OpenLB
Open Library of Bioscience
Advanced Search
Nature medicine
02, 2020;26 (2): 259-269.

Regenerative lineages and immune-mediated pruning in lung cancer metastasis.

Ashley M Laughney, Jing Hu, Nathaniel R Campbell, Samuel F Bakhoum, Manu Setty, Vincent-Philippe Lavallée, Yubin Xie, Ignas Masilionis, Ambrose J Carr, Sanjay Kottapalli, Viola Allaj, Marissa Mattar, Natasha Rekhtman, Joao B Xavier, Linas Mazutis, John T Poirier, Charles M Rudin, Dana Pe'er, Joan Massagué
Author Information
  1. Ashley M Laughney: Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ORCID
  2. Jing Hu: Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  3. Nathaniel R Campbell: Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ORCID
  4. Samuel F Bakhoum: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  5. Manu Setty: Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  6. Vincent-Philippe Lavallée: Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  7. Yubin Xie: Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ORCID
  8. Ignas Masilionis: Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ORCID
  9. Ambrose J Carr: Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  10. Sanjay Kottapalli: Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  11. Viola Allaj: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  12. Marissa Mattar: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  13. Natasha Rekhtman: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  14. Joao B Xavier: Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  15. Linas Mazutis: Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  16. John T Poirier: Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.
  17. Charles M Rudin: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ORCID
  18. Dana Pe'er: Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. peerd@mskcc.org. ORCID
  19. Joan Massagué: Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. j-massague@ski.mskcc.org. ORCID
PMID: 32042191 DOI: 10.1038/s41591-019-0750-6

Abstract

Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.

