YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma
Open accessPublished version of a preprint
Abstract
Transcriptomic profiling classifies pancreatic ductal adenocarcinoma (PDAC) into several molecular subtypes with distinctive histological and clinical characteristics. However, little is known about the molecular mechanisms that define each subtype and their correlation with clinical outcome. Mutant KRAS is the most prominent driver in PDAC, present in over 90% of tumors, but the dependence of tumors on oncogenic KRAS signaling varies between subtypes. In particular, the squamous subtype is relatively independent of oncogenic KRAS signaling and typically displays much more aggressive clinical behavior versus the progenitor subtype. Here, we identified that yes-associated protein 1 (YAP1) activation is enriched in the squamous subtype and associated with poor prognosis. Activation of YAP1 in progenitor subtype cancer cells profoundly enhanced malignant phenotypes and transformed progenitor subtype cells into squamous subtype. Conversely, depletion of YAP1 specifically suppressed tumorigenicity of squamous subtype PDAC cells. Mechanistically, we uncovered a significant positive correlation between WNT5A expression and YAP1 activity in human PDAC and demonstrated that WNT5A overexpression led to YAP1 activation and recapitulated a YAP1-dependent but Kras-independent phenotype of tumor progression and maintenance. Thus, our study identifies YAP1 oncogene as a major driver of squamous subtype PDAC and uncovers the role of WNT5A in driving PDAC malignancy through activation of the YAP pathway.
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Activated Yap, through genetic amplification of YAP or WNT5a-mediated dysregulation of the Hippo pathway, enables bypass of Kras suppression in Kras-driven murine pancreatic cancer and lung cancer models.
“Previous studies have demonstrated that activated Yap, through genetic amplification of YAP- or WNT5a-mediated dysregulation of the Hippo pathway, enables bypass of Kras suppression in Kras-driven murine pancreatic cancer and lung cancer models (37–39).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [39]
The Introduction reports that Yap1 amplification bypassed KRAS dependence in a pancreatic cancer mouse model. The section “WNT5A overexpression enables tumor maintenance and bypass of KRAS dependence” reports WNT5A-driven, YAP1-dependent tumor growth after Kras extinction in pancreatic models. The cited paper does not establish the claim for lung cancer models; page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredActivation of YAP1 oncogene drives resistance to genetic inactivation of KRAS* in a GEM model of PDAC, confirmed in KRAS*-driven CRC.
“Using a genetically engineered mouse (GEM) model of PDAC driven by inducible KRASG12D, we recently demonstrated that activation of the YAP1 oncogene drives resistance to genetic inactivation of KRAS∗, a finding further confirmed in KRAS∗-driven colorectal cancer (CRC).”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [11]
The section on WNT5A overexpression and bypass of KRAS dependence (page unavailable) states that YAP1 activation can maintain PDAC tumor growth after genetic extinction of KRAS. The section on squamous-subtype PDAC also describes relapse tumors from an inducible KrasG12D mouse model. Our copy does not report confirmation in KRAS-driven colorectal cancer, so that part of the claim is unsupported. (LLM, conf=0.86)
Experimental — accuracy not yet measuredYAP1 activation, through either gene amplification or activation of a non-canonical WNT pathway, is a major driver for bypassing KRAS dependency in PDAC.
“We had previously identified YAP1 activation, through either gene amplification or activation of a non-canonical WNT pathway, as a major driver for bypassing KRAS dependency in PDAC.9,11”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [11]
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References 54 · Cited by 75
- Authors
- Tu, B., Yao, J., Ferri-Borgogno, S., Zhao, J., Chen, S., Wang, Q., Yan, L., Zhou, X., Zhu, C., Bang, S., Chang, Q., Bristow, C. A., Kang, Y., Zheng, H., Wang, H., Fleming, J. B., Kim, M., Heffernan, T. P., Draetta, G. F., Pan, D., Maitra, A., Yao, W., Gupta, S., & Ying, H.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Pathology Department, and
- Molecular and Cellular Oncology Department,
- Yonsei University (KR)
- Weill Cornell Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Yao, Wantong
- Gupta, Sonal
- Ying, Haoqiang
- ORCID
- Tu, Bo
- Yao, Jun
- Ferri-Borgogno, Sammy
- Zhao, Jun
- Chen, Shujuan
- Wang, Qiuyun
- Zhou, Xin
- Zhu, Cihui
- Bang, Seungmin
- Chang, Qing
- Bristow, Christopher A.
- Kang, Ya’an
- Zheng, Hongwu
- Wang, Huamin
- Fleming, Jason B.
- Kim, Michael
- Heffernan, Timothy P.
- Draetta, Giulio F.
- Pan, Duojia
- Maitra, Anirban
- Yao, Wantong
- Gupta, Sonal
- Ying, Haoqiang
- Venue
- JCI Insight
- Published
- 2019-11-01
- Volume
- 4
- Issue
- 21
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC6948828
- OpenAlex
- W2974998460
- Cited by
- 75
- References
- 54
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 9 · 2023: 10 · 2022: 11 · 2021: 23 · 2020: 9 · 2019: 2
- FWCI
- 5.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA214793, P01CA117969)
- Pancreatic Cancer Action Network (17-20-25-YING, 16-70-25-YAO)
- Hirshberg Foundation for Pancreatic Cancer Research (Seed grant)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- YAP, pancreatic ductal adenocarcinoma, Wnt5a, molecular subtypes, tumor progression, prognosis
- MeSH terms
- Wnt-5a Protein, YAP-Signaling Proteins, Humans, Oncogenes, Pancreatic Neoplasms, Transcription Factors, Carcinoma, Pancreatic Ductal, Adaptor Proteins, Signal Transducing
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