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Article: An Observatory for the

Altintas, Dogus M / Comoglio, Paolo M

2023 Volume 15, Issue 18

Abstract: ... ...

Abstract	The
Language	English
Publishing date	2023-09-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15184672
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Article ; Online: Correction: hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of 'MET-addicted' cancers.

Martinelli, Ilaria / Modica, Chiara / Chiriaco, Cristina / Basilico, Cristina / Hughes, James M / Corso, Simona / Giordano, Silvia / Comoglio, Paolo M / Vigna, Elisa

Journal of experimental & clinical cancer research : CR

2022 Volume 41, Issue 1, Page(s) 180

Language	English
Publishing date	2022-05-24
Publishing country	England
Document type	Published Erratum
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-022-02398-y
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Article ; Online: MicroRNA 483-3p overexpression unleashes invasive growth of metastatic colorectal cancer via NDRG1 downregulation and ensuing activation of the ERBB3/AKT axis.

Candiello, Ermes / Reato, Gigliola / Verginelli, Federica / Gambardella, Gennaro / D Ambrosio, Antonio / Calandra, Noemi / Orzan, Francesca / Iuliano, Antonella / Albano, Raffaella / Sassi, Francesco / Luraghi, Paolo / Comoglio, Paolo M / Bertotti, Andrea / Trusolino, Livio / Boccaccio, Carla

Molecular oncology

2023 Volume 17, Issue 7, Page(s) 1280–1301

Abstract: ... cell cultures (m-colospheres), here we show that the overexpression of microRNA 483-3p (miRNA-483-3p; also known ... as MIR-483-3p), encoded by a frequently amplified gene locus, confers an aggressive phenotype. In m ... growth of miRNA-483-3p-overexpressing m-colospheres. In human colorectal tumors, miRNA-483-3p expression ...

Abstract	In colorectal cancer, the mechanisms underlying tumor aggressiveness require further elucidation. Taking advantage of a large panel of human metastatic colorectal cancer xenografts and matched stem-like cell cultures (m-colospheres), here we show that the overexpression of microRNA 483-3p (miRNA-483-3p; also known as MIR-483-3p), encoded by a frequently amplified gene locus, confers an aggressive phenotype. In m-colospheres, endogenous or ectopic miRNA-483-3p overexpression increased proliferative response, invasiveness, stem cell frequency, and resistance to differentiation. Transcriptomic analyses and functional validation found that miRNA-483-3p directly targets NDRG1, known as a metastasis suppressor involved in EGFR family downregulation. Mechanistically, miRNA-483-3p overexpression induced the signaling pathway triggered by ERBB3, including AKT and GSK3β, and led to the activation of transcription factors regulating epithelial-mesenchymal transition (EMT). Consistently, treatment with selective anti-ERBB3 antibodies counteracted the invasive growth of miRNA-483-3p-overexpressing m-colospheres. In human colorectal tumors, miRNA-483-3p expression inversely correlated with NDRG1 and directly correlated with EMT transcription factor expression and poor prognosis. These results unveil a previously unrecognized link between miRNA-483-3p, NDRG1, and ERBB3-AKT signaling that can directly support colorectal cancer invasion and is amenable to therapeutic targeting.
MeSH term(s)	Humans ; Proto-Oncogene Proteins c-akt/metabolism ; Down-Regulation/genetics ; Cell Line, Tumor ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Colorectal Neoplasms/pathology ; Colonic Neoplasms/genetics ; Transcription Factors/metabolism ; Rectal Neoplasms/genetics ; Epithelial-Mesenchymal Transition/genetics ; Gene Expression Regulation, Neoplastic ; Cell Movement/genetics ; Neoplasm Invasiveness/genetics
Chemical Substances	Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; MicroRNAs ; Transcription Factors ; MIRN483 microRNA, human
Language	English
Publishing date	2023-03-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.13408
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Article ; Online: MET∆14 promotes a ligand-dependent, AKT-driven invasive growth.

