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Lineage reversion drives WNT independence in intestinal cancer

Teng Han, Sukanya Goswami, Yang Hu, Fanying Tang, Maria Paz Zafra, Charles Murphy, Zhen Cao, John T Poirier, Ekta Khurana, Olivier Elemento, Jaclyn F. Hechtman, Rona Yaeger, View ORCID ProfileLukas E. Dow
doi: https://doi.org/10.1101/2020.01.22.914689
Teng Han
Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NYWeill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY
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Sukanya Goswami
Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY
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Yang Hu
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY
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Fanying Tang
Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NYDepartment of Physiology and Biophysics, Weill Cornell Medicine, New York, NY
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Maria Paz Zafra
Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY
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Charles Murphy
Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NYThe Tri-Institutional Training Program in Computational Biology and Medicine, New York, NY
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Zhen Cao
Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NYHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
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John T Poirier
Perlmutter Cancer Center, New York University Langone Health, New York, NY
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Ekta Khurana
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY
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Olivier Elemento
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NYEnglander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY
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Jaclyn F. Hechtman
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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Rona Yaeger
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
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Lukas E. Dow
Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NYWeill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NYDepartment of Biochemistry, Weill Cornell Medicine, New York, NY
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  • ORCID record for Lukas E. Dow
  • For correspondence: lud2005@med.cornell.edu
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ABSTRACT

The WNT pathway is a fundamental regulator of intestinal homeostasis and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer (CRC). To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that while WNT suppression blocks tumor growth in most organoid and in vivo CRC models, the accumulation of CRC-associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of p53 and SMAD4, transient TGFβ exposure drives YAP/ TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work delineates genetic and microenvironmental factors that drive WNT inhibitor resistance, identifies a new mechanism for WNT-independent CRC growth and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 23, 2020.
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Lineage reversion drives WNT independence in intestinal cancer
Teng Han, Sukanya Goswami, Yang Hu, Fanying Tang, Maria Paz Zafra, Charles Murphy, Zhen Cao, John T Poirier, Ekta Khurana, Olivier Elemento, Jaclyn F. Hechtman, Rona Yaeger, Lukas E. Dow
bioRxiv 2020.01.22.914689; doi: https://doi.org/10.1101/2020.01.22.914689
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Lineage reversion drives WNT independence in intestinal cancer
Teng Han, Sukanya Goswami, Yang Hu, Fanying Tang, Maria Paz Zafra, Charles Murphy, Zhen Cao, John T Poirier, Ekta Khurana, Olivier Elemento, Jaclyn F. Hechtman, Rona Yaeger, Lukas E. Dow
bioRxiv 2020.01.22.914689; doi: https://doi.org/10.1101/2020.01.22.914689

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