Author
Listed:
- Yu Shi
(Salk Institute for Biological Studies)
- Weina Gao
(Southern University of Science and Technology
Southern University of Science and Technology)
- Nikki K. Lytle
(University of California San Diego School of Medicine
Sanford Consortium for Regenerative Medicine)
- Peiwu Huang
(Southern University of Science and Technology
Southern University of Science and Technology
Hong Kong Baptist University)
- Xiao Yuan
(Southern University of Science and Technology
Southern University of Science and Technology)
- Amanda M. Dann
(University of California Los Angeles)
- Maya Ridinger-Saison
(Salk Institute for Biological Studies
Trovagene)
- Kathleen E. DelGiorno
(Salk Institute for Biological Studies)
- Corina E. Antal
(Salk Institute for Biological Studies)
- Gaoyang Liang
(Salk Institute for Biological Studies)
- Annette R. Atkins
(Salk Institute for Biological Studies)
- Galina Erikson
(Salk Institute for Biological Studies)
- Huaiyu Sun
(Salk Institute for Biological Studies)
- Jill Meisenhelder
(Salk Institute for Biological Studies)
- Elena Terenziani
(Salk Institute for Biological Studies
Crown Bioscience San Diego)
- Gyunghwi Woo
(Salk Institute for Biological Studies)
- Linjing Fang
(Salk Institute for Biological Studies)
- Thom P. Santisakultarm
(Salk Institute for Biological Studies)
- Uri Manor
(Salk Institute for Biological Studies)
- Ruilian Xu
(Shenzhen People’s Hospital)
- Carlos R. Becerra
(Texas Oncology—Baylor University Medical Center)
- Erkut Borazanci
(The Translational Genomics Research Institute
HonorHealth)
- Daniel D. Hoff
(The Translational Genomics Research Institute
HonorHealth)
- Paul M. Grandgenett
(University of Nebraska Medical Center)
- Michael A. Hollingsworth
(University of Nebraska Medical Center)
- Mathias Leblanc
(Salk Institute for Biological Studies)
- Sarah E. Umetsu
(University of California San Francisco)
- Eric A. Collisson
(University of California San Francisco)
- Miriam Scadeng
(University of California San Diego)
- Andrew M. Lowy
(University of California San Diego School of Medicine)
- Timothy R. Donahue
(University of California Los Angeles)
- Tannishtha Reya
(University of California San Diego School of Medicine
Sanford Consortium for Regenerative Medicine
University of California San Diego School of Medicine)
- Michael Downes
(Salk Institute for Biological Studies)
- Ronald M. Evans
(Salk Institute for Biological Studies
Salk Institute for Biological Studies)
- Geoffrey M. Wahl
(Salk Institute for Biological Studies)
- Tony Pawson
(Mount Sinai Hospital
University of Toronto)
- Ruijun Tian
(Southern University of Science and Technology
Southern University of Science and Technology
Mount Sinai Hospital)
- Tony Hunter
(Salk Institute for Biological Studies)
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3–7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8–10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial–mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell–cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.
Suggested Citation
Yu Shi & Weina Gao & Nikki K. Lytle & Peiwu Huang & Xiao Yuan & Amanda M. Dann & Maya Ridinger-Saison & Kathleen E. DelGiorno & Corina E. Antal & Gaoyang Liang & Annette R. Atkins & Galina Erikson & H, 2019.
"Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring,"
Nature, Nature, vol. 569(7754), pages 131-135, May.
Handle:
RePEc:nat:nature:v:569:y:2019:i:7754:d:10.1038_s41586-019-1130-6
DOI: 10.1038/s41586-019-1130-6
Download full text from publisher
As the access to this document is restricted, you may want to search for a different version of it.
Citations
Citations are extracted by the
CitEc Project, subscribe to its
RSS feed for this item.
Cited by:
- Xue Yang & Jianming Wang & Chun-Yuan Chang & Fan Zhou & Juan Liu & Huiting Xu & Maria Ibrahim & Maria Gomez & Grace L. Guo & Hao Liu & Wei-Xing Zong & Fredric E. Wondisford & Xiaoyang Su & Eileen Whit, 2024.
"Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice,"
Nature Communications, Nature, vol. 15(1), pages 1-15, December.
- L. Paige Ferguson & Jovylyn Gatchalian & Matthew L. McDermott & Mari Nakamura & Kendall Chambers & Nirakar Rajbhandari & Nikki K. Lytle & Sara Brin Rosenthal & Michael Hamilton & Sonia Albini & Martin, 2023.
"Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma,"
Nature Communications, Nature, vol. 14(1), pages 1-17, December.
- Gaoyang Liang & Tae Gyu Oh & Nasun Hah & Hervé Tiriac & Yu Shi & Morgan L. Truitt & Corina E. Antal & Annette R. Atkins & Yuwenbin Li & Cory Fraser & Serina Ng & Antonio F. M. Pinto & Dylan C. Nelson , 2023.
"Inhibiting stromal Class I HDACs curbs pancreatic cancer progression,"
Nature Communications, Nature, vol. 14(1), pages 1-18, December.
Corrections
All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:569:y:2019:i:7754:d:10.1038_s41586-019-1130-6. See general information about how to correct material in RePEc.
If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.
We have no bibliographic references for this item. You can help adding them by using this form .
If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.
For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .
Please note that corrections may take a couple of weeks to filter through
the various RePEc services.