• 3D bioprinting
• 3D precancer models
• biofabrication
• cancer inception
• cancer initiation
• early cancer lesions

• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/metabolism
• Humans
• Biotechnology
• Models, Biological
• Animals
• Tumor Microenvironment

• HGF
• NSCLC
• c-MET
• immunotherapy
• tumor microenvironment

• Humans
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/pathology
• Proto-Oncogene Proteins c-met/metabolism
• Tumor Microenvironment
• Hepatocyte Growth Factor/metabolism
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Signal Transduction
• Animals

• 82172716 the National Natural Science Foundation of China

• MET alterations
• cancer progression
• invasive growth
• therapeutic targeting

• 23820 Italian Association for Cancer Research
• 5109 Fondazione Umberto Veronesi

• phosphorylation
• oncogenes
• dna damage response
• proteomics
• double-strand dna breaks

• Humans
• Cell Cycle Proteins/genetics
• DNA/metabolism
• DNA Damage
• DNA-Activated Protein Kinase/genetics
• DNA-Activated Protein Kinase/metabolism
• Mitosis/genetics
• Phosphorylation
• Protein Serine-Threonine Kinases/metabolism

• 310030_197870 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)

• Humans
• Animals
• Mice
• Tyrosine Kinase Inhibitors
• Carrier Proteins
• Neoplasms
• CD8-Positive T-Lymphocytes
• Receptor Protein-Tyrosine Kinases
• Disease Models, Animal
• Cell Line, Tumor

• Exelixis, Inc.

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.

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.

hOA-DN30 efficiently impaired MET activation and the intracellular signalling cascade by dose and time dependent removal of the receptor from the cell surface (shedding). In vitro, the antibody suppressed cell growth by blocking cell proliferation and by concomitantly inducing cell death in multiple MET-addicted human tumor cell lines. In mice xenografts, hOA-DN30 induced an impressive reduction of tumor masses, with a wide therapeutic window. Moreover, the antibody showed high therapeutic efficacy against patient-derived xenografts generated from MET-addicted gastric tumors, leading to complete tumor regression and long-lasting effects after treatment discontinuation. Finally, hOA-DN30 showed a highly favorable pharmacokinetic profile and substantial tolerability in Cynomolgus monkeys.

hOA-DN30 unique ability to simultaneously erase cell surface MET and release the ‘decoy’ receptor extracellular region results in a paramount MET blocking action. Its remarkable efficacy in a large number of pre-clinical models, as well as its pharmacological features and safety profile in non-human primates, strongly envisage a successful clinical application of this novel single-arm MET therapeutic antibody for the therapy of MET-addicted cancers.

The online version contains supplementary material available at 10.1186/s13046-022-02320-6.

As an intelligent disease, tumors apply several pathways to evade the immune system. It can use alternative routes to bypass intracellular signaling pathways, such as nuclear factor-κB (NF-κB), Wnt, and mitogen-activated protein (MAP)/phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). Therefore, these mechanisms lead to therapeutic resistance in cancer. Also, these pathways play important roles in the proliferation, survival, migration, and invasion of cells. In most cancers, these signaling pathways are overactivated, caused by mutation, overexpression, etc. Since numerous molecules share these signaling pathways, the identification of key molecules is crucial to achieve favorable consequences in cancer therapy. One of the key molecules is the mesenchymal-epithelial transition factor (MET; c-Met) and its ligand hepatocyte growth factor (HGF). Another molecule is the epithelial cell adhesion molecule (EpCAM), which its binding is hemophilic. Although both of them are involved in many physiologic processes (especially in embryonic stages), in some cancers, they are overexpressed on epithelial cells. Since they share intracellular pathways, targeting them simultaneously may inhibit substitute pathways that tumor uses to evade the immune system and resistant to therapeutic agents.

Head and neck cancer is the sixth most common cancer type worldwide, comprising tumors of the upper aero/digestive tract. Approximately 50% of these cancers originate in the oral cavity. Depending on disease stage, oral cancer patients are treated with single-modality surgery, or in combination with radiotherapy with or without chemotherapy. Despite advances in these modalities, the 5-year survival rate is merely 50%. Therefore, implementation of targeted therapies, directed against signaling molecules, has gained attention. One potential target is the MET protein, which can be present on the surface of cancer cells, orchestrating aggressive behavior. As cancer cells can shed the extracellular part of MET from their surface, it is important to identify for MET positive patients whether they possess the entire and/or only the intracellular part of the receptor to assess whether targeted therapies directed against the extracellular, intracellular, or both parts of MET need to be implemented.

