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

AUTHORS

Shi YYu , Gao WWeina , Lytle NKNikki K , Huang PPeiwu , Yuan XXiao , Dann AMAmanda M , Ridinger-Saison MMaya , DelGiorno KEKathleen E , Antal CECorina E , Liang GGaoyang , Atkins ARAnnette R , Erikson GGalina , Sun HHuaiyu , Meisenhelder JJill , Terenziani EElena , Woo GGyunghwi , Fang LLinjing , Santisakultarm TPThom P , Manor UUri , Xu RRuilian , Becerra CRCarlos R , Borazanci EErkut , Von Hoff DDDaniel D , Grandgenett PMPaul M , Hollingsworth MAMichael A , Leblanc MMathias , Umetsu SESarah E , Collisson EAEric A , Scadeng MMiriam , Lowy AMAndrew M , Donahue TRTimothy R , Reya TTannishtha , Downes MMichael , Evans RMRonald M , Wahl GMGeoffrey M , Pawson TTony , Tian RRuijun , Hunter TTony . Nature. 2019 4 17; 569(7754). 131-135

PMID: 30996350[PubMed].

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. 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. Furthermore, PSC activation occurs very early during PDAC tumorigenesis, 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.

Tags: 2019