Abstract

The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and the presence of cancer cells with properties of normal tissue stem cells1,2. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration3,4,5. Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that these cells have features of normal tissue stem cells. Genetic perturbation of Wnt production or signalling suppressed tumour progression. Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies.

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Acknowledgements

We thank D. McFadden and P. Sharp for critical reading of the manuscript and T. Papagiannakopoulos for helpful discussions; H. Clevers for Lgr5CreER/+ mice; Janssen Pharmaceuticals for human tissue; J. Roper for mouse colon adenoma tissue; R. T. Bronson for expertise in animal pathology; Y. Soto-Feliciano and S. Levine for massively parallel sequencing expertise; L. Gilbert, M. Horlbeck and J. Weissman for Lgr5 CRISPR gene activation sgRNA sequences; A. Li for help with generation of TCGA data catalogues; M. Griffin, M. Jennings and G. Paradis for FACS support; E. Vasile for microscopy support; K. Cormier and the Hope Babette Tang (1983) Histology Facility for histology support; S. Bajpay, D. Canner, D. Garcia-Gali, R. Kohn, N. Marjanovich, K. Mercer, J. Replogle and R. Romero for help with experiments; K. Anderson, I. Baptista, A. Deconinck, J. Teixeira and K. Yee for administrative support; and the Swanson Biotechnology Center for excellent core facilities. This work was financially supported by the Transcend Program and Janssen Pharmaceuticals, the Lung Cancer Research Foundation, the Howard Hughes Medical Institute and, in part, by the Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute. T.T. is supported by the National Cancer Institute (K99 CA187317), the Sigrid Juselius Foundation, the Hope Funds for Cancer Research and the Maud Kuistila Foundation. T.J. is a Howard Hughes Medical Institute Investigator, a David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar.

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Affiliations

  1. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA

    • Tuomas Tammela
    • , Francisco J. Sanchez-Rivera
    • , Naniye Malli Cetinbas
    • , Katherine Wu
    • , Nikhil S. Joshi
    • , Katja Helenius
    • , Yoona Park
    • , Roxana Azimi
    • , Natanya R. Kerper
    • , R. Alexander Wesselhoeft
    • , Xin Gu
    • , Leah Schmidt
    • , Milton Cornwall-Brady
    • , Ömer H. Yilmaz
    • , Wen Xue
    • , Arjun Bhutkar
    •  & Tyler Jacks
  2. RNA Therapeutics Institute, Program in Molecular Medicine, and Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

    • Wen Xue
  3. Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland

    • Pekka Katajisto
  4. Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Stockholm, Sweden

    • Pekka Katajisto
  5. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Tyler Jacks

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Contributions

T.T. and T.J. designed and directed the study; T.T., K.W., Y.P. and R.A.W. performed all types of experiments reported in the study; F.J.S.-R. performed CRISPR gene activation experiments and analysed CRISPR-mutated loci; N.M.C. and K.H. performed gene expression analysis and N.M.C. performed ISH; N.S.J., L.S. and P.K. performed FACS; R.A. and N.R.K. performed molecular cloning and R.A. quantified Ki67+ nuclei; X.G. performed cell culture experiments; M.C.-B. developed and used microcomputed tomography analysis methodology; W.X. generated shRNA reagents; A.B. conducted bioinformatic analyses; F.J.S.-R., N.S.J., Ö.H.Y., P.K. and A.B. provided conceptual advice; T.T. and T.J. wrote the manuscript with comments from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tyler Jacks.

Reviewer Information Nature thanks H. Clevers and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    This file contains additional discussion on the differences between R-spondin and Wnt ligand stimulation.

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https://doi.org/10.1038/nature22334

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