The receptor tyrosine kinase MET has gained attention as a therapeutic target. Although MET immunoreactivity is associated with progressive disease, use of targeted therapies has not yet led to major survival benefits. A possible explanation is the lack of companion diagnostics (CDx) that account for proteolytic processing. During presenilin-regulated intramembrane proteolysis, MET’s ectodomain is shed into the extracellular space, which is followed by γ-secretase-mediated cleavage of the residual membranous C-terminal fragment. The resulting intracellular fragment is degraded by the proteasome, leading to downregulation of MET signaling. Conversely, a membrane-bound MET fragment lacking the ectodomain (MET-EC^-) can confer malignant potential. Use of C- and N-terminal MET monoclonal antibodies (moAbs) has illustrated that MET-EC^- occurs in transmembranous C-terminal MET-positive oral squamous cell carcinoma (OSCC). Here, we propose that ectodomain shedding, resulting from G-protein-coupled receptor transactivation of epidermal growth factor receptor signaling, and/or overexpression of ADAM10/17 and/or MET, stabilizes and possibly activates MET-EC^- in OSCC. As MET-EC^- is associated with poor prognosis in OSCC, it potentially has impact on the use of targeted therapies. Therefore, MET-EC^- should be incorporated in the design of CDx to improve patient stratification and ultimately prolong survival. Hence, MET-EC^- requires further investigation seen its oncogenic and predictive properties.

• GPCR and EGFR signaling
• MET
• biomarker
• ectodomain shedding
• malignant potential
• oral squamous cell carcinoma
• patient stratification
• prognosis
• receptor tyrosine kinase
• targeted therapies (moAbs and TKIs)

• 81602070 National Natural Science Foundation of China
• 81802452 National Natural Science Foundation of China
• 82073302 National Natural Science Foundation of China
• 2019M653216 China Postdoctoral Science Foundation

• Pancreatic adenocarcinoma (PAAD)
• cancer stem cell (CSC)
• international cancer genome consortium (ICGC)
• prognosis
• the cancer genome atlas (TCGA)
• weighted gene correlation network analysis (WGCNA)

• Adenocarcinoma/diagnosis
• Adenocarcinoma/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplastic Stem Cells/pathology
• Nomograms
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/genetics
• Prognosis
• Pancreatic Neoplasms

Background: Cancer stem cells (CSCs), which are characterized by self-renewal and plasticity, are highly correlated with tumor metastasis and drug resistance. To fully understand the role of CSCs in colorectal cancer (CRC), we evaluated the stemness traits and prognostic value of stemness-related genes in CRC.

Methods: In this study, the data from 616 CRC patients from The Cancer Genome Atlas (TCGA) were assessed and subtyped based on the mRNA expression-based stemness index (mRNAsi). The correlations of cancer stemness with the immune microenvironment, tumor mutational burden (TMB), and N6-methyladenosine (m6A) RNA methylation regulators were analyzed. Weighted gene co-expression network analysis (WGCNA) was performed to identify the crucial stemness-related genes and modules. Furthermore, a prognostic expression signature was constructed using the Lasso-penalized Cox regression analysis. The signature was validated via multiplex immunofluorescence staining of tissue samples in an independent cohort of 48 CRC patients.

Results: This study suggests that high-mRNAsi scores are associated with poor overall survival in stage IV CRC patients. Moreover, the levels of TMB and m6A RNA methylation regulators were positively correlated with mRNAsi scores, and low-mRNAsi scores were characterized by increased immune activity in CRC. The analysis identified 34 key genes as candidate prognosis biomarkers. Finally, a three-gene prognostic signature (PARPBP, KNSTRN, and KIF2C) was explored together with specific clinical features to construct a nomogram, which was successfully validated in an external cohort.

Conclusion: There is a unique correlation between CSCs and the prognosis of CRC patients, and the novel biomarkers related to cell stemness could accurately predict the clinical outcomes of these patients.

