|
1
|
Kashani-Ligumsky L, Scott O, Martinez G, Jeong A, Yin O, Shah S, Wang A, Zhu Y, Afshar Y. Updates and Knowledge Gaps in Placenta Accreta Spectrum Biology. Clin Obstet Gynecol 2025; 68:310-316. [PMID: 40257851 DOI: 10.1097/grf.0000000000000929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/23/2025]
Abstract
Placenta accreta spectrum (PAS) disorders have traditionally been characterized based on histopathologic grading, emphasizing the invasion of trophoblasts into the myometrium, and uterine serosa. Recent research has shifted the etiological understanding of PAS, moving away from the concept of aggressive trophoblast invasion to focusing on the critical role of scarred decidual-myometrial interface. This shift highlights the importance of defective scar tissue as a primary factor, reshaping prevention strategies, diagnostic accuracy, and treatment approaches for this increasingly prevalent iatrogenic and morbid pregnancy complication.
Collapse
Affiliation(s)
| | - Olivia Scott
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology
| | - Guadalupe Martinez
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology
| | - Anhyo Jeong
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology
| | - Ophelia Yin
- Division of Maternal Fetal Medicine and Reproductive Genetics, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California
| | - Sohum Shah
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology
| | - Amanda Wang
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology
| | - Yazhen Zhu
- California NanoSystems Institute, Crump Institute for Molecular Imaging
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles
| | - Yalda Afshar
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology
- Department of Pathology, David Geffen School of Medicine
- Molecular Biology Institute, University of California
| |
Collapse
|
|
2
|
Navon M, Ben-Shalom N, Dadiani M, Mor M, Yefet R, Bakalenik-Gavry M, Chat D, Balint-Lahat N, Barshack I, Tsarfaty I, Nili Gal-Yam E, Freund NT. Unique characteristics of autoantibodies targeting MET in patients with breast and lung cancer. JCI Insight 2025; 10:e187392. [PMID: 40401526 DOI: 10.1172/jci.insight.187392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 04/09/2025] [Indexed: 05/23/2025] Open
Abstract
The presence of B cells in tumors is correlated with favorable prognosis and efficient response to immunotherapy. While tumor-reactive antibodies have been detected in several cancer types, identifying antibodies that specifically target tumor-associated antigens remains a challenge. Here, we investigated the antibodies spontaneously elicited during breast and lung cancer that bind the cancer-associated antigen MET. We screened patients with lung (n = 25) and breast (n = 75) cancer and found that 13% had antibodies binding to both the recombinant ectodomain of MET, and the ligand binding part of MET, SEMA. MET binding in the breast cancer cohort was significantly correlated with hormone receptor-positive status. We further conducted immunoglobulin sequencing of peripheral MET-enriched B cells from 6 MET-reactive patients. The MET-enriched B cell repertoire was found to be polyclonal and prone to non-IgG1 subclass. Nine monoclonal antibodies were cloned and analyzed, and these exhibited MET binding, low thermostability, and high polyreactivity. Among these, antibodies 87B156 and 69B287 effectively bound to tumor cells and inhibited MET-expressing breast cancer cell lines. Overall, our data demonstrate that some patients with breast and lung cancer develop polyreactive antibodies that cross-react with MET. These autoantibodies have a potential contribution to immune responses against tumors.
Collapse
Affiliation(s)
- Michal Navon
- Department of Microbiology and Clinical Immunology, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Noam Ben-Shalom
- Department of Microbiology and Clinical Immunology, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Maya Dadiani
- Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel
| | - Michael Mor
- Department of Microbiology and Clinical Immunology, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, USA
| | - Ron Yefet
- Department of Microbiology and Clinical Immunology, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | | | - Dana Chat
- Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel
| | | | - Iris Barshack
- Department of Pathology, Sheba Medical Center, Ramat Gan, Israel
- Department of Pathology, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Ilan Tsarfaty
- Department of Microbiology and Clinical Immunology, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Einav Nili Gal-Yam
- Institute of Breast Oncology, Jusidman Cancer Center, Sheba Medical Center, Ramat Gan, Israel
| | - Natalia T Freund
- Department of Microbiology and Clinical Immunology, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
|
3
|
Okun SA, Lu D, Sew K, Subramaniam A, Lockwood WW. MET Activation in Lung Cancer and Response to Targeted Therapies. Cancers (Basel) 2025; 17:281. [PMID: 39858062 PMCID: PMC11764361 DOI: 10.3390/cancers17020281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/09/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
The hepatocyte growth factor receptor (MET) is a receptor tyrosine kinase (RTK) that mediates the activity of a variety of downstream pathways upon its activation. These pathways regulate various physiological processes within the cell, including growth, survival, proliferation, and motility. Under normal physiological conditions, this allows MET to regulate various development and regenerative processes; however, mutations resulting in aberrant MET activity and the consequent dysregulation of downstream signaling can contribute to cellular pathophysiology. Mutations within MET have been identified in a variety of cancers and have been shown to mediate tumorigenesis by increasing RTK activity and downstream signaling. In lung cancer specifically, a number of patients have been identified as possessing MET alterations, commonly receptor amplification (METamp) or splice site mutations resulting in loss of exon 14 (METex14). Due to MET's role in mediating oncogenesis, it has become an attractive clinical target and has led to the development of various targeted therapies, including MET tyrosine kinase inhibitors (TKIs). Unfortunately, these TKIs have demonstrated limited clinical efficacy, as patients often present with either primary or acquired resistance to these therapies. Mechanisms of resistance vary but often occur through off-target or bypass mechanisms that render downstream signaling pathways insensitive to MET inhibition. This review provides an overview of the therapeutic landscape for MET-positive cancers and explores the various mechanisms that contribute to therapeutic resistance in these cases.
Collapse
Affiliation(s)
- Sarah Anna Okun
- Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada; (S.A.O.); (K.S.); (A.S.)
- Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Daniel Lu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Katherine Sew
- Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada; (S.A.O.); (K.S.); (A.S.)
- Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Asha Subramaniam
- Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada; (S.A.O.); (K.S.); (A.S.)
- Department of Pathology and Laboratory Science, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - William W. Lockwood
- Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada; (S.A.O.); (K.S.); (A.S.)
- Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Department of Pathology and Laboratory Science, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| |
Collapse
|
|
4
|
Razzaq A, Elkahlout R, Nasrallah GK, Ibrahim FE, Samara M, Zayed H, Abdulrouf PV, Al-Jurf R, Najjar A, Farrell T, Qoronfleh MW, Rifai HA, Al-Dewik N. Exploring Differentially Methylated Genes among Preterm Birth and Full-Term Birth. Lifestyle Genom 2025; 18:76-89. [PMID: 39746347 PMCID: PMC12097759 DOI: 10.1159/000543372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 12/27/2024] [Indexed: 01/04/2025] Open
Abstract
INTRODUCTION Preterm birth (PTB) is a major contributor to neonatal morbidity and mortality. DNA methylation plays a critical role in fetal development and may serve as an epigenetic biomarker for PTB. However, few epigenetic studies have investigated PTB-specific DNA methylation changes. This study aimed to identify epigenetic differences between PTB and term birth (TB) infants. METHODS A total of 218 cord blood samples from three independent PTB studies were analyzed to identify epigenetic differences between PTB and TB infants. Differential methylation analysis was conducted while adjusting for key covariates, including gestational age, sex, and disease status. Differentially methylated regions (DMRs) (genes and promoters) and differentially methylated sites (DMSs) (CpG sites) were assessed for significant methylation differences between the two groups. RESULTS In PTB infants, several genes, including RNASE3, HGF, CLEC5A, LIPN, NXF1, and CCDC12 showed significant hypermethylation (p < 0.05), while the MUC20 and IFNL4 genes showed significant hypomethylation (p < 0.05). The eForge analysis revealed that hypermethylated (p < 0.05) CpG sites were significantly enriched in different fetal tissues such as the small and large intestines, adrenal gland, fetal heart, lungs, and kidney, whereas hypomethylated CpGs showed no significant enrichment. Gene ontology analysis indicated that differentially methylated genes were primarily involved in immune response regulation. Notably, S100A9 and S100A8 genes, which play crucial roles in neonatal immune function and sepsis risk, were hypermethylated (p < 0.05) in PTB infants. CONCLUSION This study identified PTB-associated DNA methylation changes in immune-related genes, suggesting their potential epigenetic biomarkers for PTB. These findings enhance our understanding of PTB pathogenesis and may contribute to the development of novel diagnostic and therapeutic strategies.
Collapse
Affiliation(s)
- Aleem Razzaq
- Department of Research, Women’s Wellness and Research Center, Hamad Medical Corporation, Doha, Qatar
- Translational and Precision Medicine Research Facility, Women’s Wellness and Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Razan Elkahlout
- Department of Research, Women’s Wellness and Research Center, Hamad Medical Corporation, Doha, Qatar
| | - Gheyath K. Nasrallah
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, Doha, Qatar
| | - Faisal E. Ibrahim
- Department of Research, Women’s Wellness and Research Center, Hamad Medical Corporation, Doha, Qatar
- Translational and Precision Medicine Research Facility, Women’s Wellness and Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Muthanna Samara
- Department of Psychology, Kingston University London, London, UK
| | - Hatem Zayed
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, Doha, Qatar
| | - Palli Valapila Abdulrouf
- Department of Research, Women’s Wellness and Research Center, Hamad Medical Corporation, Doha, Qatar
| | - Rana Al-Jurf
- Translational and Precision Medicine Research Facility, Women’s Wellness and Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, Qatar
| | | | - Thomas Farrell
- Department of Research, Women’s Wellness and Research Center, Hamad Medical Corporation, Doha, Qatar
- College of Medicine, Qatar University, Doha, Qatar
| | - M. Walid Qoronfleh
- Health Research & Policy Division, Q3 Research Institute (QRI), Ann Arbor, MI, USA
| | - Hilal Al Rifai
- Neonatal Intensive Care Unit (NICU), Newborn Screening Unit, Department of Pediatrics and Neonatology, Women’s Wellness and Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, Qatar
| | - Nader Al-Dewik
- Department of Research, Women’s Wellness and Research Center, Hamad Medical Corporation, Doha, Qatar
- Translational and Precision Medicine Research Facility, Women’s Wellness and Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, Qatar
- Neonatal Intensive Care Unit (NICU), Newborn Screening Unit, Department of Pediatrics and Neonatology, Women’s Wellness and Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, Qatar
- Genomics and Precision Medicine (GPM), College of Health & Life Science (CHLS), Hamad Bin Khalifa University (HBKU), Doha, Qatar
- Faculty of Health and Social Care Sciences, Kingston University, St. George’s University of London, London, UK
- Translational Research Institute (TRI), Hamad Medical Corporation (HMC), Doha, Qatar
| |
Collapse
|
|
5
|
Ballasy N, Apantaku I, Dean W, Hemberger M. Off to a good start: The importance of the placental exchange surface - Lessons from the mouse. Dev Biol 2025; 517:248-264. [PMID: 39491740 DOI: 10.1016/j.ydbio.2024.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/04/2024] [Accepted: 10/31/2024] [Indexed: 11/05/2024]
Abstract
The role of the chorio-allantoic placenta as the critical nutrient- and oxygen-supplying organ to nourish the demands of the fetus has been well recognized. This function relies on the successful establishment of the placental feto-maternal exchange unit, or interhaemal barrier, across which all nutrients as well as waste products must pass to cross from the maternal to the fetal blood circulation, or vice versa, respectively. As a consequence, defects in the establishment of this elaborate interface lead to fetal growth retardation or even embryonic lethality, depending on the severity of the defect. Beyond this essential role, however, it has also emerged that the functionality of the feto-maternal interface dictates the proper development of specific embryonic organs, with tightest links observed to the formation of the heart. In this article, we build on the foundational strength of the mouse as experimental model in which the placental causality of embryonic defects can be genetically proven. We discuss in detail the formation of the interhaemal barrier that makes up the labyrinth layer of the murine placenta, including insights into drivers of its formation and the interdependence of the cell types that make up this essential interface, from in vivo and in vitro data using mouse trophoblast stem cells. We highlight mouse genetic tools that enable the elucidation of cause-effect relationships between defects driven by either the trophoblast cells of the placenta or by embryonic cell types. We specifically emphasize gene knockouts for which a placental causality of embryonic heart defects has been demonstrated. This in-depth perspective provides much-needed insights while highlighting remaining gaps in knowledge that are essential for gaining a better understanding of the multi-facetted roles of the placenta in setting us up for a healthy start in life well beyond nutritional support alone.
