A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma
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 cells. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration....
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2018
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| Online Access: | http://hdl.handle.net/1721.1/116606 https://orcid.org/0000-0003-3675-6961 https://orcid.org/0000-0002-7045-7837 https://orcid.org/0000-0001-8031-0006 https://orcid.org/0000-0003-4617-8157 https://orcid.org/0000-0002-3393-6927 https://orcid.org/0000-0001-9076-8475 https://orcid.org/0000-0002-7577-4612 https://orcid.org/0000-0001-5785-8911 |
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| author | Katajisto, Pekka Tammela, Tuomas Cetinbas, Naniye Wu, Katherine Helenius, Katja Piritta Park, Yoona K Azimi, Roxana S. Kerper, Natanya R. Wesselhoeft IV, Robert Alexander Gu, Xin Schmidt, Leah Marie Cornwall-Brady, Milton R. Yilmaz, Omer Xue, Wen Bhutkar, Arjun Jacks, Tyler E Sanchez-Rivera, Francisco Jav Joshi, Nik |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Katajisto, Pekka Tammela, Tuomas Cetinbas, Naniye Wu, Katherine Helenius, Katja Piritta Park, Yoona K Azimi, Roxana S. Kerper, Natanya R. Wesselhoeft IV, Robert Alexander Gu, Xin Schmidt, Leah Marie Cornwall-Brady, Milton R. Yilmaz, Omer Xue, Wen Bhutkar, Arjun Jacks, Tyler E Sanchez-Rivera, Francisco Jav Joshi, Nik |
| author_sort | Katajisto, Pekka |
| collection | MIT |
| description | 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 cells. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration. 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. |
| first_indexed | 2024-09-23T08:47:04Z |
| format | Article |
| id | mit-1721.1/116606 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T08:47:04Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1166062022-09-30T11:14:40Z A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma Katajisto, Pekka Tammela, Tuomas Cetinbas, Naniye Wu, Katherine Helenius, Katja Piritta Park, Yoona K Azimi, Roxana S. Kerper, Natanya R. Wesselhoeft IV, Robert Alexander Gu, Xin Schmidt, Leah Marie Cornwall-Brady, Milton R. Yilmaz, Omer Xue, Wen Bhutkar, Arjun Jacks, Tyler E Sanchez-Rivera, Francisco Jav Joshi, Nik Koch Institute for Integrative Cancer Research at MIT Tammela, Tuomas Sanchez-Rivera, Francisco Javier Cetinbas, Naniye Wu, Katherine Joshi, Nikhil Helenius, Katja Piritta Park, Yoona K Azimi, Roxana S. Kerper, Natanya R. Wesselhoeft IV, Robert Alexander Gu, Xin Schmidt, Leah Marie Cornwall-Brady, Milton R. Yilmaz, Omer Xue, Wen Bhutkar, Arjun Jacks, Tyler E 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 cells. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration. 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. 2018-06-26T14:06:46Z 2018-06-26T14:06:46Z 2017-05 2016-07 2018-06-25T14:23:04Z Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/116606 Tammela, Tuomas et al. “A Wnt-Producing Niche Drives Proliferative Potential and Progression in Lung Adenocarcinoma.” Nature 545, 7654 (May 2017): 355–359 © 2017 Macmillan Publishers Limited, part of Springer Nature https://orcid.org/0000-0003-3675-6961 https://orcid.org/0000-0002-7045-7837 https://orcid.org/0000-0001-8031-0006 https://orcid.org/0000-0003-4617-8157 https://orcid.org/0000-0002-3393-6927 https://orcid.org/0000-0001-9076-8475 https://orcid.org/0000-0002-7577-4612 https://orcid.org/0000-0001-5785-8911 http://dx.doi.org/10.1038/NATURE22334 Nature Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | Katajisto, Pekka Tammela, Tuomas Cetinbas, Naniye Wu, Katherine Helenius, Katja Piritta Park, Yoona K Azimi, Roxana S. Kerper, Natanya R. Wesselhoeft IV, Robert Alexander Gu, Xin Schmidt, Leah Marie Cornwall-Brady, Milton R. Yilmaz, Omer Xue, Wen Bhutkar, Arjun Jacks, Tyler E Sanchez-Rivera, Francisco Jav Joshi, Nik A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma |
| title | A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma |
| title_full | A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma |
| title_fullStr | A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma |
| title_full_unstemmed | A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma |
| title_short | A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma |
| title_sort | wnt producing niche drives proliferative potential and progression in lung adenocarcinoma |
| url | http://hdl.handle.net/1721.1/116606 https://orcid.org/0000-0003-3675-6961 https://orcid.org/0000-0002-7045-7837 https://orcid.org/0000-0001-8031-0006 https://orcid.org/0000-0003-4617-8157 https://orcid.org/0000-0002-3393-6927 https://orcid.org/0000-0001-9076-8475 https://orcid.org/0000-0002-7577-4612 https://orcid.org/0000-0001-5785-8911 |
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