• N6-methyladenosine
• cancer stem cell
• colorectal cancer
• machine learning
• tumor immune microenvironment

• Carcinoma, Squamous Cell/pathology
• Chemoradiotherapy
• Combined Modality Therapy
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/therapy
• Humans
• Neoplasm Recurrence, Local

• P30 CA008748 NCI NIH HHS
• NIH

• Amatuximab
• C-MET
• Cancer stem cell
• Mesothelin
• Pancreatic cancer
• Peritoneal metastasis
• pMET

• Animals
• Antibodies, Monoclonal/administration & dosage
• Antibodies, Monoclonal/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/prevention & control
• Carcinoma, Pancreatic Ductal/secondary
• Cell Adhesion/drug effects
• Cell Aggregation/drug effects
• Cell Division/drug effects
• Cell Movement/drug effects
• Cell Self Renewal/drug effects
• Deoxycytidine/administration & dosage
• Deoxycytidine/analogs & derivatives
• Deoxycytidine/pharmacology
• Drug Resistance, Neoplasm/drug effects
• Drug Synergism
• Female
• GPI-Linked Proteins/antagonists & inhibitors
• GPI-Linked Proteins/biosynthesis
• GPI-Linked Proteins/genetics
• GPI-Linked Proteins/immunology
• Humans
• Mesothelin
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Proteins/antagonists & inhibitors
• Neoplasm Proteins/biosynthesis
• Neoplasm Proteins/genetics
• Neoplasm Proteins/immunology
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/pathology
• Organ Size/drug effects
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/pathology
• Peritoneal Neoplasms/prevention & control
• Peritoneal Neoplasms/secondary
• Peritoneum/drug effects
• Peritoneum/metabolism
• Peritoneum/pathology
• Peritonitis/drug therapy
• Peritonitis/pathology
• Gemcitabine
• Pancreatic Neoplasms

The 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 (MET addiction). More frequently, ligand stimulation of wild-type MET contributes to progression toward metastasis (MET expedience). Thus, while MET inhibitors alone are effective in the first case, combination therapy with ligand inhibitors is required in the second condition.

In 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 single chain Fab derived from the DN30 MET antibody with a recombinant ‘ad-hoc’ engineered MET extracellular domain (decoyMET), encompassing the HGF binding site but lacking the DN30 epitope.

The hybrid molecules correctly bind MET and HGF, inhibit HGF-induced MET downstream signaling, and quench HGF-driven biological responses, such as growth, motility and invasion, in cancer cells of different origin. Two metastatic models were generated in mice knocked-in by the human HGF gene: (i) orthotopic transplantation of pancreatic cancer cells; (ii) subcutaneous injection of primary cells derived from a cancer of unknown primary. Treatment with hybrid molecules strongly affects time of onset, number, and size of metastatic lesions.

These results provide a strategy to treat metastatic dissemination driven by the HGF/MET axis.

The online version contains supplementary material available at 10.1186/s13046-020-01822-5.

• Fusion proteins
• HGF
• MET
• Metastasis
• Targeted therapy

• Adipokines
• Cancer cell plasticity
• Cancer stem cells (CSCs)
• Cellular crosstalk
• Drug resistance
• HGF/c-Met signalling
• Hepatokines
• Immune escape
• Inflammation
• Mesenchymal stem cells (MSCs)
• Metabolic stress
• Metastasis
• Neo-angiogenesis
• Tumor heterogeneity
• Tumor microenvironment (TME)

• Crizotinib
• MET mutation
• Next-generation sequencing
• Non-small cell lung cancer
• Targeted therapy

• Biological evaluation
• Cu-catalyzed three-component reaction
• Docking study
• N-Sulfonylamidine
• c-Met inhibitors

• HGF
• MET
• glioblastoma
• mesenchymal subtype
• tumor-associated macrophages

Membrane-anchored full-length MET stimulated by its ligand HGF/SF induces various biological responses, including survival, growth, and invasion. This panel of responses, referred to invasive growth, is required for embryogenesis and tissue regeneration in adults. On the contrary, MET deregulation is associated with tumorigenesis in many kinds of cancer. In addition to its well-documented ligand-stimulated downstream signaling, the receptor can be cleaved by proteases such as secretases, caspases, and calpains. These cleavages are involved either in MET receptor inactivation or, more interestingly, in generating active fragments that can modify cell fate. For instance, MET fragments can promote cell death or invasion. Given a large number of proteases capable of cleaving MET, this receptor appears as a prototype of proteolytic-cleavage-regulated receptor tyrosine kinase. In this review, we describe and discuss the mechanisms and consequences, both physiological and pathological, of MET proteolytic cleavages.