Collapse
Affiliation(s)
- Noura Ballasy
- Dept. of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
| | - Ifeoluwa Apantaku
- Dept. of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
| | - Wendy Dean
- Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada; Dept. of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
| | - Myriam Hemberger
- Dept. of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.
| |
Collapse
|
|
6
|
López-García I, Oh S, Chaney C, Tsunezumi J, Drummond I, Oxburgh L, Carroll TJ, Marciano DK. Epithelial tubule interconnection driven by HGF-Met signaling in the kidney. Proc Natl Acad Sci U S A 2024; 121:e2416887121. [PMID: 39705305 PMCID: PMC11670081 DOI: 10.1073/pnas.2416887121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 11/11/2024] [Indexed: 12/22/2024] Open
Abstract
The formation of functional epithelial tubules is critical for the development and maintenance of many organ systems. While the mechanisms of tubule formation by epithelial cells are well studied, the process of tubule anastomosis-where tubules connect to form a continuous network-remains poorly understood. In this study, we utilized single-cell RNA sequencing to analyze embryonic mouse kidney tubules undergoing anastomosis. Our analysis identified hepatocyte growth factor (HGF) as a key potential mediator of this process. To investigate this further, we developed an assay using epithelial spheroids with fluorescently tagged apical surfaces, allowing us to visualize and quantify tubule-tubule connections. Our results demonstrate that HGF promotes tubule anastomosis, and it does so through the MAPK signaling pathway and MMPs, independently of cell proliferation. Remarkably, treatment with HGF and collagenase was sufficient to induce tubule anastomosis in embryonic mouse kidneys. These findings provide a foundational understanding of how to enhance the formation of functional tubular networks. This has significant clinical implications for the use of in vitro-grown kidney tissues in transplant medicine, potentially improving the success and integration of transplanted tissues.
Collapse
Affiliation(s)
- Isabel López-García
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX75235
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX75235
| | - Sunhee Oh
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX75235
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX75235
| | - Christopher Chaney
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX75235
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX7235
| | - Jun Tsunezumi
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX75235
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX75235
- Molecular Pathology Division, Kanagawa Cancer Center Research Institute, Kanagawa241-8515, Japan
| | - Iain Drummond
- Mount Desert Island Biological Laboratory, Bar Harbor, ME04609
| | | | - Thomas J. Carroll
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX7235
| | - Denise K. Marciano
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX75235
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX75235
| |
Collapse
|
|
7
|
Gallo S, Folco CB, Crepaldi T. The MET Oncogene: An Update on Targeting Strategies. Pharmaceuticals (Basel) 2024; 17:1473. [PMID: 39598385 PMCID: PMC11597589 DOI: 10.3390/ph17111473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 10/28/2024] [Accepted: 10/30/2024] [Indexed: 11/29/2024] Open
Abstract
The MET receptor, commonly known as HGF (hepatocyte growth factor) receptor, is a focus of extensive scientific research. MET has been linked to embryonic development, tissue regeneration following injury, tumorigenesis, and cancer metastasis. These functions underscore its involvement in numerous cellular processes, including stemness, proliferation, motility, cell dissociation, and survival. However, the enigmatic nature of MET becomes apparent in the context of cancer. When MET remains persistently activated, since its gene undergoes genetic alterations, it initiates a complex signaling cascade setting in motion an aggressive and metastatic program that is characteristic of malignant cells and is known as "invasive growth". The expanding knowledge of MET signaling has opened up numerous opportunities for therapeutic interventions, particularly in the realm of oncology. Targeting MET presents a promising strategy for developing novel anti-cancer treatments. In this review, we provide an updated overview of drugs designed to modulate MET signaling, highlighting MET kinase inhibitors, degraders, anti-MET/HGF monoclonal antibodies, and MET-targeted antibody-drug conjugates. Through this review, we aim to contribute to the ongoing advancement of therapeutic strategies targeting MET signaling.
Collapse
Affiliation(s)
- Simona Gallo
- Department of Oncology, University of Turin, Regione Gonzole 10, 10143 Orbassano, Italy; (S.G.); (C.B.F.)
- Candiolo Cancer Institute, FPO-IRCCS, SP142, Km 3.95, 10060 Candiolo, Italy
| | - Consolata Beatrice Folco
- Department of Oncology, University of Turin, Regione Gonzole 10, 10143 Orbassano, Italy; (S.G.); (C.B.F.)
- Candiolo Cancer Institute, FPO-IRCCS, SP142, Km 3.95, 10060 Candiolo, Italy
| | - Tiziana Crepaldi
- Department of Oncology, University of Turin, Regione Gonzole 10, 10143 Orbassano, Italy; (S.G.); (C.B.F.)
- Candiolo Cancer Institute, FPO-IRCCS, SP142, Km 3.95, 10060 Candiolo, Italy
| |
Collapse
|
|
8
|
Murthi P, Kalionis B. Homeobox genes in the human placenta: Twists and turns on the path to find novel targets. Placenta 2024; 157:28-36. [PMID: 38908943 DOI: 10.1016/j.placenta.2024.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 05/25/2024] [Accepted: 06/16/2024] [Indexed: 06/24/2024]
Abstract
Fetal growth restriction (FGR) is a clinically important human pregnancy disorder that is thought to originate early in pregnancy and while its aetiology is not well understood, the disorder is associated with placental insufficiency. Currently treatment for FGR is limited by increased surveillance using ultrasound monitoring and premature delivery, or corticosteroid medication in the third trimester to prolong pregnancy. There is a pressing need for novel strategies to detect and treat FGR at its early stage. Homeobox genes are well established as master regulators of early embryonic development and increasing evidence suggests they are also important in regulating early placental development. Most important is that specific homeobox genes are abnormally expressed in human FGR. This review focusses on identifying the molecular pathways controlled by homeobox genes in the normal and FGR-affected placenta. This information will begin to address the knowledge gap in the molecular aetiology of FGR and lay the foundation for identifying potential diagnostic and therapeutic targets.
Collapse
Affiliation(s)
- Padma Murthi
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia; Department of Maternal Fetal Medicine, Pregnancy Research Centre, Royal Women's Hospital and Department of Obstetrics, Gynaecology and Newborn Health, University of Melbourne, Parkville, Victoria, Australia.
| | - Bill Kalionis
- Department of Maternal Fetal Medicine, Pregnancy Research Centre, Royal Women's Hospital and Department of Obstetrics, Gynaecology and Newborn Health, University of Melbourne, Parkville, Victoria, Australia.
| |
Collapse
|
|
9
|
Hong G, Xie W, Ahmed K, Oborn C, Soltys CL, Kannu P. A genetic mouse model mimicking MET related human osteofibrous dysplasia is characterized by delays in fracture repair and defective osteogenesis. FASEB J 2024; 38:e23810. [PMID: 39042586 DOI: 10.1096/fj.202400075rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 06/21/2024] [Accepted: 06/26/2024] [Indexed: 07/25/2024]
Abstract
Osteofibrous dysplasia (OFD) is a rare, benign, fibro-osseous lesion that occurs most commonly in the tibia of children. Tibial involvement leads to bowing and predisposes to the development of a fracture which exhibit significantly delayed healing processes, leading to prolonged morbidity. We previously identified gain-of-function mutations in the MET gene as a cause for OFD. In our present study, we test the hypothesis that gain-of-function MET mutations impair bone repair due to reduced osteoblast differentiation. A heterozygous Met exon 15 skipping (MetΔ15-HET) mouse was created to imitate the human OFD mutation. The mutation results in aberrant and dysregulation of MET-related signaling determined by RNA-seq in the murine osteoblasts extracted from the wide-type and genetic mice. Although no gross skeletal defects were identified in the mice, fracture repair was delayed in MetΔ15-HET mice, with decreased bone formation observed 2-week postfracture. Our data are consistent with a novel role for MET-mediated signaling regulating osteogenesis.
Collapse
Affiliation(s)
- Guoju Hong
- Traumatology & Orthopedics Institute, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China
- Department of Orthopedic, the Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China
- Division of Orthopaedic Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - William Xie
- Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Kashif Ahmed
- Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Connor Oborn
- Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
| | - Carrie-Lynn Soltys
- Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
| | - Peter Kannu
- Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
10
|
Alpaslan M, Fastré E, Mestre S, van Haeringen A, Repetto GM, Keymolen K, Boon LM, Belva F, Giacalone G, Revencu N, Sznajer Y, Riches K, Keeley V, Mansour S, Gordon K, Martin-Almedina S, Dobbins S, Ostergaard P, Quere I, Brouillard P, Vikkula M. Pathogenic variants in HGF give rise to childhood-to-late onset primary lymphoedema by loss of function. Hum Mol Genet 2024; 33:1250-1261. [PMID: 38676400 PMCID: PMC11227619 DOI: 10.1093/hmg/ddae060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 03/01/2024] [Accepted: 03/19/2024] [Indexed: 04/28/2024] Open
Abstract
Developmental and functional defects in the lymphatic system are responsible for primary lymphoedema (PL). PL is a chronic debilitating disease caused by increased accumulation of interstitial fluid, predisposing to inflammation, infections and fibrosis. There is no cure, only symptomatic treatment is available. Thirty-two genes or loci have been linked to PL, and another 22 are suggested, including Hepatocyte Growth Factor (HGF). We searched for HGF variants in 770 index patients from the Brussels PL cohort. We identified ten variants predicted to cause HGF loss-of-function (six nonsense, two frameshifts, and two splice-site changes; 1.3% of our cohort), and 14 missense variants predicted to be pathogenic in 17 families (2.21%). We studied co-segregation within families, mRNA stability for non-sense variants, and in vitro functional effects of the missense variants. Analyses of the mRNA of patient cells revealed degradation of the nonsense mutant allele. Reduced protein secretion was detected for nine of the 14 missense variants expressed in COS-7 cells. Stimulation of lymphatic endothelial cells with these 14 HGF variant proteins resulted in decreased activation of the downstream targets AKT and ERK1/2 for three of them. Clinically, HGF-associated PL was diverse, but predominantly bilateral in the lower limbs with onset varying from early childhood to adulthood. Finally, aggregation study in a second independent cohort underscored that rare likely pathogenic variants in HGF explain about 2% of PL. Therefore, HGF signalling seems crucial for lymphatic development and/or maintenance in human beings and HGF should be included in diagnostic genetic screens for PL.