References

  1. Beumer, J. & Clevers, H. Regulation and plasticity of intestinal stem cells during homeostasis and regeneration. Development 143, 3639–3649 (2016).
  2. Kumar, P. A. et al. Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 147, 525–538 (2011). [PMID: 22036562]
  3. Vaughan, A. E. et al. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517, 621–625 (2015).
  4. Zuo, W. et al. p63()Krt5() distal airway stem cells are essential for lung regeneration. Nature 517, 616–620 (2015).
  5. Zacharias, W. J. et al. Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature 555, 251–255 (2018). [PMID: 6020060]
  6. Zaret, K. S. & Grompe, M. Generation and regeneration of cells of the liver and pancreas. Science 322, 1490–1494 (2008). [PMID: 2641009]
  7. Kotton, D. N. & Morrisey, E. E. Lung regeneration: mechanisms, applications and emerging stem cell populations. Nat. Med. 20, 822–832 (2014). [PMID: 4229034]
  8. Murry, C. E. & Keller, G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661–680 (2008).
  9. Tata, P. R. et al. Developmental history provides a roadmap for the emergence of tumor plasticity. Dev. Cell. 44, 679–693 (2018). [PMID: 5875457]
  10. Massagué, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016). [PMID: 26791720]
  11. Klein, A. M. et al. Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell 161, 1187–1201 (2015). [PMID: 26000487]
  12. Zilionis, R. et al. Single-cell barcoding and sequencing using droplet microfluidics. Nat. Protoc. 12, 44–73 (2017). [PMID: 27929523]
  13. Azizi, E. et al. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell 174, 1293–1308 (2018). [PMID: 29961579]
  14. van Dijk, D. et al. Recovering gene interactions from single-cell data using data diffusion. Cell 174, 716–729 (2018). [PMID: 29961576]
  15. Levine, J. H. et al. Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis. Cell 162, 184–197 (2015). [PMID: 26095251]
  16. Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016). [PMID: 27015306]
  17. Tirosh, I. et al. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature 539, 309–313 (2016). [PMID: 5465819]
  18. Lavin, Y. et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 169, 750–765 (2017). [PMID: 5737939]
  19. Shen, R. & Seshan, V. E. FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res. 44, e131 (2016). [PMID: 5027494]
  20. Cheng, D. T. et al. Memorial sloan kettering-integrated mutation profiling of actionable cancer targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J. Mol. Diagn. 17, 251–264 (2015). [PMID: 25801821]
  21. Bremnes, R. M. et al. The role of tumor-infiltrating lymphocytes in development, progression, and prognosis of non-small cell lung cancer. J. Thorac. Oncol. 11, 789–800 (2016). [PMID: 26845192]
  22. Morrisey, E. E. & Hogan, B. L. Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev. Cell 18, 8–23 (2010). [PMID: 20152174]
  23. Du, Y. N. et al. Lung gene expression analysis (LGEA): an integrative web portal for comprehensive gene expression data analysis in lung development. Thorax 72, 481–484 (2017). [PMID: 28070014]
  24. Du, Y. N., Guo, M. Z., Whitsett, J. A. & Xu, Y. ‘LungGENS’: a web-based tool for mapping single-cell gene expression in the developing lung. Thorax 70, 1092–1094 (2015). [PMID: 26130332]
  25. Treutlein, B. et al. Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq. Nature 509, 371–375 (2014). [PMID: 24739965]
  26. Guha, A. et al. Neuroepithelial body microenvironment is a niche for a distinct subset of Clara-like precursors in the developing airways. Proc. Natl Acad. Sci. USA 109, 12592–12597 (2012). [PMID: 22797898]
  27. Haghverdi, L., Buttner, M., Wolf, F. A., Buettner, F. & Theis, F. J. Diffusion pseudotime robustly reconstructs lineage branching. Nat. Methods 13, 845–848 (2016). [PMID: 27571553]
  28. Setty, M. et al. Wishbone identifies bifurcating developmental trajectories from single-cell data. Nat. Biotechnol. 34, 637–645 (2016). [PMID: 27136076]
  29. Jobe, A. H., Whitsett, J. & Abman, S. H. (eds) Fetal and Neonatal Lung Development: Clinical Correlates and Technologies for the Future (Cambridge University Press, 2016).
  30. Nakamura, N. et al. Identification of tumor markers and differentiation markers for molecular diagnosis of lung adenocarcinoma. Oncogene 25, 4245–4255 (2006). [PMID: 16491115]
  31. Smith, B. A. et al. A human adult stem cell signature marks aggressive variants across epithelial cancers. Cell. Rep. 24, 3353–3366 (2018). [PMID: 6382070]
  32. Niakan, K. K. et al. Sox17 promotes differentiation in mouse embryonic stem cells by directly regulating extraembryonic gene expression and indirectly antagonizing self-renewal. Genes Dev. 24, 312–326 (2010). [PMID: 20123909]
  33. Seguin, C. A., Draper, J. S., Nagy, A. & Rossant, J. Establishment of endoderm progenitors by SOX transcription factor expression in human embryonic stem cells. Cell Stem Cell 3, 182–195 (2008).
  34. Okubo, T., Knoepfler, P. S., Eisenman, R. N. & Hogan, B. L. N-myc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation. Development 132, 1363–1374 (2005). [PMID: 15716345]
  35. Rawlins, E. L., Clark, C. P., Xue, Y. & Hogan, B. L. The Id2 distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development 136, 3741–3745 (2009). [PMID: 2766341]
  36. Gyorffy, B., Surowiak, P., Budczies, J. & Lanczky, A. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS ONE 8, e82241 (2013). [PMID: 3867325]
  37. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).
  38. Winslow, M. M. et al. Suppression of lung adenocarcinoma progression by Nkx2-1. Nature 473, 101–104 (2011). [PMID: 3088778]
  39. Jung, H., Hsiung, B., Pestal, K., Procyk, E. & Raulet, D. H. RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry. J. Exp. Med. 209, 2409–2422 (2012). [PMID: 23166357]
  40. Long, E. O. Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol. Rev. 224, 70–84 (2008). [PMID: 2587243]
