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

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, Huaiyu Sun, Jill Meisenhelder, Elena Terenziani, Gyunghwi Woo, Linjing Fang, Thom P. Santisakultarm, Uri Manor, Ruilian Xu, Carlos R. Becerra, Erkut Borazanci, Daniel D. Hoff, Paul M. Grandgenett, Michael A. Hollingsworth, Mathias Leblanc, Sarah E. Umetsu, Eric A. Collisson, Miriam Scadeng, Andrew M. Lowy, Timothy R. Donahue, Tannishtha Reya, Michael Downes, Ronald M. Evans, Geoffrey M. Wahl, Tony Pawson, Ruijun Tian () and Tony Hunter ()
Additional contact information
Yu Shi: Salk Institute for Biological Studies
Weina Gao: Southern University of Science and Technology
Nikki K. Lytle: University of California San Diego School of Medicine
Peiwu Huang: Southern University of Science and Technology
Xiao Yuan: Southern University of Science and Technology
Amanda M. Dann: University of California Los Angeles
Maya Ridinger-Saison: Salk Institute for Biological Studies
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
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
Daniel D. Hoff: The Translational Genomics Research Institute
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
Michael Downes: Salk Institute for Biological Studies
Ronald M. Evans: Salk Institute for Biological Studies
Geoffrey M. Wahl: Salk Institute for Biological Studies
Tony Pawson: Mount Sinai Hospital
Ruijun Tian: Southern University of Science and Technology
Tony Hunter: Salk Institute for Biological Studies

Nature, 2019, vol. 569, issue 7754, 131-135

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1130-6

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