Collapse
Affiliation(s)
- Murat Alpaslan
- Human Molecular Genetics, de Duve Institute, University of Louvain, Avenue Hippocrate 74, Brussels 1200, Belgium
| | - Elodie Fastré
- Human Molecular Genetics, de Duve Institute, University of Louvain, Avenue Hippocrate 74, Brussels 1200, Belgium
| | - Sandrine Mestre
- Department of vascular medicine, Hospital Saint-Eloi, University Hospital of Montpellier, Avenue Augustin Fliche 80, Montpellier 34090, France
| | - Arie van Haeringen
- Leiden University Medical Center, Albinusdreef 2, Leiden 2333, the Netherlands
| | - Gabriela M Repetto
- Clinica Alemana Universidad del Desarrollo, Av Plaza 680, Las Condes, Lo Barnechea, Región Metropolitana 7710167, Chile
| | - Kathelijn Keymolen
- Clinical Sciences, Research Group Reproduction and Genetics, Centre for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, Brussels 1090, Belgium
| | - Laurence M Boon
- Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, Avenue Hippocrate 10, Brussels 1200, Belgium
| | - Florence Belva
- Department of Lymphatic Surgery, AZ Sint-Maarten Hospital, VASCERN PPL European Reference Centre, Liersesteenweg 435, Mechelen 2800, Belgium
| | - Guido Giacalone
- Department of Lymphatic Surgery, AZ Sint-Maarten Hospital, VASCERN PPL European Reference Centre, Liersesteenweg 435, Mechelen 2800, Belgium
| | - Nicole Revencu
- Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Avenue Hippocrate 10, Brussels 1200, Belgium
| | - Yves Sznajer
- Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Avenue Hippocrate 10, Brussels 1200, Belgium
| | - Katie Riches
- University Hospitals of Derby and Burton NHS Foundation Trust, Uttoxeter Rd, Derby DE22 3NE, United Kingdom
| | - Vaughan Keeley
- University Hospitals of Derby and Burton NHS Foundation Trust, Uttoxeter Rd, Derby DE22 3NE, United Kingdom
- University of Nottingham Medical School, Nottingham, East Block, Lenton, Nottingham NG7 2UH, United Kingdom
| | - Sahar Mansour
- Cardiovascular and Genomics Research Institute, St. George's University of London, Blackshaw Rd, London SW17 0QT, United Kingdom
- South West Thames Regional Centre for Genomics, St. George's Universities Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Kristiana Gordon
- Cardiovascular and Genomics Research Institute, St. George's University of London, Blackshaw Rd, London SW17 0QT, United Kingdom
- Dermatology and Lymphovascular Medicine, St. George's Universities NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Silvia Martin-Almedina
- Cardiovascular and Genomics Research Institute, St. George's University of London, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Sara Dobbins
- Cardiovascular and Genomics Research Institute, St. George's University of London, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Pia Ostergaard
- Cardiovascular and Genomics Research Institute, St. George's University of London, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Isabelle Quere
- Department of vascular medicine, Hospital Saint-Eloi, University Hospital of Montpellier, Avenue Augustin Fliche 80, Montpellier 34090, France
| | - Pascal Brouillard
- Human Molecular Genetics, de Duve Institute, University of Louvain, Avenue Hippocrate 74, Brussels 1200, Belgium
| | - Miikka Vikkula
- Human Molecular Genetics, de Duve Institute, University of Louvain, Avenue Hippocrate 74, Brussels 1200, Belgium
- WELBIO Department, WEL Research Institute, Avenue Pasteur, 6, Wavre 1300, Belgium
| |
Collapse
|
|
11
|
Vogel JW, Alexander-Bloch AF, Wagstyl K, Bertolero MA, Markello RD, Pines A, Sydnor VJ, Diaz-Papkovich A, Hansen JY, Evans AC, Bernhardt B, Misic B, Satterthwaite TD, Seidlitz J. Deciphering the functional specialization of whole-brain spatiomolecular gradients in the adult brain. Proc Natl Acad Sci U S A 2024; 121:e2219137121. [PMID: 38861593 PMCID: PMC11194492 DOI: 10.1073/pnas.2219137121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 04/27/2024] [Indexed: 06/13/2024] Open
Abstract
Cortical arealization arises during neurodevelopment from the confluence of molecular gradients representing patterned expression of morphogens and transcription factors. However, whether similar gradients are maintained in the adult brain remains unknown. Here, we uncover three axes of topographic variation in gene expression in the adult human brain that specifically capture previously identified rostral-caudal, dorsal-ventral, and medial-lateral axes of early developmental patterning. The interaction of these spatiomolecular gradients i) accurately reconstructs the position of brain tissue samples, ii) delineates known functional territories, and iii) can model the topographical variation of diverse cortical features. The spatiomolecular gradients are distinct from canonical cortical axes differentiating the primary sensory cortex from the association cortex, but radiate in parallel with the axes traversed by local field potentials along the cortex. We replicate all three molecular gradients in three independent human datasets as well as two nonhuman primate datasets and find that each gradient shows a distinct developmental trajectory across the lifespan. The gradients are composed of several well-known transcription factors (e.g., PAX6 and SIX3), and a small set of genes shared across gradients are strongly enriched for multiple diseases. Together, these results provide insight into the developmental sculpting of functionally distinct brain regions, governed by three robust transcriptomic axes embedded within brain parenchyma.
Collapse
Affiliation(s)
- Jacob W. Vogel
- Department of Clinical Sciences Malmö, SciLifeLab, Lund University, Lund, Sweden202 13
- Lifespan Informatics and Neuroimaging Center, University of Pennsylvania, Philadelphia, PA19104
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA19104
| | - Aaron F. Alexander-Bloch
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA19104
- Department of Child and Adolescent Psychiatry and Behavioral Science, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
- Penn-Children’s Hospital of Philadelphia Lifespan Brain Institute, University of Pennsylvania, Philadelphia, PA19104
| | - Konrad Wagstyl
- Wellcome Centre for Human Neuroimaging, Institute of Neurology, University College London, LondonWC1N 3AR, United Kingdom
| | - Maxwell A. Bertolero
- Lifespan Informatics and Neuroimaging Center, University of Pennsylvania, Philadelphia, PA19104
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA19104
| | - Ross D. Markello
- McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QCH3A 2B4, Canada
| | - Adam Pines
- Lifespan Informatics and Neuroimaging Center, University of Pennsylvania, Philadelphia, PA19104
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA19104
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA94305
| | - Valerie J. Sydnor
- Lifespan Informatics and Neuroimaging Center, University of Pennsylvania, Philadelphia, PA19104
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA19104
| | - Alex Diaz-Papkovich
- Quantitative Life Sciences, McGill University, Montreal, QCH3A 1E3, Canada
- McGill Genome Centre, McGill University, Montreal, QCH3A 0G1, Canada
| | - Justine Y. Hansen
- McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QCH3A 2B4, Canada
| | - Alan C. Evans
- McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QCH3A 2B4, Canada
| | - Boris Bernhardt
- McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QCH3A 2B4, Canada
| | - Bratislav Misic
- McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QCH3A 2B4, Canada
| | - Theodore D. Satterthwaite
- Lifespan Informatics and Neuroimaging Center, University of Pennsylvania, Philadelphia, PA19104
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA19104
- Penn-Children’s Hospital of Philadelphia Lifespan Brain Institute, University of Pennsylvania, Philadelphia, PA19104
| | - Jakob Seidlitz
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA19104
- Department of Child and Adolescent Psychiatry and Behavioral Science, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
- Penn-Children’s Hospital of Philadelphia Lifespan Brain Institute, University of Pennsylvania, Philadelphia, PA19104
| |
Collapse
|
|
12
|
López-García I, Oh S, Chaney C, Tsunezumi J, Drummond I, Oxburgh L, Carroll T, Marciano DK. Epithelial tubule interconnection driven by HGF-Met signaling in the kidney. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.03.597185. [PMID: 38895378 PMCID: PMC11185679 DOI: 10.1101/2024.06.03.597185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
The formation of functional epithelial tubules is a central feature of many organ systems. Although the process of tubule formation by epithelial cells is well-studied, the way in which tubules connect with each other (i.e. anastomose) to form functional networks both in vivo and in vitro is not well understood. A key, unanswered question in the kidney is how the renal vesicles of the embryonic kidney connect with the nascent collecting ducts to form a continuous urinary system. We performed a ligand-receptor pair analysis on single cell RNA-seq data from embryonic mouse kidney tubules undergoing anastomosis to select candidates that might mediate this process in vivo. This analysis identified hepatocyte growth factor (HGF), which has known roles in cell proliferation, migration, and tubulogenesis, as one of several possible candidates. To test this possibility, we designed a novel assay to quantitatively examine epithelial tubule anastomosis in vitro using epithelial spheroids with fluorescently-tagged apical surfaces to enable direct visualization of anastomosis. This revealed that HGF is a potent inducer of tubule anastomosis. Tubule anastomosis occurs through a proliferation-independent mechanism that acts through the MAPK signaling cascade and matrix metalloproteinases (MMPs), the latter suggestive of a role in extracellular matrix turnover. Accordingly, treatment of explanted embryonic mouse kidneys with HGF and collagenase was sufficient to induce kidney tubule anastomosis. These results lay the groundwork for investigating how to promote functional interconnections between tubular epithelia, which have important clinical implications for utilizing in vitro grown kidney tissue in transplant medicine.
