · cites this paper as [42]

    The section on dormant, drug-resistant melanoma subpopulations describes MITF-high and AXL-high expression programs, but does not link the listed genes to an invasive melanoma phenotype. Searches for the named genes and invasive-phenotype terminology found no passage establishing that association. The SALL4-knockdown result is presented as the citing authors’ own finding, rather than a finding attributed to this source. (LLM, conf=0.73)

    Experimental — accuracy not yet measured
  • The proportions of HSCs expressing G2/M/S-phase genes were enhanced upon IFNa treatment.

    “Consistent with previous reports in mice 43 , the proportions of HSCs expressing G2/M/S-phase genes were enhanced upon IFNa treatment ( Fig. 2h,i) .”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [43]

    The section on malignant-cell cell cycles (page unavailable) describes G1/S and G2/M signatures in melanoma cells, not HSCs. Searches for IFNa treatment, hematopoietic stem cells, and mouse HSC proliferation found no passage addressing the cited prior report. (LLM, conf=0.76)

    Experimental — accuracy not yet measured
  • IFNa has been shown to induce HSC and progenitors into cell cycle entry.

    “As IFNa has been shown to induce HSC and progenitors into cell cycle entry 43 , we posited that differential induction of progenitor subtypes into proliferation may underlie the shifts in differentiation.”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [43]

    The section on cell-cycle heterogeneity describes cycling malignant melanoma cells, not hematopoietic stem cells or progenitors. Searches for IFN-alpha, HSCs, and hematopoietic progenitor cell-cycle entry found no passage in our copy addressing whether IFN-alpha induces those cells to enter the cell cycle; no page numbers were supplied. (LLM, conf=0.76)

    Experimental — accuracy not yet measured
  • Nearly all prior work comparing single-cell datasets first partitions the data discretely before downstream analysis.

    “Almost all previous work quantifying differences between single-cell datasets relies on discrete partitioning of the data before downstream analysis9–16.”

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Authors
Tirosh, I., Izar, B., Prakadan, S. M., Wadsworth, M. H., Treacy, D., Trombetta, J. J., Rotem, A., Rodman, C., Lian, C., Murphy, G., Fallahi-Sichani, M., Dutton-Regester, K., Lin, J.-R., Cohen, O., Shah, P., Lu, D., Genshaft, A. S., Hughes, T. K., Ziegler, C. G. K., Kazer, S. W., Gaillard, A., Kolb, K. E., Villani, A.-C., Johannessen, C. M., Andreev, A. Y., Van Allen, E. M., Bertagnolli, M., Sorger, P. K., Sullivan, R. J., Flaherty, K. T., Frederick, D. T., Jané-Valbuena, J., Yoon, C. H., Rozenblatt-Rosen, O., Shalek, A. K., Regev, A., & Garraway, L. A.
Affiliations
  • Broad Institute (US)
  • Brigham and Women's Hospital (US)
  • Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Program in Therapeutic Sciences, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Harvard University (US)
  • Massachusetts General Hospital (US)
Corresponding author
  • Tirosh, Itay
  • Izar, Benjamin
  • Yoon, Charles H.
  • Shalek, Alex K.
  • Regev, Aviv
  • Garraway, Levi A.
Venue
Science
Published
2016-04-08
Volume
352
Issue
6282
Pages
189-196
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W2332292689
Cited by
4,944
References
70
Citations by year
2026: 546 · 2025: 629 · 2024: 633 · 2023: 606 · 2022: 582 · 2021: 608 · 2020: 486 · 2019: 336 · 2018: 265 · 2017: 195 · 2016: 41 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 2
FWCI
145.13
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • PMC
Funders
  • National Cancer Institute (NCI) (P01CA163222, R35CA197737)
  • Dr. Miriam and Sheldon Adelson Medical Research Foundation
  • Melanoma Research Alliance
  • Ludwig Center at Harvard Medical School
  • Howard Hughes Medicine Institute
  • Klarman Cell Observatory
  • STARR Cancer Consortium
  • Broad Institute
  • Searle Scholars Program
  • Beckman Young Investigator Program
  • Dana-Farber Cancer Institute
  • Human Frontier Science Program
  • Integrative Cancer Biology Program (U54CA112962)
  • NCI (1U24CA180922, P30-CA14051, K99CA194163)
  • NIH (DP2 OD020839, P50GM107618)
  • Ludwig Center at Harvard
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
Keywords
metastatic melanoma, tumor microenvironment, tumor heterogeneity, MITF, AXL kinase, drug resistance, tumor-infiltrating T cells, T cell exhaustion, clonal expansion, tumor stroma, endothelial cells, cell-cell interactions, immunotherapy
MeSH terms
Base Sequence, Cell Communication, Cell Cycle, Humans, Immunotherapy, Lymphocyte Activation, Melanoma, Neoplasm Metastasis, RNA, Skin Neoplasms, T-Lymphocytes, Stromal Cells, Sequence Analysis, RNA, Drug Resistance, Neoplasm, Genomics, Endothelial Cells, Microphthalmia-Associated Transcription Factor, Single-Cell Analysis, Tumor Microenvironment, Transcriptome

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