Cerqua, Marina / Botti, Orsola / Arigoni, Maddalena / Gioelli, Noemi / Serini, Guido / Calogero, Raffaele / Boccaccio, Carla / Comoglio, Paolo M / Altintas, Dogus M

Life science alliance

2022 Volume 5, Issue 10

Abstract: ... ...

Abstract	MET
MeSH term(s)	Humans ; Ligands ; Oncogenes ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-met/genetics ; Proto-Oncogene Proteins c-met/metabolism
Chemical Substances	Ligands ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2022-05-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202201409
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Article ; Online: A receptor-antibody hybrid hampering MET-driven metastatic spread.

Modica, Chiara / Basilico, Cristina / Chiriaco, Cristina / Borrelli, Nicla / Comoglio, Paolo M / Vigna, Elisa

Journal of experimental & clinical cancer research : CR

2021 Volume 40, Issue 1, Page(s) 32

Abstract: Background: 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 ... ...

Abstract	Background: 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. Methods: 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. Results: 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. Conclusion: These results provide a strategy to treat metastatic dissemination driven by the HGF/MET axis.
MeSH term(s)	A549 Cells ; Animals ; Binding Sites, Antibody ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Female ; Hepatocyte Growth Factor/antagonists & inhibitors ; Hepatocyte Growth Factor/immunology ; Humans ; Immunoconjugates/immunology ; Immunoconjugates/pharmacology ; Immunoglobulin Fab Fragments/immunology ; Mice ; Mice, SCID ; Neoplasm Metastasis ; Neoplasms/drug therapy ; Neoplasms/immunology ; Proto-Oncogene Proteins c-met/antagonists & inhibitors ; Proto-Oncogene Proteins c-met/immunology ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/pharmacology ; Xenograft Model Antitumor Assays
Chemical Substances	HGF protein, human ; Immunoconjugates ; Immunoglobulin Fab Fragments ; Recombinant Proteins ; Hepatocyte Growth Factor (67256-21-7) ; MET protein, human (EC 2.7.10.1) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1)
Language	English
Publishing date	2021-01-14
Publishing country	England
Document type	Journal Article
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-020-01822-5
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Article ; Online: hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of 'MET-addicted' cancers.

Martinelli, Ilaria / Modica, Chiara / Chiriaco, Cristina / Basilico, Cristina / Hughes, James M / Corso, Simona / Giordano, Silvia / Comoglio, Paolo M / Vigna, Elisa

Journal of experimental & clinical cancer research : CR

2022 Volume 41, Issue 1, Page(s) 112

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 ... ...

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 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. Conclusions: 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.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Mice ; Proto-Oncogene Proteins c-met/metabolism ; Signal Transduction ; Stomach Neoplasms
Chemical Substances	Proto-Oncogene Proteins c-met (EC 2.7.10.1)
Language	English
Publishing date	2022-03-29
Publishing country	England
Document type	Journal Article
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-022-02320-6
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Article ; Online: Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy.

Comoglio, Paolo M / Trusolino, Livio / Boccaccio, Carla

Nature reviews. Cancer

2018 Volume 18, Issue 6, Page(s) 341–358

Abstract: The MET oncogene encodes an unconventional receptor tyrosine kinase with pleiotropic functions: it initiates and sustains neoplastic transformation when genetically altered ('oncogene addiction') and fosters cancer cell survival and tumour dissemination ... ...

Abstract	The MET oncogene encodes an unconventional receptor tyrosine kinase with pleiotropic functions: it initiates and sustains neoplastic transformation when genetically altered ('oncogene addiction') and fosters cancer cell survival and tumour dissemination when transcriptionally activated in the context of an adaptive response to adverse microenvironmental conditions ('oncogene expedience'). Moreover, MET is an intrinsic modulator of the self-renewal and clonogenic ability of cancer stem cells ('oncogene inherence'). Here, we provide the latest findings on MET function in cancer by focusing on newly identified genetic abnormalities in tumour cells and recently described non-mutational MET activities in stromal cells and cancer stem cells. We discuss how MET drives cancer clonal evolution and progression towards metastasis, both ab initio and under therapeutic pressure. We then elaborate on the use of MET inhibitors in the clinic with a critical appraisal of failures and successes. Ultimately, we advocate a rationale to improve the outcome of anti-MET therapies on the basis of thorough consideration of the entire spectrum of MET-mediated biological responses, which implicates adequate patient stratification, meaningful biomarkers and appropriate clinical end points.
MeSH term(s)	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
Chemical Substances	Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-met (EC 2.7.10.1)
Language	English
Publishing date	2018-04-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2062767-1
ISSN	1474-1768 ; 1474-175X
ISSN (online)	1474-1768
ISSN	1474-175X
DOI	10.1038/s41568-018-0002-y
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Article ; Online: MET, a driver of invasive growth and cancer clonal evolution under therapeutic pressure.