Collapse
Affiliation(s)
- Isabel López-García
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Sunhee Oh
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Chris Chaney
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Jun Tsunezumi
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
- Department of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Miyazaki, Japan
| | - Iain Drummond
- Mount Dessert Island Biological Laboratory, Maine, USA
| | - Leif Oxburgh
- Kidney Regenerative Medicine Laboratory, Rogosin Institute, New York, 10021, USA
| | - Thomas Carroll
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Denise K. Marciano
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
- Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
| |
Collapse
|
|
13
|
Guérin C, Tulasne D. Recording and classifying MET receptor mutations in cancers. eLife 2024; 13:e92762. [PMID: 38652103 PMCID: PMC11042802 DOI: 10.7554/elife.92762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 04/04/2024] [Indexed: 04/25/2024] Open
Abstract
Tyrosine kinase inhibitors (TKI) directed against MET have been recently approved to treat advanced non-small cell lung cancer (NSCLC) harbouring activating MET mutations. This success is the consequence of a long characterization of MET mutations in cancers, which we propose to outline in this review. MET, a receptor tyrosine kinase (RTK), displays in a broad panel of cancers many deregulations liable to promote tumour progression. The first MET mutation was discovered in 1997, in hereditary papillary renal cancer (HPRC), providing the first direct link between MET mutations and cancer development. As in other RTKs, these mutations are located in the kinase domain, leading in most cases to ligand-independent MET activation. In 2014, novel MET mutations were identified in several advanced cancers, including lung cancers. These mutations alter splice sites of exon 14, causing in-frame exon 14 skipping and deletion of a regulatory domain. Because these mutations are not located in the kinase domain, they are original and their mode of action has yet to be fully elucidated. Less than five years after the discovery of such mutations, the efficacy of a MET TKI was evidenced in NSCLC patients displaying MET exon 14 skipping. Yet its use led to a resistance mechanism involving acquisition of novel and already characterized MET mutations. Furthermore, novel somatic MET mutations are constantly being discovered. The challenge is no longer to identify them but to characterize them in order to predict their transforming activity and their sensitivity or resistance to MET TKIs, in order to adapt treatment.
Collapse
Affiliation(s)
- Célia Guérin
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesLilleFrance
| | - David Tulasne
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesLilleFrance
| |
Collapse
|
|
14
|
Fang Y, Wan JP, Wang Z, Song SY, Zhang CX, Yang L, Zhang QY, Yan CY, Wu FY, Lu SY, Sun F, Han B, Zhao SX, Dong M, Song HD. Deficiency of the HGF/Met pathway leads to thyroid dysgenesis by impeding late thyroid expansion. Nat Commun 2024; 15:3165. [PMID: 38605010 PMCID: PMC11009301 DOI: 10.1038/s41467-024-47363-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 03/28/2024] [Indexed: 04/13/2024] Open
Abstract
The mechanisms of bifurcation, a key step in thyroid development, are largely unknown. Here we find three zebrafish lines from a forward genetic screening with similar thyroid dysgenesis phenotypes and identify a stop-gain mutation in hgfa and two missense mutations in met by positional cloning from these zebrafish lines. The elongation of the thyroid primordium along the pharyngeal midline was dramatically disrupted in these zebrafish lines carrying a mutation in hgfa or met. Further studies show that MAPK inhibitor U0126 could mimic thyroid dysgenesis in zebrafish, and the phenotypes are rescued by overexpression of constitutively active MEK or Snail, downstream molecules of the HGF/Met pathway, in thyrocytes. Moreover, HGF promotes thyrocyte migration, which is probably mediated by downregulation of E-cadherin expression. The delayed bifurcation of the thyroid primordium is also observed in thyroid-specific Met knockout mice. Together, our findings reveal that HGF/Met is indispensable for the bifurcation of the thyroid primordium during thyroid development mediated by downregulation of E-cadherin in thyrocytes via MAPK-snail pathway.
Collapse
Affiliation(s)
- Ya Fang
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of Soochow University, Medical Center of Soochow University, Suzhou, Jiangsu, 215000, China
| | - Jia-Ping Wan
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
- Department of Endocrinology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zheng Wang
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Shi-Yang Song
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
- Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cao-Xu Zhang
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Liu Yang
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Qian-Yue Zhang
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Chen-Yan Yan
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Feng-Yao Wu
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Sang-Yu Lu
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Feng Sun
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Bing Han
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Shuang-Xia Zhao
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| | - Mei Dong
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| | - Huai-Dong Song
- Department of Molecular Diagnostics & Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| |
Collapse
|
|
15
|
Afshar Y, Yin O, Jeong A, Martinez G, Kim J, Ma F, Jang C, Tabatabaei S, You S, Tseng HR, Zhu Y, Krakow D. Placenta accreta spectrum disorder at single-cell resolution: a loss of boundary limits in the decidua and endothelium. Am J Obstet Gynecol 2024; 230:443.e1-443.e18. [PMID: 38296740 DOI: 10.1016/j.ajog.2023.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 09/25/2023] [Accepted: 10/01/2023] [Indexed: 02/02/2024]
Abstract
BACKGROUND Placenta accreta spectrum disorders are associated with severe maternal morbidity and mortality. Placenta accreta spectrum disorders involve excessive adherence of the placenta preventing separation at birth. Traditionally, this condition has been attributed to excessive trophoblast invasion; however, an alternative view is a fundamental defect in decidual biology. OBJECTIVE This study aimed to gain insights into the understanding of placenta accreta spectrum disorder by using single-cell and spatially resolved transcriptomics to characterize cellular heterogeneity at the maternal-fetal interface in placenta accreta spectrum disorders. STUDY DESIGN To assess cellular heterogeneity and the function of cell types, single-cell RNA sequencing and spatially resolved transcriptomics were used. A total of 12 placentas were included, 6 placentas with placenta accreta spectrum disorder and 6 controls. For each placenta with placenta accreta spectrum disorder, multiple biopsies were taken at the following sites: placenta accreta spectrum adherent and nonadherent sites in the same placenta. Of note, 2 platforms were used to generate libraries: the 10× Chromium and NanoString GeoMX Digital Spatial Profiler for single-cell and spatially resolved transcriptomes, respectively. Differential gene expression analysis was performed using a suite of bioinformatic tools (Seurat and GeoMxTools R packages). Correction for multiple testing was performed using Clipper. In situ hybridization was performed with RNAscope, and immunohistochemistry was used to assess protein expression. RESULTS In creating a placenta accreta cell atlas, there were dramatic difference in the transcriptional profile by site of biopsy between placenta accreta spectrum and controls. Most of the differences were noted at the site of adherence; however, differences existed within the placenta between the adherent and nonadherent site of the same placenta in placenta accreta. Among all cell types, the endothelial-stromal populations exhibited the greatest difference in gene expression, driven by changes in collagen genes, namely collagen type III alpha 1 chain (COL3A1), growth factors, epidermal growth factor-like protein 6 (EGFL6), and hepatocyte growth factor (HGF), and angiogenesis-related genes, namely delta-like noncanonical Notch ligand 1 (DLK1) and platelet endothelial cell adhesion molecule-1 (PECAM1). Intraplacental tropism (adherent versus non-adherent sites in the same placenta) was driven by differences in endothelial-stromal cells with notable differences in bone morphogenic protein 5 (BMP5) and osteopontin (SPP1) in the adherent vs nonadherent site of placenta accreta spectrum. CONCLUSION Placenta accreta spectrum disorders were characterized at single-cell resolution to gain insight into the pathophysiology of the disease. An atlas of the placenta at single cell resolution in accreta allows for understanding in the biology of the intimate maternal and fetal interaction. The contributions of stromal and endothelial cells were demonstrated through alterations in the extracellular matrix, growth factors, and angiogenesis. Transcriptional and protein changes in the stroma of placenta accreta spectrum shift the etiologic explanation away from "invasive trophoblast" to "loss of boundary limits" in the decidua. Gene targets identified in this study may be used to refine diagnostic assays in early pregnancy, track disease progression over time, and inform therapeutic discoveries.
Collapse
Affiliation(s)
- Yalda Afshar
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA.
| | - Ophelia Yin
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA
| | - Anhyo Jeong
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
| | - Guadalupe Martinez
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
| | - Jina Kim
- Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Feiyang Ma
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA
| | - Christine Jang
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
| | - Sarah Tabatabaei
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
| | - Sungyong You
- Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA; Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Hsian-Rong Tseng
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, Los Angeles, CA
| | - Yazhen Zhu
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, Los Angeles, CA; Department of Pathology, University of California, Los Angeles, Los Angeles, CA
| | - Deborah Krakow
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; Departments of Orthopedic Surgery and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
| |
Collapse
|
|
16
|
Ghosh A, Kumar R, Kumar RP, Ray S, Saha A, Roy N, Dasgupta P, Marsh C, Paul S. The GATA transcriptional program dictates cell fate equilibrium to establish the maternal-fetal exchange interface and fetal development. Proc Natl Acad Sci U S A 2024; 121:e2310502121. [PMID: 38346193 PMCID: PMC10895349 DOI: 10.1073/pnas.2310502121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 01/08/2024] [Indexed: 02/15/2024] Open
Abstract
The placenta establishes a maternal-fetal exchange interface to transport nutrients and gases between the mother and the fetus. Establishment of this exchange interface relies on the development of multinucleated syncytiotrophoblasts (SynT) from trophoblast progenitors, and defect in SynT development often leads to pregnancy failure and impaired embryonic development. Here, we show that mouse embryos with conditional deletion of transcription factors GATA2 and GATA3 in labyrinth trophoblast progenitors (LaTPs) have underdeveloped placenta and die by ~embryonic day 9.5. Single-cell RNA sequencing analysis revealed excessive accumulation of multipotent LaTPs upon conditional deletion of GATA factors. The GATA factor-deleted multipotent progenitors were unable to differentiate into matured SynTs. We also show that the GATA factor-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. Loss of either GATA2 or GATA3 in cytotrophoblast-derived human trophoblast stem cells (human TSCs) drastically inhibits SynT differentiation potential. Identification of GATA2 and GATA3 target genes along with comparative bioinformatics analyses revealed that GATA factors directly regulate hundreds of common genes in human TSCs, including genes that are essential for SynT development and implicated in preeclampsia and fetal growth retardation. Thus, our study uncovers a conserved molecular mechanism, in which coordinated function of GATA2 and GATA3 promotes trophoblast progenitor-to-SynT commitment, ensuring establishment of the maternal-fetal exchange interface.
Collapse
Affiliation(s)
- Ananya Ghosh
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Rajnish Kumar
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160
- Institute for Reproduction and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS 66160
| | - Ram P Kumar
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160
- Institute for Reproduction and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS 66160
| | - Soma Ray
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Abhik Saha
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Namrata Roy
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Purbasa Dasgupta
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Courtney Marsh
- Institute for Reproduction and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS 66160
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160
| | - Soumen Paul
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160
- Institute for Reproduction and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS 66160
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160
| |
Collapse
|
|
17
|
Zhang C, Sun C, Zhao Y, Ye B, Yu G. Signaling pathways of liver regeneration: Biological mechanisms and implications. iScience 2024; 27:108683. [PMID: 38155779 PMCID: PMC10753089 DOI: 10.1016/j.isci.2023.108683] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2023] Open
Abstract
The liver possesses a unique regenerative ability to restore its original mass, in this regard, partial hepatectomy (PHx) and partial liver transplantation (PLTx) can be executed smoothly and safely, which has important implications for the treatment of liver disease. Liver regeneration (LR) can be the very complicated procedure that involves multiple cytokines and transcription factors that interact with each other to activate different signaling pathways. Activation of these pathways can drive the LR process, which can be divided into three stages, namely, the initiation, progression, and termination stages. Therefore, it is important to investigate the pathways involved in LR to elucidate the mechanism of LR. This study reviews the latest research on the key signaling pathways in the different stages of LR.
