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 resistance3,4,5,6,7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8,9,10, 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.
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All source data for full immunoblot scan images and statistical analyses presented in figure panels are included in the Supplementary Information. RNA sequencing data have been deposited in the Gene Expression Omnibus under accession numbers GSE99187 and GSE119694. All raw mass spectrometry data have been deposited to the MassIVE repository (ftp://massive.ucsd.edu/MSV000081136).
The custom scripts for quantification of immunohistochemistry images with Image J and multiplex immunofluorescence images with Imaris will be freely available upon reasonable request.
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We thank F. McCormick and M. Wang (UCSF) for sharing reagents and results, R. Shaw (Salk) for KPf/fL mice, M. Karin (UCSD) for mouse cancer samples and comments on the manuscript, H. Han and E. Menashi (Tgen) for experimental suggestions and reagents, J. Zimmerman and S. Simon for laboratory support, N. Cernac and J. Chang for laboratory assistance, J. Chambers and K. Suter-Brady for animal work, T. Zhang and K. Mcintyre for histology services. This work was supported by the following grants: Ministry of Science and Technology of China (2016YFA0501403) and National Natural Science Foundation of China (21575057) to R.T.; NIH CA014195, CA082683, CA080100, Lustgarten Foundation (awards 388246 and 552873), Helmsley Charitable Trust (2012-PG-MED002), and William Isacoff Research Foundation to T.H.; SU2C Pancreatic Cancer Dream Team (SU2C-AACR-DT-05-09, SU2C-AACR-DT-20-16) to D.D.V.H., R.M.E., G.W., T.H., A.M.L., T.R. and M.D.; NRSA F31CA206416 and T32GM007752 to N.K.L.; F32CA217033 to G.L.; Flinn Foundation to E.B.; NIH CA178015, CA227807 and CA222862 to E.A.C.; NIH CA197699 and CA186043 to T.R.; NIH CA155620 to A.M.L.; NIH P50CA127297, U01CA210240, P30CA36727 and 5R50CA211462 to P.M.G. and M.A.H. R.M.E. is a Howard Hughes Medical Institute Investigator and March of Dimes Chair in Molecular and Developmental Biology, and supported by Lustgarten, Ipsen/Biomeasure, Freeberg and William Isacoff Research Foundation. We thank Salk core facilities and staff, financially supported by NCI CCSG CA014195, including Advanced Biophotonics, Flow Cytometry, Functional Genomics, Integrative Genomics and Bioinformatics, Next Generation Sequencing and Transgenic Cores. Y.S. received a fellowship from the Helmsley Charitable Trust. T.H. is a Frank and Else Schilling American Cancer Society Professor and the Renato Dulbecco Chair in Cancer Research.
Nature thanks Claus Jørgensen, Amina Ann Qutub and the other anonymous reviewer(s) for their contribution to the peer review of this work.