0000000001107590
AUTHOR
Cristina Basilico
HGF/MET Axis Induces Tumor Secretion of Tenascin-C and Promotes Stromal Rewiring in Pancreatic Cancer
Simple Summary It has been previously shown that activation of the MET receptor by its ligand, the hepatocyte growth factor (HGF), modulates the tumor-stroma cross-talk in models of pancreatic cancer. We now wish to cast light on the molecular mechanisms by which this ligand/receptor pair sustains the interaction between cancer cells and the tumor microenviroment. To this end, we compared data obtained by large-scale analysis of gene expression in pancreatic cancer cells grown in the presence of HGF versus cells grown in the presence of HGF and treated with specific inhibitors of HGF/MET signaling. By clustering differentially expressed genes according to functional groups, we identified ca…
Targeting the MET oncogene by concomitant inhibition of receptor and ligand via an antibody-"decoy" strategy
MET, a master gene sustaining "invasive growth," is a relevant target for cancer precision therapy. In the vast majority of tumors, wild-type MET behaves as a "stress-response" gene and relies on the ligand (HGF) to sustain cell "scattering," invasive growth and apoptosis protection (oncogene "expedience"). In this context, concomitant targeting of MET and HGF could be crucial to reach effective inhibition. To test this hypothesis, we combined an anti-MET antibody (MvDN30) inducing "shedding" (i.e., removal of MET from the cell surface), with a "decoy" (i.e., the soluble extracellular domain of the MET receptor) endowed with HGF-sequestering ability. To avoid antibody/decoy interaction-and …
Additional file 7 of A receptor-antibody hybrid hampering MET-driven metastatic spread
Additional file 7: Supplementary Fig. 7. Serum concentration of AbDec-L1 after single i.v. administration to Sprague Dawley rats at different time points.
Additional file 3 of A receptor-antibody hybrid hampering MET-driven metastatic spread
Additional file 3: Supplementary Fig. 3. IVIS images of lungs excised from hHGF-ki mice that received intra-pancreatic injection of HPAF-II cells.
Additional file 2 of hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of ‘MET-addicted’ cancers
Additional file 2.
Additional file 6 of A receptor-antibody hybrid hampering MET-driven metastatic spread
Additional file 6: Supplementary Fig. 6. Analysis of CL-901 primary tumors treated with AbDec-L1.
Additional file 2 of A receptor-antibody hybrid hampering MET-driven metastatic spread
Additional file 2: Supplementary Fig. 2. IVIS images of livers excised from hHGF-ki mice that received intra-pancreatic injection of Capan-1 cells.
MET/HGF Co-Targeting in Pancreatic Cancer: A Tool to Provide Insight into the Tumor/Stroma Crosstalk
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. …
Additional file 1 of hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of ‘MET-addicted’ cancers
Additional file 1.
Additional file 3 of hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of ‘MET-addicted’ cancers
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Additional file 5 of A receptor-antibody hybrid hampering MET-driven metastatic spread
Additional file 5: Supplementary Fig. 5. IVIS images of organs excised from hHGF-ki mice that received sub-cuteaneous injection of CL-901 cells.
Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody
The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist antibody (DN30) inducing the physical removal of the receptor from the cell surface and resulting in suppression of the biological responses to MET. In its bivalent form, the antibody displayed a residual agonist activity, due to dimerization of the lingering receptors, and partial activation of the downstream signaling cascade. The balance between the two opposing activities is variable in different…
Additional file 4 of A receptor-antibody hybrid hampering MET-driven metastatic spread
Additional file 4: Supplementary Fig. 4. Immunohistochemical analysis of MET phosphorylation in pancreatic primary tumors treated with AbDec-L1.
Additional file 1 of A receptor-antibody hybrid hampering MET-driven metastatic spread
Additional file 1: Supplementary Fig. 1. IVIS analysis of primary tumors excised from mice that received intra-pancreatic injections of Capan-1 or HPAF-II pancreatic cancer cells.
A receptor-antibody hybrid hampering MET-driven metastatic spread
AbstractBackgroundThe receptor encoded by the MET oncogene and its ligand Hepatocyte Growth Factor (HGF) are at the core of the invasive-metastatic behavior. In a number of instances genetic alterations result in ligand-independent onset of malignancy (METaddiction). More frequently, ligand stimulation of wild-type MET contributes to progression toward metastasis (METexpedience). Thus, while MET inhibitors alone are effective in the first case, combination therapy with ligand inhibitors is required in the second condition.MethodsIn this paper, we generated hybrid molecules gathering HGF and MET inhibitory properties. This has been achieved by ‘head-to-tail’ or ‘tail-to-head’ fusion of a sin…
hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of ‘MET-addicted’ cancers
Abstract Background The tyrosine kinase receptor encoded by the MET oncogene is a major player in cancer. When MET is responsible for the onset and progression of the transformed phenotype (MET-addicted cancers), an efficient block of its oncogenic activation results in potent tumor growth inhibition. Methods Here we describe a molecular engineered MET antibody (hOA-DN30) and validate its pharmacological activity in MET-addicted cancer models in vitro and in vivo. Pharmacokinetics and safety profile in non-human primates have also been assessed. Results hOA-DN30 efficiently impaired MET activation and the intracellular signalling cascade by dose and time dependent removal of the receptor fr…