Collapse
Affiliation(s)
- Chunyan Zhang
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Caifang Sun
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Yabin Zhao
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Bingyu Ye
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - GuoYing Yu
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| |
Collapse
|
|
18
|
Mi X, Chen C, Feng C, Qin Y, Chen ZJ, Yang Y, Zhao S. The Functions and Application Prospects of Hepatocyte Growth Factor in Reproduction. Curr Gene Ther 2024; 24:347-355. [PMID: 39005061 DOI: 10.2174/0115665232291010240221104445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 02/01/2024] [Accepted: 02/13/2024] [Indexed: 07/16/2024]
Abstract
Hepatocyte growth factor (HGF) is expressed in multiple systems and mediates a variety of biological activities, such as mitosis, motility, and morphogenesis. A growing number of studies have revealed the expression patterns and functions of HGF in ovarian and testicular physiology from the prenatal to the adult stage. HGF regulates folliculogenesis and steroidogenesis by modulating the functions of theca cells and granulosa cells in the ovary. It also mediates somatic cell proliferation and steroidogenesis, thereby affecting spermatogenesis in males. In addition to its physiological effects on the reproductive system, HGF has shown advantages in preclinical studies over recent years for the treatment of male and female infertility, particularly in women with premature ovarian insufficiency. This review aims to summarize the pleiotropic functions of HGF in the reproductive system and to provide prospects for its clinical application.
Collapse
Affiliation(s)
- Xin Mi
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Caiyi Chen
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Chen Feng
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Yingying Qin
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Zi-Jiang Chen
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
- Research Unit of Gametogenesis and Health of ART-Offspring (No.2021RU001), Chinese Academy of Medical Sciences, Jinan, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yajuan Yang
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Shidou Zhao
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| |
Collapse
|
|
19
|
Fraser M, Seetharamu N, Diamond M, Lee CS. Profile of Capmatinib for the Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC): Patient Selection and Perspectives. Cancer Manag Res 2023; 15:1233-1243. [PMID: 37941971 PMCID: PMC10629434 DOI: 10.2147/cmar.s386799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 09/19/2023] [Indexed: 11/10/2023] Open
Abstract
Aberrant c-MET (Mesenchymal-Epithelial Transition) signaling contributes to cancer cell development, proliferation, and metastases of non-small cell lung cancer (NSCLC). MET exon 14 (METex14) skipping mutation is noted in approximately 4% of NSCLC cases and is targetable with the recently approved tyrosine kinase inhibitors capmatinib and tepotinib. Capmatinib, the focus of this review article, is a highly selective MET inhibitor approved for use in patients with METex14 mutated NSCLC. In this review, we discuss cMET as a target, the pharmacology of capmatinib, key trials of capmatinib in MET-altered lung cancer, and toxicity profile. We highlight some ongoing capmatinib clinical trials that expand their role to other subsets of patients, especially those with EGFR mutations, who develop MET alterations as a resistance pathway. We further provide our perspective on the management of METex14 NSCLC, strategies for sequencing agents, and toxicity management.
Collapse
Affiliation(s)
- Madison Fraser
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, NY, USA
| | - Nagashree Seetharamu
- Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Lake Success, NY, USA
| | - Matthew Diamond
- Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Lake Success, NY, USA
| | - Chung-Shien Lee
- Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Lake Success, NY, USA
- Department of Clinical Health Professions, St. John’s University, Queens, NY, USA
| |
Collapse
|
|
20
|
Fernandes M, Paget S, Kherrouche Z, Truong MJ, Vinchent A, Meneboo JP, Sebda S, Werkmeister E, Descarpentries C, Figeac M, Cortot AB, Tulasne D. Transforming properties of MET receptor exon 14 skipping can be recapitulated by loss of the CBL ubiquitin ligase binding site. FEBS Lett 2023; 597:2301-2315. [PMID: 37468447 DOI: 10.1002/1873-3468.14702] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 06/07/2023] [Accepted: 06/19/2023] [Indexed: 07/21/2023]
Abstract
MET is a receptor tyrosine kinase that is activated in many cancers through various mechanisms. MET exon 14 (Ex14) skipping occurs in 3% of nonsmall cell lung tumors. However, the contribution of the regulatory sites lost upon this skipping, which include a phosphorylated serine (S985) and a binding site for the E3 ubiquitin ligase CBL (Y1003), remains elusive. Sequencing of 2808 lung tumors revealed 71 mutations leading to MET exon 14 skipping and three mutations affecting Y1003 or S985. In addition, MET exon 14 skipping and MET Y1003F induced similar transcriptional programs, increased the activation of downstream signaling pathways, and increased cell mobility. Therefore, the MET Y1003F mutation is able to fully recapitulate responses induced by MET exon 14 skipping, suggesting that loss of the CBL binding site is the main contributor of cell transformation induced by MET Ex14 mutations.
Collapse
Affiliation(s)
- Marie Fernandes
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Univ. Lille, France
| | - Sonia Paget
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Univ. Lille, France
| | - Zoulika Kherrouche
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Univ. Lille, France
| | - Marie-José Truong
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Univ. Lille, France
| | - Audrey Vinchent
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Univ. Lille, France
| | - Jean-Pascal Meneboo
- Plateau de Génomique Fonctionnelle et Structurale, CHU Lille, Univ. Lille, France
| | - Shéhérazade Sebda
- Plateau de Génomique Fonctionnelle et Structurale, CHU Lille, Univ. Lille, France
| | - Elisabeth Werkmeister
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US41 - UMS2014 - PLBS, Univ. Lille, France
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR9017 - CIIL - Center for Infection and Immunity of Lille, Univ. Lille, France
| | | | - Martin Figeac
- Plateau de Génomique Fonctionnelle et Structurale, CHU Lille, Univ. Lille, France
| | - Alexis B Cortot
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Univ. Lille, France
- Thoracic Oncology Department, CHU Lille, Univ. Lille, France
| | - David Tulasne
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Univ. Lille, France
| |
Collapse
|
|
21
|
Lim RK, Buschman M, Khasanov A, Ledesma A, Chen J, Nguyen T, Guo J, Li L, Huang J, Niu J, Kerwin L, Wang R, Guo Y, Zhu T, Kaufmann G, Zhang Y, Zhou H, Ji H, Fu Y. Discovery of novel cMET-targeting antibody Fab drug conjugates as potential treatment for solid tumors with highly expressed cMET. Expert Opin Biol Ther 2023; 23:1137-1149. [PMID: 38078403 DOI: 10.1080/14712598.2023.2292633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 12/05/2023] [Indexed: 12/18/2023]
Abstract
BACKGROUND Solid tumors are becoming prevalent affecting both old and young populations. Numerous solid tumors are associated with high cMET expression. The complexity of solid tumors combined with the highly interconnected nature of the cMET/HGF pathway with other cellular pathways make the pursuit of finding an effective treatment extremely challenging. The current standard of care for these malignancies is mostly small molecule-based chemotherapy. Antibody-based therapeutics as well as antibody drug conjugates are promising emerging classes against cMET-overexpressing solid tumors. RESEARCH DESIGN AND METHODS In this study, we described the design, synthesis, in vitro and in vivo characterization of cMET-targeting Fab drug conjugates (FDCs) as an alternative therapeutic strategy. The format is comprised of a Fab conjugated to a potent cytotoxic drug via a cleavable linker employing lysine-based and cysteine-based conjugation chemistries. RESULTS We found that the FDCs have potent anti-tumor efficacies in cancer cells with elevated overexpression of cMET. Moreover, they demonstrated a remarkable anti-tumor effect in a human gastric xenograft mouse model. CONCLUSIONS The FDC format has the potential to overcome some of the challenges presented by the other classes of therapeutics. This study highlights the promise of antibody fragment-based drug conjugate formats for the treatment of solid tumors.
Collapse
Affiliation(s)
- Reyna Kv Lim
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Matthew Buschman
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Alisher Khasanov
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Arthur Ledesma
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - John Chen
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Thanhtruc Nguyen
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Joanna Guo
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Lingna Li
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Jonathan Huang
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Jin Niu
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Lisa Kerwin
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Rengang Wang
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Yurong Guo
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Tong Zhu
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Gunnar Kaufmann
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Yanliang Zhang
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Heyou Zhou
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Henry Ji
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| | - Yanwen Fu
- Antibody Discovery & Technology, Sorrento Therapeutics, Inc, San Diego, CA, USA
| |
Collapse
|
|
22
|
Park YK, Jang BC. The Receptor Tyrosine Kinase c-Met Promotes Lipid Accumulation in 3T3-L1 Adipocytes. Int J Mol Sci 2023; 24:ijms24098086. [PMID: 37175792 PMCID: PMC10179087 DOI: 10.3390/ijms24098086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/23/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
The receptor tyrosine kinase c-Met is elaborated in embryogenesis, morphogenesis, metabolism, cell growth, and differentiation. JNJ38877605 (JNJ) is an inhibitor of c-Met with anti-tumor activity. The c-Met expression and its role in adipocyte differentiation are unknown. Here, we investigated the c-Met expression and phosphorylation, knockdown (KD) effects, and pharmacological inhibition of c-Met by JNJ on fat accumulation in murine preadipocyte 3T3-L1 cells. During 3T3-L1 preadipocyte differentiation, strikingly, c-Met expression at the protein and mRNA levels and the protein phosphorylation on Y1234/1235 and Y1349 is crucial for inducing its kinase catalytic activity and activating a docking site for signal transducers were increased in a time-dependent manner. Of note, JNJ treatment at 20 μM that strongly inhibits c-Met phosphorylation without altering its total expression resulted in less lipid accumulation and triglyceride (TG) content with no cytotoxicity. JNJ further reduced the expression of adipogenic regulators, including CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), acetyl CoA carboxylase (ACC), and perilipin A. Moreover, JNJ treatment increased cAMP-activated protein kinase (AMPK) and liver kinase B-1 (LKB-1) phosphorylation but decreased ATP levels. Significantly, KD of c-Met suppressed fat accumulation and triglyceride (TG) quantity and reduced the expression of C/EBP-α, PPAR-γ, FAS, ACC, and perilipin A. Collectively, the present results demonstrate that c-Met is a novel, highly conserved mediator of adipogenesis regulating lipid accumulation in murine adipocytes.