  41. Er, E. E. et al. Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization. Nat. Cell Biol. 20, 966–978 (2018). [PMID: 6467203]
  42. Weber, K. et al. RGB marking facilitates multicolor clonal cell tracking. Nat. Med. 17, 504–509 (2011).
  43. Finak, G. et al. MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol. 16, 278 (2015). [PMID: 4676162]
  44. Nowotschin, S. et al. The emergent landscape of the mouse gut endoderm at single-cell resolution. Nature 569, 361 (2019). [PMID: 6724221]
  45. Mathelier, A. et al. JASPAR 2014: an extensively expanded and updated open-access database of transcription factor binding profiles. Nucleic Acids Res. 42, D142–D147 (2014).
  46. Mathelier, A. et al. JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 44, D110–D115 (2016).
  47. Novershtern, N. et al. Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 144, 296–309 (2011). [PMID: 3049864]
  48. Jeffrey, K. L. et al. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat. Immunol. 7, 274–283 (2006).
  49. Halko, N. M. P. & Tropp, J. A. Finding structure with randomness: probabilistic algorithms for constructing apprxoimate matrix decompositions. SIAM Rev. 53, 217–288 (2011).
  50. Valle, S., Li, W. H. & Qin, S. J. Selection of the number of principal components: the variance of the reconstruction error criterion with a comparison to other methods. Ind. Eng. Chem. Res. 38, 4389–4401 (1999).
  51. van der Maaten, L. & Hinton, G. Visualizing data using t-SNE. J. Mach. Learn. Res. 9, 2579–2605 (2008).
  52. Jacomy, M., Venturini, T., Heymann, S. & Bastian, M. ForceAtlas2, a continuous graph layout algorithm for handy network visualization designed for the Gephi software. PLoS ONE 9, e98679 (2014). [PMID: 24914678]
  53. Liberzon, A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739–1740 (2011). [PMID: 21546393]
  54. Rock, J. R. et al. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc. Natl Acad. Sci. USA 106, 12771–12775 (2009). [PMID: 19625615]
  55. Li, S. et al. Molecular signatures of antibody responses derived from a systems biology study of five human vaccines. Nat. Immunol. 15, 195–204 (2014). [PMID: 24336226]
  56. Abbas, A. R. et al. Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data. Genes Immun. 6, 319–331 (2005). [PMID: 15789058]
  57. Mor-Vaknin, N., Punturieri, A., Sitwala, K. & Markovitz, D. M. Vimentin is secreted by activated macrophages. Nat. Cell Biol. 5, 59–63 (2003). [PMID: 12483219]
  58. Zepp, J. A. et al. Distinct mesenchymal lineages and niches promote epithelial self-renewal and myofibrogenesis in the lung. Cell 170, 1134–1148 e1110 (2017). [PMID: 28886382]
  59. Lee, J. H. et al. Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6. Cell 170, 1149–1163 (2017). [PMID: 28886383]
  60. Xia, H. et al. Calcium-binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis. J. Clin. Invest. 127, 2586–2597 (2017). [PMID: 28530639]
  61. Degryse, A. L. et al. Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis. Am. J. Physiol. Lung Cell Mol. Physiol. 299, L442–L452 (2010). [PMID: 20562227]
  62. Tanjore, H. et al. Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis. Am. J. Respir. Crit. Care Med. 180, 657–665 (2009). [PMID: 19556518]
  63. Lawson, W. E. et al. Characterization of fibroblast-specific protein 1 in pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 171, 899–907 (2005). [PMID: 15618458]
  64. Li, Z. H., Dulyaninova, N. G., House, R. P., Almo, S. C. & Bresnick, A. R. S100A4 regulates macrophage chemotaxis. Mol. Biol. Cell 21, 2598–2610 (2010). [PMID: 20519440]
  65. Moore, K. W., Malefyt, deWaal, Coffman, R. & O’Garra, R. L. A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001). [PMID: 11244051]
  66. Priceman, S. J. et al. Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood 115, 1461–1471 (2010). [PMID: 20008303]
  67. Lambrechts, D. et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24, 1277–1289 (2018). [PMID: 29988129]
  68. Zilionis, R. et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 50, 1317–1334 (2019).
  69. Coifman, R. R. et al. Geometric diffusions as a tool for harmonic analysis and structure definition of data: diffusion maps. Proc. Natl Acad. Sci. USA 102, 7426–7431 (2005). [PMID: 15899970]
  70. Setty, M. et al. Characterization of cell fate probabilities in single-cell data with Palantir. Nat. Biotechnol. 37, 451–460 (2019).
  71. Davoli, T., Uno, H., Wooten, E. C. & Elledge, S. J. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 355, eaaf8399 (2017). [PMID: 5592794]
  72. Yarilin, D. et al. Machine-based method for multiplex in situ molecular characterization of tissues by immunofluorescence detection. Sci. Rep. 5, 9534 (2015). [PMID: 4821037]
  73. Otsu, N. Threshold selection method from gray-level histograms. IEEE T. Syst. Man. Cyb. 9, 62–66 (1979).
  74. He, K., Gkioxari, G., Dollar, P. & Girshick, R. Mask R-CNN. IEEE Trans. Pattern Analysis Machine Intelligence 42, 386–397 (2020).
  75. Loken, M. R., Parks, D. R. & Herzenberg, L. A. Two-color immunofluorescence using a fluorescence-activated cell sorter. J. Histochem. Cytochem. 25, 899–907 (1977).

Grants

  1. R01 CA164729/NCI NIH HHS
  2. R01 CA229215/NCI NIH HHS
  3. P30 CA008748/NCI NIH HHS
  4. DP1 HD084071/NICHD NIH HHS
  5. U2C CA233284/NCI NIH HHS
  6. U54 CA209975/NCI NIH HHS
  7. P01 CA129243/NCI NIH HHS
  8. DP5 OD026395/NIH HHS
  9. F30 CA220954/NCI NIH HHS

MeSH Term

Adenocarcinoma
Animals
Bronchi
Cell Differentiation
Cell Lineage
Cluster Analysis
Databases, Genetic
Disease Progression
Endoderm
Female
Humans
Hydrogels
Immune System
Killer Cells, Natural
Lung
Lung Neoplasms
Mice
Neoplasm Metastasis
Phenotype
Pulmonary Alveoli
Regeneration
Signal Transduction

Chemicals

Hydrogels
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000110 (The single cell transcriptional landscape of human lung adenocarcinoma (primary tumours and metastases))

Word Cloud

Similar Articles

Cited By