Boccaccio, Carla / Comoglio, Paolo M

Current opinion in cell biology

2014 Volume 31, Page(s) 98–105

Abstract: The MET oncogene, encoding the hepatocyte growth factor receptor, drives invasive growth, a genetic program largely overlapping with epithelial-mesenchymal transition, and governing physiological and pathological processes such as tissue development and ... ...

Abstract	The MET oncogene, encoding the hepatocyte growth factor receptor, drives invasive growth, a genetic program largely overlapping with epithelial-mesenchymal transition, and governing physiological and pathological processes such as tissue development and regeneration, as well as cancer dissemination. Recent studies show that MET enables cells to overcome damages inflicted by cancer anti-proliferative targeted therapies, radiotherapy or anti-angiogenic agents. After exposure to such therapies, clones of MET-amplified cancer cells arise within the context of genetically heterogeneous tumors and-exploiting an ample platform of signaling pathways-drive recurrence. In cancer stem cells, not only amplification, but also MET physiological expression, inherited from the cell of origin (a stem/progenitor), can contribute to tumorigenesis and therapeutic resistance, by sustaining the inherent self-renewing, self-preserving and invasive growth phenotype.
MeSH term(s)	Animals ; Clonal Evolution ; Humans ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/therapy ; Proto-Oncogene Proteins c-met/genetics ; Proto-Oncogene Proteins c-met/metabolism ; Signal Transduction
Chemical Substances	MET protein, human (EC 2.7.10.1) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1)
Language	English
Publishing date	2014-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1026381-0
ISSN	1879-0410 ; 0955-0674
ISSN (online)	1879-0410
ISSN	0955-0674
DOI	10.1016/j.ceb.2014.09.008
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Article ; Online: Reviving oncogenic addiction to MET bypassed by BRAF (G469A) mutation.

Virzì, Anna Rita / Gentile, Alessandra / Benvenuti, Silvia / Comoglio, Paolo M

Proceedings of the National Academy of Sciences of the United States of America

2018 Volume 115, Issue 40, Page(s) 10058–10063

Abstract: Cancer clonal evolution is based on accrual of driving genetic alterations that are expected to cooperate and progressively increase malignancy. Little is known on whether any genetic alteration can hinder the oncogenic function of a coexisting ... ...

