MET/HGF Co-Targeting in Pancreatic Cancer: A Tool to Provide Insight into the Tumor/Stroma Crosstalk

Abstract

The 'onco-receptor' MET (Hepatocyte Growth Factor Receptor) is involved in the activation of the invasive growth program that is essential during embryonic development and critical for wound healing and organ regeneration during adult life. When aberrantly activated, MET and its stroma-secreted ligand HGF (Hepatocyte Growth Factor) concur to tumor onset, progression, and metastasis in solid tumors, thus representing a relevant target for cancer precision medicine. In the vast majority of tumors, wild-type MET behaves as a 'stress-response' gene, and relies on ligand stimulation to sustain cancer cell 'scattering', invasion, and protection form apoptosis. Moreover, the MET/HGF axis is involved in the crosstalk between cancer cells and the surrounding microenvironment. Pancreatic cancer (namely, pancreatic ductal adenocarcinoma, PDAC) is an aggressive malignancy characterized by an abundant stromal compartment that is associated with early metastases and resistance to conventional and targeted therapies. Here, we discuss the role of the MET/HGF axis in tumor progression and dissemination considering as a model pancreatic cancer, and provide a proof of concept for the application of dual MET/HGF inhibition as an adjuvant therapy in pancreatic cancer patients.

Keywords: HGF; MET; metastasis; pancreatic cancer; target therapy; tumor microenvironment.

Figure 1

Schematic structure of MET and HGF. (A) MET structure. SEMA, a seven-bladed β-propeller domain shared with Semaphorins and Plexins; PSI, a cysteine-rich domain present also in Plexins, Semaphorins, and Integrins; IPT, four immunoglobulin-like domains present also in Plexins and Transcription factors; JM, juxtamembrane domain, a region containing residues that act as negative regulators of the kinase activity; TK, tyrosine kinase domain endowed with enzymatic activity; tail, a C-terminal domain containing the multifunctional docking site. In green the α-chain, in brown the β-chain of MET. The grey line represents the cell membrane. (B) HGF structure. HL, hairpin loop; K1–K4, kringle domains; SPH, serine-protease homology domain, devoid of protease activity. In blue the α-chain, in red the β-chain of HGF. S-S, disulphide bond linking the α- and β-chains of the two molecules.

Figure 2

MET signaling in the physiological context. Upon MET activation, signal-relay molecules are recruited to the receptor, resulting in activation of the MAPK (mitogen-activated protein kinase)/Akt signaling pathways. This process controls the genetic program known as ‘invasive growth’ that in the physiological context plays a pivotal role in embryogenesis and in tissue homeostasis during adult life. PI3K, phosphoinositide 3-kinase; GRB2, growth factor receptor-bound protein 2; STAT, signal transducer and activator of transcription protein; GAB1, GRB2-associated-binding protein 1; PLC-γ, phospholipase Cγ1

Figure 3

The dynamic bidirectional tumor/stroma interaction. Cancer-associated fibroblasts (CAFs) secrete pro-HGF that is converted in the active mature form by enzymes acting in the tumor microenvironment. Tumor cells can influence CAF activity by mechanisms that have not yet been completely elucidated. The fibrotic components of the extracellular matrix are depicted in grey.

Figure 4

Concomitant MET/HGF targeting induces a reversion of the epithelial-to-mesenchymal transition (EMT) phenotype as well as a decrease of activated α-SMA positive fibroblasts in an orthotopic model of pancreatic cancer. HPAF-II cells were orthotopically injected in SCID mice genetically modified to secrete physiological levels of human HGF (hHGF knock-in); after 2 days, mice were divided into four groups and treated with vehicle, MvDN30 (10 mg/kg), decoyMET^K842E (10 mg/kg), or the combination of the two in a 1:1 ratio. Treatments were administered every 2 days by intraperitoneal injection. After 5 weeks of treatment, mice were sacrificed, and primary tumors were collected and processed for an immunofluorescence analysis. (A) E-cadherin and vimentin staining. Bar is 50 µm. (B) α-SMA staining. Bar is 50 µm.