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

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.

• Authors: 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 Von 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, Tony Hunter
• Journal: Nature (Nature) Vol. 569 Issue 7754 Pg. 131-135 (05 2019) ISSN: 1476-4687 [Electronic] England
• PMID: 30996350 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• LIF protein, human
• Leukemia Inhibitory Factor
• Lif protein, mouse
• Receptors, OSM-LIF

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology, therapeutic use)
• Carcinogenesis (genetics)
• Carcinoma, Pancreatic Ductal (diagnosis, drug therapy, pathology)
• Cell Differentiation (drug effects, immunology)
• Cell Line, Tumor
• Disease Progression
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition
• Female
• Humans
• Leukemia Inhibitory Factor (antagonists & inhibitors, blood, metabolism)
• Male
• Mass Spectrometry
• Mice
• Pancreatic Neoplasms (diagnosis, drug therapy, pathology)
• Paracrine Communication (drug effects)
• Receptors, OSM-LIF (deficiency, genetics, metabolism)
• Tumor Microenvironment