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Nature. 2019 May;569(7754):131-135. doi: 10.1038/s41586-019-1130-6. Epub 2019 Apr 17.

Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.

Author information

1
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA. yshi@salk.edu.
2
Department of Chemistry, Southern University of Science and Technology, Shenzhen, China.
3
Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, China.
4
Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA.
5
Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
6
State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.
7
Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
8
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
9
Trovagene, San Diego, CA, USA.
10
Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, CA, USA.
11
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
12
Crown Bioscience San Diego, San Diego, CA, USA.
13
Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, CA, USA.
14
Institute of Oncology, Shenzhen People's Hospital, Shenzhen, China.
15
Texas Oncology-Baylor University Medical Center, Dallas, TX, USA.
16
The Translational Genomics Research Institute, Scottsdale, AZ, USA.
17
HonorHealth, Scottsdale, AZ, USA.
18
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
19
Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
20
Hematology Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
21
Center for Functional MRI, Department of Radiology, University of California San Diego, La Jolla, CA, USA.
22
Department of Surgery, Division of Surgical Oncology, University of California San Diego School of Medicine, La Jolla, CA, USA.
23
Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA, USA.
24
Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA, USA.
25
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
26
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
27
Department of Chemistry, Southern University of Science and Technology, Shenzhen, China. tianrj@sustech.edu.cn.
28
Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, China. tianrj@sustech.edu.cn.
29
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. tianrj@sustech.edu.cn.
30
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA. hunter@salk.edu.

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.

PMID:
30996350
PMCID:
PMC6565370
[Available on 2019-10-17]
DOI:
10.1038/s41586-019-1130-6

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