• antibody-drug conjugate
• c-Met
• hepatocellular carcinoma
• oxaliplatin
• targeted chemotherapy

Since its first documentation, breast cancer (BC) has been a conundrum that ails millions of women every year. This cancer has been well studied by researchers all over the world, which has improved the patient outcome significantly. There are many diagnostic markers to identify the disease, but early detection and then subclassification of this cancer remain dubious. Even after the correct diagnosis, more than half the patients come back with a more aggressive and metastatic tumor. The underpinning mechanism that governs the resistance includes over-amplification of receptors, mutations in key gene targets, and activation of different signaling. A plethora of drugs have been devised that have shown promising results in clinical settings. However, in recent times, the role played by cancer stem cells in disease progression and their interaction in mediating the resistance to cellular insults have come into the limelight. As breast cancer stem cells (BCSCs) are dormant in nature, it is highly likely that they fail to directly respond to the cytotoxic drugs which are meant for ablating rapidly proliferating cells. Furthermore, the absence of well-characterized, drug-able surface markers to date, has limited the application of targeted therapies in complete eradication of the disease. In this review, our intent is to discuss versatile therapeutics in practice followed by discussing the upcoming therapy strategies in the pipeline for BC. Furthermore, we focus on the roles played by BCSCs in mediating the resistance, and therefore, the aspects of new therapeutics against BCSCs under development that may ease the burden in future has also been discussed.

• BCSC
• TRAIL therapy
• breast cancer
• cancer stem cell
• chemoresistance
• conventional therapies
• tumor microenvironment

• 6,7-Dimethoxy-4-anilinoquinoline
• antitumour
• c-Met
• inhibitor
• synthesis

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.

• HGF
• MET
• metastasis
• pancreatic cancer
• target therapy
• tumor microenvironment

• angiogenesis
• endothelial cell
• fatty acid synthase
• lipids
• mTOR
• mTORC1
• malonyl-CoA
• metabolism
• post-translational modifications
• protein malonylation

Hepatocyte growth factor (HGF) is the ligand for the tyrosine kinase receptor c-Met (Mesenchymal Epithelial Transition Factor also known as Hepatocyte Growth Factor Receptor, HGFR), a receptor with expression throughout epithelial and endothelial cell types. Activation of c-Met enhances cell proliferation, invasion, survival, angiogenesis, and motility. The c-Met pathway also stimulates tissue repair in normal cells. A body of past research shows that increased levels of HGF and/or overexpression of c-Met are associated with poor prognosis in several solid tumors, including lung cancer, as well as cancers of the head and neck, gastro-intestinal tract, breast, ovary and cervix. The HGF/c-Met signaling network is complex; both ligand-dependent and ligand-independent signaling occur. This article will provide an update on signaling through the HGF/c-Met axis, the mechanism of action of HGF/c-Met inhibitors, the lung cancer patient populations most likely to benefit, and possible mechanisms of resistance to these inhibitors. Although c-Met as a target in non-small cell lung cancer (NSCLC) showed promise based on preclinical data, clinical responses in NSCLC patients have been disappointing in the absence of MET mutation or MET gene amplification. New therapeutics that selectively target c-Met or HGF, or that target c-Met and a wider spectrum of interacting tyrosine kinases, will be discussed.

