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Cited by 431Pancreatic and Hepatic Oncology ResearchPancreatitis Pathology and TreatmentPancreatic function and diabetes

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

Open access
Shi, Yu, Gao, Weina, Lytle, Nikki K., Huang, Peiwu, Yuan, Xiao, Dann, Amanda M., Ridinger-Saison, Maya, DelGiorno, Kathleen E. +30 more·2019·Nature
DOI 10.1038/s41586-019-1130-6PMC PMC6565370
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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 biology 1,2. 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 resistance 3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis 8-10, 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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  • Production of TGFβ, LIF, GAS6, FGF5, GDF15 and HGF promotes invasive and proliferative behaviour in cancer cells.

    “The production of TGFβ, leukaemia inhibitory factor (LIF), growth arrest-specific protein 6 (GAS6), fibroblast growth factor 5 (FGF5), growth differentiation factor 15 (GDF15) and hepatocyte growth factor (HGF) promotes invasive and proliferative behaviour in cancer cells52,109–112.”

    From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [109]

    The paper’s main text (indexed as Abstract; page unavailable) identifies stellate-cell-produced LIF as a paracrine factor that promotes pancreatic cancer progression, and reports reduced epithelial–mesenchymal transition markers after LIF blockade. It does not establish that LIF promotes both invasive and proliferative behaviour in cancer cells; in the reported chemotherapy experiment, LIF blockade was accompanied by increased cancer-cell proliferation. In this multi-citation sentence, the paper supports the LIF-related progression claim, not the full behavioural claim. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Shi, Y., Gao, W., Lytle, N. K., Huang, P., Yuan, X., Dann, A. M., Ridinger-Saison, M., DelGiorno, K. E., Antal, C. E., Liang, G., Atkins, A. R., Erikson, G., Sun, H., Meisenhelder, J., Terenziani, E., Woo, G., Fang, L., Santisakultarm, T. P., Manor, U., Xu, R., Becerra, C. R., Borazanci, E., Von Hoff, D. D., Grandgenett, P. M., Hollingsworth, M. A., Leblanc, M., Umetsu, S. E., Collisson, E. A., Scadeng, M., Lowy, A. M., Donahue, T. R., Reya, T., Downes, M., Evans, R. M., Wahl, G. M., Pawson, T., Tian, R., & Hunter, T.
Affiliations
  • Salk Institute for Biological Studies (US)
  • Southern University of Science and Technology (CN)
  • University of California San Diego (US)
  • Hong Kong Baptist University (HK)
  • University of California, Los Angeles (US)
  • ShenZhen People’s Hospital (CN)
  • Baylor University Medical Center (US)
  • Translational Genomics Research Institute (US)
  • Fred and Pamela Buffett Cancer Center (US)
  • University of California, San Francisco (US)
  • Mount Sinai Hospital (CA)
Corresponding author
  • Shi, Yu
  • Tian, Ruijun
  • Hunter, Tony
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2019-04-17
Volume
569
Issue
7754
Pages
131-135
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-019-1130-6
PMC
PMC6565370
OpenAlex
W2936366750
Cited by
431
References
9
Citations by year
2026: 30 · 2025: 50 · 2024: 62 · 2023: 60 · 2022: 77 · 2021: 76 · 2020: 58 · 2019: 18
FWCI
23.93
Type
journal article
Language
en
Update notices
correction (2021-11-30)
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Cancer Institute (R01CA186043, R01CA178015, R01CA155620, F31CA206416, F32CA217033, P50CA127297, R01CA080100, R35CA197687, R01CA082683, R01CA222862, P30CA014195, U01CA210240, P30CA036727, R35CA197699, R50CA211462, R01CA227807)
  • National Institute of General Medical Sciences (T32GM007752)
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
pancreatic ductal adenocarcinoma, leukemia inhibitory factor, pancreatic stellate cells, paracrine signaling, tumor microenvironment, tumor stroma, epithelial-mesenchymal transition, tumor cell differentiation, chemoresistance, circulating biomarkers, tumor progression, secretome, tumor response monitoring
MeSH terms
Animals, Antibodies, Monoclonal, Cell Differentiation, Female, Humans, Male, Pancreatic Neoplasms, Mass Spectrometry, Disease Progression, Drug Resistance, Neoplasm, Paracrine Communication, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Mice, Leukemia Inhibitory Factor, Receptors, OSM-LIF, Epithelial-Mesenchymal Transition, Tumor Microenvironment, Carcinogenesis

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