Abstract	Cancer clonal evolution is based on accrual of driving genetic alterations that are expected to cooperate and progressively increase malignancy. Little is known on whether any genetic alteration can hinder the oncogenic function of a coexisting alteration, so that therapeutic targeting of the one can, paradoxically, revive the function of the other. We report the case of a driver oncogene (MET) that is not only bypassed, but also disabled by the mutation of a downstream transducer (BRAF), and reignited by inhibition of the latter. In a metastasis originated from a cancer of unknown primary (CUP), the MET oncogene was amplified eightfold, but unexpectedly, the kinase was dephosphorylated and inactive. As result, specific drugs targeting MET (JNJ-38877605) failed to inhibit growth of xenografts derived from the patient. In addition to MET amplification, the patient harbored, as sole proliferative driver, a mutation hyperactivating BRAF (G469A). Surprisingly, specific blockade of the BRAF pathway was equally ineffective, and it was accompanied by rephosphorylation of the amplified MET oncoprotein and by revived addiction to MET. Mechanistically, MET inactivation in the context of the BRAF-activating mutation is driven through a negative feedback loop involving inactivation of PP2A phosphatase, which in turn leads to phosphorylation on MET inhibitory Ser985. Disruption of this feedback loop allows PP2A reactivation, removing the inhibitory phosphorylation from Ser985 and thereby unleashing MET kinase activity. Evidence is provided for a mechanism of therapeutic resistance to single-oncoprotein targeting, based on reactivation of a genetic alteration functionally dormant in targeted cancer cells.
MeSH term(s)	A549 Cells ; Amino Acid Substitution ; Animals ; Humans ; Mice, Inbred NOD ; Mice, SCID ; Mutation, Missense ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Protein Phosphatase 2/genetics ; Protein Phosphatase 2/metabolism ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; Proto-Oncogene Proteins c-met/antagonists & inhibitors ; Proto-Oncogene Proteins c-met/genetics ; Proto-Oncogene Proteins c-met/metabolism ; Pyrazoles/pharmacology ; Pyridazines/pharmacology ; Xenograft Model Antitumor Assays
Chemical Substances	JNJ38877605 ; Pyrazoles ; Pyridazines ; MET protein, human (EC 2.7.10.1) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Protein Phosphatase 2 (EC 3.1.3.16)
Language	English
Publishing date	2018-09-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1721147115
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Article ; Online: Mutated axon guidance gene PLXNB2 sustains growth and invasiveness of stem cells isolated from cancers of unknown primary.

Brundu, Serena / Napolitano, Virginia / Franzolin, Giulia / Lo Cascio, Ettore / Mastrantonio, Roberta / Sardo, Gabriele / Cascardi, Eliano / Verginelli, Federica / Sarnataro, Sergio / Gambardella, Gennaro / Pisacane, Alberto / Arcovito, Alessandro / Boccaccio, Carla / Comoglio, Paolo M / Giraudo, Enrico / Tamagnone, Luca

EMBO molecular medicine

2023 Volume 15, Issue 3, Page(s) e16104

Abstract: The genetic changes sustaining the development of cancers of unknown primary (CUP) remain elusive. The whole-exome genomic profiling of 14 rigorously selected CUP samples did not reveal specific recurring mutation in known driver genes. However, by ... ...

Abstract	The genetic changes sustaining the development of cancers of unknown primary (CUP) remain elusive. The whole-exome genomic profiling of 14 rigorously selected CUP samples did not reveal specific recurring mutation in known driver genes. However, by comparing the mutational landscape of CUPs with that of most other human tumor types, it emerged a consistent enrichment of changes in genes belonging to the axon guidance KEGG pathway. In particular, G842C mutation of PlexinB2 (PlxnB2) was predicted to be activating. Indeed, knocking down the mutated, but not the wild-type, PlxnB2 in CUP stem cells resulted in the impairment of self-renewal and proliferation in culture, as well as tumorigenic capacity in mice. Conversely, the genetic transfer of G842C-PlxnB2 was sufficient to promote CUP stem cell proliferation and tumorigenesis in mice. Notably, G842C-PlxnB2 expression in CUP cells was associated with basal EGFR phosphorylation, and EGFR blockade impaired the viability of CUP cells reliant on the mutated receptor. Moreover, the mutated PlxnB2 elicited CUP cell invasiveness, blocked by EGFR inhibitor treatment. In sum, we found that a novel activating mutation of the axon guidance gene PLXNB2 sustains proliferative autonomy and confers invasive properties to stem cells isolated from cancers of unknown primary, in EGFR-dependent manner.
MeSH term(s)	Animals ; Humans ; Mice ; Axon Guidance ; ErbB Receptors/genetics ; Mutation ; Neoplasm Recurrence, Local ; Neoplasms, Unknown Primary/genetics ; Nerve Tissue Proteins/genetics ; Neoplastic Stem Cells/pathology
Chemical Substances	ErbB Receptors (EC 2.7.10.1) ; PLXNB2 protein, human ; Plxnb2 protein, mouse ; Nerve Tissue Proteins
Language	English
Publishing date	2023-02-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.202216104
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