Collapse
Affiliation(s)
- Yu-Kyoung Park
- Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Republic of Korea
- Department of Physiology, Senotherapy-Based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, 170, Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of Korea
| | - Byeong-Churl Jang
- Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Republic of Korea
| |
Collapse
|
|
23
|
de Nola G, Leclercq B, Mougel A, Taront S, Simonneau C, Forneris F, Adriaenssens E, Drobecq H, Iamele L, Dubuquoy L, Melnyk O, Gherardi E, de Jonge H, Vicogne J. Dimerization of kringle 1 domain from hepatocyte growth factor/scatter factor provides a potent MET receptor agonist. Life Sci Alliance 2022; 5:5/12/e202201424. [PMID: 35905995 PMCID: PMC9348577 DOI: 10.26508/lsa.202201424] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 07/01/2022] [Accepted: 07/06/2022] [Indexed: 12/22/2022] Open
Abstract
We designed and characterized a potent full MET receptor agonist consisting of two recombinantly linked HGF/SF kringle 1 domains and demonstrated its potential in epithelial tissue regeneration. Hepatocyte growth factor/scatter factor (HGF/SF) and its cognate receptor MET play several essential roles in embryogenesis and regeneration in postnatal life of epithelial organs such as the liver, kidney, lung, and pancreas, prompting a strong interest in harnessing HGF/SF-MET signalling for regeneration of epithelial organs after acute or chronic damage. The limited stability and tissue diffusion of native HGF/SF, however, which reflect the tightly controlled, local mechanism of action of the morphogen, have led to a major search of HGF/SF mimics for therapy. In this work, we describe the rational design, production, and characterization of K1K1, a novel minimal MET agonist consisting of two copies of the kringle 1 domain of HGF/SF in tandem orientation. K1K1 is highly stable and displays biological activities equivalent or superior to native HGF/SF in a variety of in vitro assay systems and in a mouse model of liver disease. These data suggest that this engineered ligand may find wide applications in acute and chronic diseases of the liver and other epithelial organs dependent of MET activation.
Collapse
Affiliation(s)
- Giovanni de Nola
- Department of Molecular Medicine, University of Pavia, Unit of Immunology and General Pathology Section, Pavia, Italy
| | - Bérénice Leclercq
- University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019, UMR 9017, CIIL, Center for Infection and Immunity of Lille, Lille, France
| | - Alexandra Mougel
- University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019, UMR 9017, CIIL, Center for Infection and Immunity of Lille, Lille, France
| | - Solenne Taront
- University of Lille, Inserm, CHU Lille, U1286, INFINITE, Institute for Translational Research in Inflammation, Lille, France
| | - Claire Simonneau
- Roche Pharmaceutical Research and Early Development (pRED), Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Federico Forneris
- The Armenise-Harvard Laboratory of Structural Biology, Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
| | - Eric Adriaenssens
- University of Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020, UMR 1277, Canther, Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France
| | - Hervé Drobecq
- University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019, UMR 9017, CIIL, Center for Infection and Immunity of Lille, Lille, France
| | - Luisa Iamele
- Department of Molecular Medicine, University of Pavia, Unit of Immunology and General Pathology Section, Pavia, Italy
| | - Laurent Dubuquoy
- University of Lille, Inserm, CHU Lille, U1286, INFINITE, Institute for Translational Research in Inflammation, Lille, France
| | - Oleg Melnyk
- University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019, UMR 9017, CIIL, Center for Infection and Immunity of Lille, Lille, France
| | - Ermanno Gherardi
- Department of Molecular Medicine, University of Pavia, Unit of Immunology and General Pathology Section, Pavia, Italy
| | - Hugo de Jonge
- Department of Molecular Medicine, University of Pavia, Unit of Immunology and General Pathology Section, Pavia, Italy
| | - Jérôme Vicogne
- University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019, UMR 9017, CIIL, Center for Infection and Immunity of Lille, Lille, France
| |
Collapse
|
|
24
|
Groen in ’t Woud S, Maj C, Renkema KY, Westland R, Galesloot T, van Rooij IALM, Vermeulen SH, Feitz WFJ, Roeleveld N, Schreuder MF, van der Zanden LFM. A Genome-Wide Association Study into the Aetiology of Congenital Solitary Functioning Kidney. Biomedicines 2022; 10:3023. [PMID: 36551779 PMCID: PMC9775328 DOI: 10.3390/biomedicines10123023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/15/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022] Open
Abstract
Congenital solitary functioning kidney (CSFK) is a birth defect that occurs in 1:1500 children and predisposes them to kidney injury. Its aetiology is likely multifactorial. In addition to known monogenic causes and environmental risk factors, common genetic variation may contribute to susceptibility to CSFK. We performed a genome-wide association study among 452 patients with CSFK and two control groups of 669 healthy children and 5363 unaffected adults. Variants in two loci reached the genome-wide significance threshold of 5 × 10-8, and variants in 30 loci reached the suggestive significance threshold of 1 × 10-5. Of these, an identified locus with lead single nucleotide variant (SNV) rs140804918 (odds ratio 3.1, p-value = 1.4 × 10-8) on chromosome 7 was most promising due to its close proximity to HGF, a gene known to be involved in kidney development. Based on their known molecular functions, both KCTD20 and STK38 could explain the suggestive significant association with lead SNV rs148413365 on chromosome 6. Our findings need replication in an independent cohort of CSFK patients before they can be established definitively. However, our analysis suggests that common variants play a role in CSFK aetiology. Future research could enhance our understanding of the molecular mechanisms involved.
Collapse
Affiliation(s)
- Sander Groen in ’t Woud
- Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Radboud Institute for Molecular Life Sciences, Department of Paediatric Nephrology, Radboudumc Amalia Children’s Hospital, 6500 HB Nijmegen, The Netherlands
| | - Carlo Maj
- Centre for Human Genetics, University of Marburg, 35037 Marburg, Germany
| | - Kirsten Y. Renkema
- Department of Genetics, University Medical Center Utrecht, Utrecht University, 3584 CS Utrecht, The Netherlands
| | - Rik Westland
- Department of Pediatric Nephrology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, 1105AZ Amsterdam, The Netherlands
| | - Tessel Galesloot
- Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Iris A. L. M. van Rooij
- Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Sita H. Vermeulen
- Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Wout F. J. Feitz
- Division of Pediatric Urology, Department of Urology, Radboud Institute for Molecular Life Sciences, Radboudumc Amalia Children’s Hospital, 6500 HB Nijmegen, The Netherlands
| | - Nel Roeleveld
- Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Michiel F. Schreuder
- Radboud Institute for Molecular Life Sciences, Department of Paediatric Nephrology, Radboudumc Amalia Children’s Hospital, 6500 HB Nijmegen, The Netherlands
| | - Loes F. M. van der Zanden
- Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| |
Collapse
|
|
25
|
Bedir Ö, Gram A, Grazul-Bilska AT, Kowalewski MP. The effects of follicle stimulating hormone (FSH)-induced controlled ovarian hyperstimulation and nutrition on implantation-related gene expression in caruncular tissues of non-pregnant sheep. Theriogenology 2022; 195:229-237. [DOI: 10.1016/j.theriogenology.2022.10.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/21/2022] [Accepted: 10/27/2022] [Indexed: 11/05/2022]
|
|
26
|
Altintas DM, Gallo S, Basilico C, Cerqua M, Bocedi A, Vitacolonna A, Botti O, Casanova E, Rancati I, Milanese C, Notari S, Gambardella G, Ricci G, Mastroberardino PG, Boccaccio C, Crepaldi T, Comoglio PM. The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the Receptor Precursor. Int J Mol Sci 2022; 23:ijms232012427. [PMID: 36293286 PMCID: PMC9604360 DOI: 10.3390/ijms232012427] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/28/2022] [Accepted: 10/13/2022] [Indexed: 11/29/2022] Open
Abstract
The tyrosine kinase receptor encoded by the MET oncogene has been extensively studied. Surprisingly, one extracellular domain, PSI, evolutionary conserved between plexins, semaphorins, and integrins, has no established function. The MET PSI sequence contains two CXXC motifs, usually found in protein disulfide isomerases (PDI). Using a scrambled oxidized RNAse enzymatic activity assay in vitro, we show, for the first time, that the MET extracellular domain displays disulfide isomerase activity, abolished by PSI domain antibodies. PSI domain deletion or mutations of CXXC sites to AXXA or SXXS result in a significant impairment of the cleavage of the MET 175 kDa precursor protein, abolishing the maturation of α and β chains, of, respectively, 50 kDa and 145 kDa, disulfide-linked. The uncleaved precursor is stuck in the Golgi apparatus and, interestingly, is constitutively phosphorylated. However, no signal transduction is observed as measured by AKT and MAPK phosphorylation. Consequently, biological responses to the MET ligand—hepatocyte growth factor (HGF)—such as growth and epithelial to mesenchymal transition, are hampered. These data show that the MET PSI domain is functional and is required for the maturation, surface expression, and biological functions of the MET oncogenic protein.
Collapse
Affiliation(s)
- Dogus Murat Altintas
- IFOM, FIRC Institute for Molecular Oncology, Via Adamello 16, 20139 Milano, Italy
- Correspondence: (D.M.A.); (P.M.C.)
| | - Simona Gallo
- Department of Oncology, University of Turin, 10060 Candiolo, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, Italy
| | | | - Marina Cerqua
- IFOM, FIRC Institute for Molecular Oncology, Via Adamello 16, 20139 Milano, Italy
| | - Alessio Bocedi
- Department of Chemical Sciences and Technologies, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Annapia Vitacolonna
- Department of Oncology, University of Turin, 10060 Candiolo, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, Italy
| | - Orsola Botti
- IFOM, FIRC Institute for Molecular Oncology, Via Adamello 16, 20139 Milano, Italy
| | - Elena Casanova
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, Italy
| | - Ilaria Rancati
- IFOM, FIRC Institute for Molecular Oncology, Via Adamello 16, 20139 Milano, Italy
| | - Chiara Milanese
- IFOM, FIRC Institute for Molecular Oncology, Via Adamello 16, 20139 Milano, Italy
| | - Sara Notari
- Department of Chemical Sciences and Technologies, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Giorgia Gambardella
- Department of Chemical Sciences and Technologies, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Giorgio Ricci
- Department of Chemical Sciences and Technologies, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Pier Giorgio Mastroberardino
- IFOM, FIRC Institute for Molecular Oncology, Via Adamello 16, 20139 Milano, Italy
- Department of Life, Health, and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Carla Boccaccio
- Department of Oncology, University of Turin, 10060 Candiolo, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, Italy
| | - Tiziana Crepaldi
- Department of Oncology, University of Turin, 10060 Candiolo, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, Italy
| | - Paolo Maria Comoglio
- IFOM, FIRC Institute for Molecular Oncology, Via Adamello 16, 20139 Milano, Italy
- Correspondence: (D.M.A.); (P.M.C.)