• c-Met (mesenchymal epithelial transition factor or hepatocyte growth factor receptor)
• hepatocyte growth factor (HGF)
• lung cancer
• targeted therapy

• Cell Survival/genetics
• Clonal Evolution/genetics
• Humans
• Molecular Targeted Therapy
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplastic Stem Cells/metabolism
• Oncogene Addiction/genetics
• Oncogenes
• Protein Kinase Inhibitors/therapeutic use
• Proto-Oncogene Proteins c-met/genetics
• Proto-Oncogene Proteins c-met/metabolism
• Stromal Cells/metabolism

• Gastric cancer
• c-Met
• hepatocyte growth factor (HGF)
• molecular targeted therapy
• personalized medicine

• Diels et Gilg
• Epithelial mesenchymal transition
• Hepatocyte growth factor
• Isoquercitrin

• MET oncogene
• MET target therapy
• anti-HGF therapy
• antibodies
• decoy

Given the difficulty in obtaining adequate tissue in NSCLC, we investigated the utility of circulating tumor cells (CTCs) for MET status assessment in NSCLC patients. We used two platforms for CTC capture, and assessed MET expression in CTCs and matched-bronchial biopsies in patients with advanced-stage III/IV lung adenocarcinoma. Baseline peripheral blood was collected from 256 advanced-stage III/IV NSCLC patients from Genentech clinical trials, and from 106 patients with advanced-stage III/IV lung adenocarcinoma treated at the Department of Pneumology, Pasteur Hospital, Nice. CTCs were enriched using CellSearch (Genentech), or ISET technologies (Pasteur Hospital). MET expression was evaluated by immunofluorescence on CellSearch, and by immunocytochemistry on ISET-enriched CTCs and on matched FFPE tissue sections (Pasteur Hospital). CTCs were detected in 83 of 256 (32%) patients evaluated on CellSearch, with 30 samples (12%) exhibiting ≥ 5 CTCs/7.5 ml blood. On ISET, CTC were observed in 80 of 106 patients (75%), and 79 patients (75%) exhibited ≥ 5 CTCs/4 ml blood. MET expression on ISET CTCs was positive in 72% of cases, and the MET expression on matched-patient tissue was positive in 65% patients using the Onartuzumab IHC scoring algorithm (93% concordance). Quantification of MET expression using H-scores showed strong correlation between MET expression in tissue and CTCs (Spearman correlation, 0.93). MET status in CTCs isolated on ISET filters from blood samples of advanced-stage NSCLC patients correlated strongly with MET status in tumor tissue, illustrating the potential for using CTCs as a non-invasive, real-time biopsy to determine MET status of patients entering clinical trials.

• MET protein expression
• NSCLC
• circulating tumor cells
• immunocytochemistry
• targeted therapy

• 3D simulation
• Cancer modeling
• Computational simulation
• Desmoplasia
• Mathematical modeling
• Nonlinear model
• Vascular tumor

• Animals
• Blood Vessels/growth & development
• Blood Vessels/metabolism
• Cell Communication
• Cells/metabolism
• Connective Tissue/metabolism
• Extracellular Matrix/metabolism
• Fibroblasts/metabolism
• Humans
• Lymphoid Tissue/growth & development
• Lymphoid Tissue/metabolism
• Models, Biological
• Neoplasms/blood supply
• Neoplasms/pathology
• Stromal Cells/metabolism
• Vascular Remodeling

• R01 CA180149 NCI NIH HHS
• R15 CA203605 NCI NIH HHS
• U54 CA143907 NCI NIH HHS

Colon cancer is one of the leading causes of cancer-related deaths worldwide, despite recent advances in clinical oncology. Accumulating evidence sheds light on the existence of cancer stem cells and their role in conferring therapeutic resistance. Cancer stem cells are a minor fraction of cancer cells, which enable tumor heterogeneity and initiate tumor formation. In addition, these cells are resistant to various cytotoxic factors. Therefore, elimination of cancer stem cells is difficult but essential to cure the malignant foci completely. Herein, we review the recent evidence for intestinal stem cells and colon cancer stem cells, methods to detect the tumor-initiating cells, and clinical significance of cancer stem cell markers. We also describe the emerging problems of cancer stem cell theory, including bidirectional conversion and intertumoral heterogeneity of stem cell phenotype.

