Faculty Collaboration Database

Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature 2019 May;569(7754):131-135

Date

04/19/2019

Pubmed ID

30996350

Pubmed Central ID

PMC6565370

DOI

10.1038/s41586-019-1130-6

Scopus ID

2-s2.0-85064686834 (requires institutional sign-in at Scopus site)   267 Citations

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.

Author List

Shi Y, Gao W, Lytle NK, Huang P, Yuan X, Dann AM, Ridinger-Saison M, DelGiorno KE, Antal CE, Liang G, Atkins AR, Erikson G, Sun H, Meisenhelder J, Terenziani E, Woo G, Fang L, Santisakultarm TP, Manor U, Xu R, Becerra CR, Borazanci E, Von Hoff DD, Grandgenett PM, Hollingsworth MA, Leblanc M, Umetsu SE, Collisson EA, Scadeng M, Lowy AM, Donahue TR, Reya T, Downes M, Evans RM, Wahl GM, Pawson T, Tian R, Hunter T

Author

Nikki K. Lytle PhD Assistant Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antibodies, Monoclonal
Carcinogenesis
Carcinoma, Pancreatic Ductal
Cell Differentiation
Cell Line, Tumor
Disease Progression
Drug Resistance, Neoplasm
Epithelial-Mesenchymal Transition
Female
Humans
Leukemia Inhibitory Factor
Male
Mass Spectrometry
Mice
Pancreatic Neoplasms
Paracrine Communication
Receptors, OSM-LIF
Tumor Microenvironment