| |
Collapse
|
|
27
|
Qu H, Khalil RA. Role of ADAM and ADAMTS Disintegrin and Metalloproteinases in Normal Pregnancy and Preeclampsia. Biochem Pharmacol 2022; 206:115266. [PMID: 36191626 DOI: 10.1016/j.bcp.2022.115266] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 11/16/2022]
Abstract
Normal pregnancy (NP) involves intricate processes starting with egg fertilization, proceeding to embryo implantation, placentation and gestation, and culminating in parturition. These pregnancy-related processes require marked uteroplacental and vascular remodeling by proteolytic enzymes and metalloproteinases. A disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS) are members of the zinc-dependent family of proteinases with highly conserved protein structure and sequence homology, which include a pro-domain, and a metalloproteinase, disintegrin and cysteine-rich domain. In NP, ADAMs and ADAMTS regulate sperm-egg fusion, embryo implantation, trophoblast invasion, placental angiogenesis and spiral arteries remodeling through their ectodomain proteolysis of cell surface cytokines, cadherins and growth factors as well as their adhesion with integrins and cell-cell junction proteins. Preeclampsia (PE) is a serious complication of pregnancy characterized by new-onset hypertension (HTN) in pregnancy (HTN-Preg) at or after 20 weeks of gestation, with or without proteinuria. Insufficient trophoblast invasion of the uterine wall, inadequate expansive remodeling of the spiral arteries, reduced uteroplacental perfusion pressure, and placental ischemia/hypoxia are major initiating events in the pathogenesis of PE. Placental ischemia/hypoxia increase the release of reactive oxygen species (ROS), which lead to aberrant expression/activity of certain ADAMs and ADAMTS. In PE, abnormal expression/activity of specific ADAMs and ADAMTS that function as proteolytic sheddases could alter proangiogenic and growth factors, and promote the release of antiangiogenic factors and inflammatory cytokines into the placenta and maternal circulation leading to generalized inflammation, endothelial cell injury and HTN-Preg, renal injury and proteinuria, and further decreases in uteroplacental blood flow, exaggeration of placental ischemia, and consequently fetal growth restriction. Identifying the role of ADAMs and ADAMTS in NP and PE has led to a better understanding of the underlying molecular and vascular pathways, and advanced the potential for novel biomarkers for prediction and early detection, and new approaches for the management of PE.
Collapse
Affiliation(s)
- Hongmei Qu
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA
| | - Raouf A Khalil
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.
| |
Collapse
|
|
28
|
Zhao Y, Ye W, Wang YD, Chen WD. HGF/c-Met: A Key Promoter in Liver Regeneration. Front Pharmacol 2022; 13:808855. [PMID: 35370682 PMCID: PMC8968572 DOI: 10.3389/fphar.2022.808855] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 02/11/2022] [Indexed: 01/18/2023] Open
Abstract
Hepatocyte growth factor (HGF) is a peptide-containing multifunctional cytokine that acts on various epithelial cells to regulate cell growth, movement and morphogenesis, and tissue regeneration of injured organs. HGF is sequestered by heparin-like protein in its inactive form and is widespread in the extracellular matrix of most tissues. When the liver loses its average mass, volume, or physiological and biochemical functions due to various reasons, HGF binds to its specific receptor c-Met (cellular mesenchymal-epithelial transition) and transmits the signals into the cells, and triggers the intrinsic kinase activity of c-Met. The downstream cascades of HGF/c-Met include JAK/STAT3, PI3K/Akt/NF-κB, and Ras/Raf pathways, affecting cell proliferation, growth, and survival. HGF has important clinical significance for liver fibrosis, hepatocyte regeneration after inflammation, and liver regeneration after transplantation. And the development of HGF as a biological drug for regenerative therapy of diseases, that is, using recombinant human HGF protein to treat disorders in clinical trials, is underway. This review summarizes the recent findings of the HGF/c-Met signaling functions in liver regeneration.
Collapse
Affiliation(s)
- Yang Zhao
- Key Laboratory of Receptors-Mediated Gene Regulation, The People's Hospital of Hebi, School of Medicine, Henan University, Kaifeng, China
| | - Wenling Ye
- Key Laboratory of Receptors-Mediated Gene Regulation, The People's Hospital of Hebi, School of Medicine, Henan University, Kaifeng, China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation, The People's Hospital of Hebi, School of Medicine, Henan University, Kaifeng, China
| |
Collapse
|
|
29
|
Appraisal of Hepatocyte Growth Factor Signal Transduction in the Duality of HIV Associated Pre-Eclampsia. Pregnancy Hypertens 2022; 28:128-133. [DOI: 10.1016/j.preghy.2022.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 02/19/2022] [Accepted: 03/14/2022] [Indexed: 11/17/2022]
|
|
30
|
Li G, Wang Y, Cao G, Ma Y, Li YX, Zhao Y, Shao X, Wang YL. Hypoxic stress disrupts HGF/Met signaling in human trophoblasts: implications for the pathogenesis of preeclampsia. J Biomed Sci 2022; 29:8. [PMID: 35114998 PMCID: PMC8815204 DOI: 10.1186/s12929-022-00791-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 01/21/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Preeclampsia (PE), a placenta-associated pregnancy complication, is the leading cause of maternal and perinatal morbidity and mortality. Met/Erk signaling is inhibited in the placentas of patients with early-onset preeclampsia (E-PE), but the underlying mechanisms remain elusive. In this study, the expression modes of Met and endocytic vesicles in normal and preeclamptic placentas were compared. Biotinylation internalization/recycling assays were used to measure the endocytosis of Met under hypoxia and normoxia in HTR8/SVneo cells. In addition, the expression level of Cbl, a specific E3 ligase of Met, was measured under hypoxia and normoxia, and the endocytosis of Met was studied by using confocal microscopy. RESULTS We found considerable intracellular accumulation of Met, which was colocalized with caveolin-1 (CAV-1), in trophoblasts from E-PE placentas. Prolonged hypoxic stimulation led to the remarkable augmentation of CAV-1-mediated Met endocytosis in HTR8/SVneo cells. In addition, the expression of Cbl was substantially repressed by sustained hypoxia, disrupting ubiquitin degradation and the subsequent intracellular accumulation of Met in HTR8/SVneo cells. The abnormal degradation of Met hampered the ability of hepatocyte growth factor (HGF) to promote trophoblast cell invasion. In E-PE placentas, aberrant upregulation of CAV-1 and downregulation of Cbl were observed in parallel to the intracellular accumulation of Met. CONCLUSIONS These findings reveal that prolonged hypoxic stress induces the augmentation of endocytosis and repression of ubiquitin-mediated Met degradation, which leads to the impaired regulation of trophoblast invasion by HGF/Met signaling. These data provide novel evidence for elucidating the pathogenesis of preeclampsia, especially of the early-onset subtype.
Collapse
Affiliation(s)
- Guanlin Li
- Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Yongqing Wang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Guangming Cao
- Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Beijing, China
| | - Yeling Ma
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Yu-Xia Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Yangyu Zhao
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
| | - Xuan Shao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
- University of the Chinese Academy of Sciences, Beijing, China.
| | - Yan-Ling Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
- University of the Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
|
31
|
Li G, Wang Y, Cao G, Ma Y, Li YX, Zhao Y, Shao X, Wang YL. Hypoxic stress disrupts HGF/Met signaling in human trophoblasts: implications for the pathogenesis of preeclampsia. J Biomed Sci 2022; 29:8. [DOI: pmid: 35114998 doi: 10.1186/s12929-022-00791-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 01/21/2022] [Indexed: 05/17/2025] Open
Abstract
Abstract
Background
Preeclampsia (PE), a placenta-associated pregnancy complication, is the leading cause of maternal and perinatal morbidity and mortality. Met/Erk signaling is inhibited in the placentas of patients with early-onset preeclampsia (E-PE), but the underlying mechanisms remain elusive. In this study, the expression modes of Met and endocytic vesicles in normal and preeclamptic placentas were compared. Biotinylation internalization/recycling assays were used to measure the endocytosis of Met under hypoxia and normoxia in HTR8/SVneo cells. In addition, the expression level of Cbl, a specific E3 ligase of Met, was measured under hypoxia and normoxia, and the endocytosis of Met was studied by using confocal microscopy.
Results
We found considerable intracellular accumulation of Met, which was colocalized with caveolin-1 (CAV-1), in trophoblasts from E-PE placentas. Prolonged hypoxic stimulation led to the remarkable augmentation of CAV-1-mediated Met endocytosis in HTR8/SVneo cells. In addition, the expression of Cbl was substantially repressed by sustained hypoxia, disrupting ubiquitin degradation and the subsequent intracellular accumulation of Met in HTR8/SVneo cells. The abnormal degradation of Met hampered the ability of hepatocyte growth factor (HGF) to promote trophoblast cell invasion. In E-PE placentas, aberrant upregulation of CAV-1 and downregulation of Cbl were observed in parallel to the intracellular accumulation of Met.
Conclusions
These findings reveal that prolonged hypoxic stress induces the augmentation of endocytosis and repression of ubiquitin-mediated Met degradation, which leads to the impaired regulation of trophoblast invasion by HGF/Met signaling. These data provide novel evidence for elucidating the pathogenesis of preeclampsia, especially of the early-onset subtype.
Collapse
|
|
32
|
BMP9 Promotes an Epithelial Phenotype and a Hepatocyte-like Gene Expression Profile in Adult Hepatic Progenitor Cells. Cells 2022; 11:cells11030365. [PMID: 35159174 PMCID: PMC8834621 DOI: 10.3390/cells11030365] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 11/24/2022] Open
Abstract
Bone morphogenetic protein 9 (BMP9), a member of the TGF-β superfamily, has emerged as a new player in chronic liver diseases (CLDs). Its levels increase in the fibrotic liver where it promotes fibrogenesis. It also regulates hepatic progenitor cells (oval cells in rodents), a cell population that contributes to repopulate the liver and recover functionality upon severe damage, but it can also be pro-fibrogenic, depending upon the hepatic microenvironment. Here we analyze the effect of chronic exposure to BMP9 in oval cells. We show that cells chronically treated with BMP9 (B9T-OC) display a more epithelial and hepatocyte-like phenotype while acquiring proliferative and survival advantages. Since our previous studies had revealed a functional crosstalk between BMP9 and the HGF/c-Met signaling pathways in oval cells, we analyzed a possible role for HGF/c-Met in BMP9-induced long-term effects. Data evidence that active c-Met signaling is necessary to obtain maximum effects in terms of BMP9-triggered hepatocytic differentiation potential, further supporting functionally relevant cooperation between these pathways. In conclusion, our work reveals a novel action of BMP9 in liver cells and helps elucidate the mechanisms that serve to increase oval cell regenerative potential, which could be therapeutically modulated in CLD.