• bidirectional conversion
• cancer stem cell
• colon cancer
• epigenetics
• genetics
• intestinal stem cell
• tumor heterogeneity

• angiogenesis
• asparagine
• endothelial cell
• glutamine
• metabolism

Targeted therapeutic agents, such as inhibitors of epithelial growth factor receptor (EGFR), have transformed the management of non-small cell lung cancer (NSCLC) patients. MET-amplified NSCLC cells display resistance to EGFR-targeting agents, but are addicted to MET signaling for survival and proliferation and are sensitive to MET inhibition. However, responsive cancer cells invariably develop resistance to MET-targeted treatment.

The tumor microenvironment plays a major role in resistance to anticancer therapy. We demonstrated that fibroblasts block the response of MET-amplified NSCLC cells to the MET kinase inhibitor, JNJ38877605 in an HGF-dependent manner. Thus, MET-amplified NSCLC cells become addicted to HGF upon pharmacological inhibition of MET. HGF restored phosphorylation of MET, EGFR and RON, and maintained pro-survival AKT and ERK signaling in MET-inhibited cells.

We developed a small molecule inhibitor of pro-HGF activation, SRI31215, which acts as a triplex inhibitor of the pro-HGF activating proteases matriptase, hepsin and HGF activator (HGFA). SRI31215 blocked crosstalk between tumor cells and fibroblasts and overcame fibroblast-mediated resistance to MET inhibition by preventing fibroblast-mediated reactivation of AKT and ERK signaling. Structurally unrelated triplex inhibitors of matriptase, hepsin and HGFA that we developed in parallel showed similar biological activity.

Our data suggest that simultaneous inhibition of HGF and MET is required to overcome resistance to MET inhibitors in MET-amplified NSCLC cells. This provides a rationale for the development of novel combination therapeutic strategies for the treatment of NSCLC patients with MET amplification.

• HGF
• MET
• NSCLC

• MET
• cancer stem cell (CSC)
• epithelial-mesenchymal transition (EMT)

• ADAM10 Protein/antagonists & inhibitors
• ADAM10 Protein/physiology
• ADAM17 Protein/antagonists & inhibitors
• ADAM17 Protein/physiology
• Antineoplastic Agents/metabolism
• Antineoplastic Agents/pharmacology
• Body Fluids/chemistry
• Drug Design
• Drug Resistance, Neoplasm/physiology
• Enzyme Activation
• Humans
• Immunotherapy
• Macrophages/metabolism
• Molecular Targeted Therapy
• Neoplasm Proteins/analysis
• Neoplasm Proteins/antagonists & inhibitors
• Neoplasm Proteins/physiology
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Neoplasms/physiopathology
• Peptide Fragments/analysis
• Peptide Fragments/metabolism
• Protein Domains
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Proteolysis/drug effects
• Receptors, Cell Surface/metabolism
• Substrate Specificity
• Tissue Inhibitor of Metalloproteinases/physiology
• Tumor Microenvironment

• K99 CA207744 NCI NIH HHS
• R01 CA096504 NCI NIH HHS
• U54 CA112967 NCI NIH HHS

• MET receptor
• Resistance
• Récepteur MET
• Résistance primaire
• Résistance secondaire
• TKI
• Targeted therapy
• Thérapie ciblée

• HGF-dependant and independent tumors
• bivalent humanized antibody
• c-Met
• cancer

• MET oncogene
• glioblastoma
• glioblastoma stem‐like cells
• radiosensitization
• radiotherapy

• Animals
• Ataxia Telangiectasia Mutated Proteins/metabolism
• Aurora Kinase A/metabolism
• Cell Survival
• Cyclin-Dependent Kinase Inhibitor p21/metabolism
• DNA Repair
• Glioblastoma/radiotherapy
• Heterografts
• Humans
• Mice
• Oncogene Protein v-akt/metabolism
• Proto-Oncogene Proteins c-met/antagonists & inhibitors
• Stem Cells/physiology
• Stem Cells/radiation effects

• G-quadruplex structure
• MET promoter
• TMPyP4
• anticancer treatment

• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• G-Quadruplexes/drug effects
• Hep G2 Cells
• Humans
• Neoplasms/genetics
• Nucleic Acid Conformation/drug effects
• Porphyrins/pharmacology
• Promoter Regions, Genetic/drug effects
• Proto-Oncogene Proteins c-met/chemistry
• Proto-Oncogene Proteins c-met/genetics
• Sp1 Transcription Factor/metabolism