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Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq
Itay Tirosh,Benjamin Izar,Daniel J. Treacy,John J. Trombetta,Asaf Rotem,Christopher Rodman,Christine G. Lian,George F. Murphy,Mohammad Fallahi-Sichani,Ken Dutton-Regester,Jia-Ren Lin,Ofir Cohen,Parin Shah,Diana Lu,Alexandra-Chloé Villani,Aleksandr Andreev,E.M. Van Allen,Monica M. Bertagnolli,Peter K. Sorger,Ryan J. Sullivan,Keith T. Flaherty,Dennie T. Frederick,Judit Jané-Valbuena,Orit Rozenblatt-Rosen,Sanjay M. Prakadan,Marc H. Wadsworth,Alex S. Genshaft,Travis K. Hughes,Carly G. K. Ziegler,Samuel W. Kazer,Alethe Gaillard de Saint Germain,Kellie E. Kolb,Cory M. Johannessen,Clifford H. Yoon,Alex K. Shalek,Aviv Regev,Levi A. Garraway +36 more
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TLDR
Tirosh et al. as discussed by the authors applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells.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 Melanoma cells show transcriptional heterogeneity. To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies.read more
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Integrative analysis of 111 reference human epigenomes
Anshul Kundaje,Wouter Meuleman,Jason Ernst,Angela Yen,Pouya Kheradpour,Zhizhuo Zhang,Jianrong Wang,Lucas D. Ward,Abhishek Sarkar,Gerald Quon,Matthew L. Eaton,Yi-Chieh Wu,Andreas R. Pfenning,Xinchen Wang,Melina Claussnitzer,Yaping Liu,Mukul S. Bansal,Soheil Feizi-Khankandi,Ah Ram Kim,Richard C Sallari,Nicholas A Sinnott-Armstrong,Laurie A. Boyer,Elizabeta Gjoneska,Li-Huei Tsai,Manolis Kellis +24 more
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Revealing the vectors of cellular identity with single-cell genomics
TL;DR: Single-cell genomics has now made it possible to create a comprehensive atlas of human cells and has reopened definitions of a cell's identity and of the ways in which identity is regulated by the cell's molecular circuitry.
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The Tabula Sapiens: a multiple organ single cell transcriptomic atlas of humans
TL;DR: A human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor, enabled molecular characterization of more than 400 cell types, their distribution across tissues and tissue specific variation in gene expression.
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Decade-long leukaemia remissions with persistence of CD4+ CAR T cells
J. Joseph Melenhorst,Gregory M. Chen,Meng Wang,David L. Porter,Changya Chen,McKensie Collins,Peng Gao,Shovik Bandyopadhyay,Hongxing Sun,Ziran Zhao,Stefan Lundh,Iulian Pruteanu-Malinici,Christopher L. Nobles,Sayantan Maji,Noelle V. Frey,Saar Gill,Lifeng Tian,Irina Kulikovskaya,Minnal Gupta,David E Ambrose,Megan M. Davis,Joseph A. Fraietta,Jennifer Brogdon,Regina M. Young,Anne Chew,Bruce L. Levine,Don L. Siegel,Cécile Alanio,E. John Wherry,Frederic D. Bushman,Simon F. Lacey,Kai Tan,Carl H. June +32 more
TL;DR: In this article , the authors studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia who achieved a complete remission in 2010.
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Macrophages as tools and targets in cancer therapy
TL;DR: In this paper , the authors proposed a set of macrophage-targeting strategies that include inhibitors of cytokines and chemokines involved in the recruitment and polarization of tumour-promoting myeloid cells as well as activators of their antitumorigenic and immunostimulating functions.
References
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Zhihong Zheng,Enguo Chen,Weiguo Lu,Gary Mouradian,Matthew R. Hodges,Mingyu Liang,Pengyuan Liu,Pengyuan Liu,Yan Lu +8 more
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A Feed-Forward Mechanosignaling Loop Confers Resistance to Therapies Targeting the MAPK Pathway in BRAF-Mutant Melanoma.
Christophe Girard,Margaux Lecacheur,Rania Ben Jouira,Berestjuk I,Serena Diazzi,Virginie Prod'homme,Aude Mallavialle,Frédéric Larbret,Maeva Gesson,Sébastien Schaub,Sabrina Pisano,Stéphane Audebert,Bernard Mari,Cedric Gaggioli,Eleonora Leucci,Jean-Christophe Marine,Marcel Deckert,Sophie Tartare-Deckert +17 more
TL;DR: It is concluded that MAPK pathway targeting therapies mechanically reprogram melanoma cells to confer a drug-protective matrix environment, which fuels a YAP/MRTF-dependent feed-forward loop associated with tumor stiffening, mechanosensing, and therapy resistance.
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