Collapse
|
|
33
|
Prasad RR, Mishra DK, Kumar M, Yadava PK. Human telomerase reverse transcriptase promotes the epithelial to mesenchymal transition in lung cancer cells by enhancing c-MET upregulation. Heliyon 2022; 8:e08673. [PMID: 35024489 PMCID: PMC8732784 DOI: 10.1016/j.heliyon.2021.e08673] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/01/2021] [Accepted: 12/21/2021] [Indexed: 10/25/2022] Open
Abstract
Human telomerase reverse transcriptase (hTERT), the essential catalytic subunit of telomerase, is associated with telomere homeostasis to prevent replicative senescence and cellular aging. However, hTERT reactivation also has been linked to the acquisition of several hallmarks of cancer, although the underlying mechanism beyond telomere extension remains elusive. This study demonstrated that hTERT overexpression promotes, whereas its inhibition by shRNA suppresses, epithelial-mesenchymal transition (EMT) in lung cancer cells (A549 and H1299). We found that hTERT modulates the expression of EMT markers E-cadherin, vimentin, and cytokeratin-18a through upregulation of the c-MET. Ectopic expression of hTERT induces expression of c-MET, while hTERT-shRNA treatment significantly decreases the c-MET level in A549 and H1299 through differential expression of p53 and c-Myc. Reporter assay suggests the regulation of c-MET expression by hTERT to be at the promoter level. An increase in c-MET level significantly promotes the expression of mesenchymal markers, including vimentin and N-cadherin, while a notable increase in epithelial markers E-cadherin and cytokeratin-18a is observed after the c-MET knockdown in A549.
Collapse
Affiliation(s)
- Ram Raj Prasad
- Applied Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - Deepak Kumar Mishra
- Applied Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - Manoj Kumar
- Applied Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - Pramod Kumar Yadava
- Applied Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.,Department of Biological Sciences, Indian Institute for Science Education and Research, Berhampur 760010, Odisha, India
| |
Collapse
|
|
34
|
Liedtke C, Nevzorova YA, Luedde T, Zimmermann H, Kroy D, Strnad P, Berres ML, Bernhagen J, Tacke F, Nattermann J, Spengler U, Sauerbruch T, Wree A, Abdullah Z, Tolba RH, Trebicka J, Lammers T, Trautwein C, Weiskirchen R. Liver Fibrosis-From Mechanisms of Injury to Modulation of Disease. Front Med (Lausanne) 2022; 8:814496. [PMID: 35087852 PMCID: PMC8787129 DOI: 10.3389/fmed.2021.814496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
The Transregional Collaborative Research Center "Organ Fibrosis: From Mechanisms of Injury to Modulation of Disease" (referred to as SFB/TRR57) was funded for 13 years (2009-2021) by the German Research Council (DFG). This consortium was hosted by the Medical Schools of the RWTH Aachen University and Bonn University in Germany. The SFB/TRR57 implemented combined basic and clinical research to achieve detailed knowledge in three selected key questions: (i) What are the relevant mechanisms and signal pathways required for initiating organ fibrosis? (ii) Which immunological mechanisms and molecules contribute to organ fibrosis? and (iii) How can organ fibrosis be modulated, e.g., by interventional strategies including imaging and pharmacological approaches? In this review we will summarize the liver-related key findings of this consortium gained within the last 12 years on these three aspects of liver fibrogenesis. We will highlight the role of cell death and cell cycle pathways as well as nutritional and iron-related mechanisms for liver fibrosis initiation. Moreover, we will define and characterize the major immune cell compartments relevant for liver fibrogenesis, and finally point to potential signaling pathways and pharmacological targets that turned out to be suitable to develop novel approaches for improved therapy and diagnosis of liver fibrosis. In summary, this review will provide a comprehensive overview about the knowledge on liver fibrogenesis and its potential therapy gained by the SFB/TRR57 consortium within the last decade. The kidney-related research results obtained by the same consortium are highlighted in an article published back-to-back in Frontiers in Medicine.
Collapse
Affiliation(s)
- Christian Liedtke
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Yulia A. Nevzorova
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
- Department of Immunology, Ophthalmology and Otolaryngology, School of Medicine, Complutense University Madrid, Madrid, Spain
| | - Tom Luedde
- Medical Faculty, Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Henning Zimmermann
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Daniela Kroy
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Marie-Luise Berres
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Jürgen Bernhagen
- Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München (KUM), Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Tilman Sauerbruch
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Alexander Wree
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Zeinab Abdullah
- Institute for Molecular Medicine and Experimental Immunology, University Hospital of Bonn, Bonn, Germany
| | - René H. Tolba
- Institute for Laboratory Animal Science and Experimental Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Jonel Trebicka
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
| | - Twan Lammers
- Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), University Hospital RWTH Aachen, Aachen, Germany
| |
Collapse
|
|
35
|
Clark JF, Soriano PM. Pulling back the curtain: The hidden functions of receptor tyrosine kinases in development. Curr Top Dev Biol 2022; 149:123-152. [PMID: 35606055 PMCID: PMC9127239 DOI: 10.1016/bs.ctdb.2021.12.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Receptor tyrosine kinases (RTKs) are a conserved superfamily of transmembrane growth factor receptors that drive numerous cellular processes during development and in the adult. Upon activation, multiple adaptors and signaling effector proteins are recruited to binding site motifs located within the intracellular domain of the RTK. These RTK-effector interactions drive subsequent intracellular signaling cascades involved in canonical RTK signaling. Genetic dissection has revealed that alleles of Fibroblast Growth Factor receptors (FGFRs) that lack all canonical RTK signaling still retain some kinase-dependent biological activity. Here we examine how genetic analysis can be used to understand the mechanism by which RTKs drive multiple developmental processes via canonical signaling while revealing noncanonical activities. Recent data from both FGFRs and other RTKs highlight potential noncanonical roles in cell adhesion and nuclear signaling. The data supporting such functions are discussed as are recent technologies that have the potential to provide valuable insight into the developmental significance of these noncanonical activities.
Collapse
Affiliation(s)
- James F Clark
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Philippe M Soriano
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
| |
Collapse
|
|
36
|
Garcia-Robledo JE, Rosell R, Ruíz-Patiño A, Sotelo C, Arrieta O, Zatarain-Barrón L, Ordoñez C, Jaller E, Rojas L, Russo A, de Miguel-Pérez D, Rolfo C, Cardona AF. KRAS and MET in non-small-cell lung cancer: two of the new kids on the 'drivers' block. Ther Adv Respir Dis 2022; 16:17534666211066064. [PMID: 35098800 PMCID: PMC8808025 DOI: 10.1177/17534666211066064] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 10/14/2021] [Indexed: 12/30/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) is a heterogeneous disease, and therapeutic management has advanced to identify various critical oncogenic mutations that promote lung cancer tumorigenesis. Subsequent studies have developed targeted therapies against these oncogenes in the hope of personalized treatment based on the tumor's molecular genomics. This review presents a comprehensive review of the biology, new therapeutic interventions, and resistance patterns of two well-defined subgroups, tumors with KRAS and MET alterations. We also discuss the status of molecular testing practices for these two key oncogenic drivers, considering the progressive introduction of next-generation sequencing (NGS) and RNA sequencing in regular clinical practice.
Collapse
Affiliation(s)
| | - Rafael Rosell
- Cancer Biology and Precision Medicine Program, Germans Trias i Pujol Research Institute (IGTP)/Dr. Rosell Oncology Institute (IOR), Quirón-Dexeus University Institute, Barcelona, Spain
| | - Alejandro Ruíz-Patiño
- Direction of Research and Education, Luis Carlos Sarmiento Angulo Cancer Treatment and Research Center (CTIC), Bogotá, Colombia
- Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia Molecular Oncology and Biology Systems Research Group (Fox-G), Universidad El Bosque, Bogotá, Colombia
- Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia Molecular Oncology and Biology Systems Research Group (Fox-G), Universidad El Bosque, Bogotá, Colombia
| | - Carolina Sotelo
- Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia Molecular Oncology and Biology Systems Research Group (Fox-G), Universidad El Bosque, Bogotá, Colombia
| | - Oscar Arrieta
- Thoracic Oncology Unit and Personalized Oncology Laboratory, National Cancer Institute (INCan), México City, México
| | - Lucia Zatarain-Barrón
- Thoracic Oncology Unit and Personalized Oncology Laboratory, National Cancer Institute (INCan), México City, México
| | - Camila Ordoñez
- Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia Molecular Oncology and Biology Systems Research Group (Fox-G), Universidad El Bosque, Bogotá, Colombia
| | - Elvira Jaller
- Department of Internal Medicine, Universidad El Bosque, Bogotá, Colombia
| | - Leonardo Rojas
- Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia Department of Clinical Oncology, Clínica Colsanitas, Bogotá, Colombia Clinical and Translational Oncology Group, Clínica del Country, Bogotá, Colombia
| | - Alessandro Russo
- Medical Oncology Unit, A.O. Papardo, Messina, Italy Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Diego de Miguel-Pérez
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Christian Rolfo
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | | |
Collapse
|
|
37
|
Grundy M, Narendran A. The hepatocyte growth factor/mesenchymal epithelial transition factor axis in high-risk pediatric solid tumors and the anti-tumor activity of targeted therapeutic agents. Front Pediatr 2022; 10:910268. [PMID: 36034555 PMCID: PMC9399617 DOI: 10.3389/fped.2022.910268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 07/15/2022] [Indexed: 01/04/2023] Open
Abstract
Clinical trials completed in the last two decades have contributed significantly to the improved overall survival of children with cancer. In spite of these advancements, disease relapse still remains a significant cause of death in this patient population. Often, increasing the intensity of current protocols is not feasible because of cumulative toxicity and development of drug resistance. Therefore, the identification and clinical validation of novel targets in high-risk and refractory childhood malignancies are essential to develop effective new generation treatment protocols. A number of recent studies have shown that the hepatocyte growth factor (HGF) and its receptor Mesenchymal epithelial transition factor (c-MET) influence the growth, survival, angiogenesis, and metastasis of cancer cells. Therefore, the c-MET receptor tyrosine kinase and HGF have been identified as potential targets for cancer therapeutics and recent years have seen a race to synthesize molecules to block their expression and function. In this review we aim to summarize the literature that explores the potential and biological rationale for targeting the HGF/c-MET pathway in common and high-risk pediatric solid tumors. We also discuss selected recent and ongoing clinical trials with these agents in relapsed pediatric tumors that may provide applicable future treatments for these patients.
Collapse
Affiliation(s)
- Megan Grundy
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Aru Narendran
- POETIC Laboratory for Preclinical and Drug Discovery Studies, Division of Pediatric Oncology, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada
| |
Collapse
|
|
38
|
Kreicberga I, Junga A, Pilmane M. Investigation of HoxB3 and Growth Factors Expression in Placentas of Various Gestational Ages. J Dev Biol 2021; 10:jdb10010002. [PMID: 35076557 PMCID: PMC8788416 DOI: 10.3390/jdb10010002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/17/2021] [Accepted: 12/23/2021] [Indexed: 12/04/2022] Open
Abstract
An evaluation of transforming growth factor beta (TGFβ), hepatocyte growth factor (HGF), basic fibroblast growth factor (FGF-2), fibroblast growth factors receptor 1 (FGFR1) and Hox-positive cells in the human placenta, and their correlation with gestational time at delivery and pregnancy outcomes, may provide not only a better understanding of the role of Hox genes and growth factors in human development, but also may be of clinical importance in reproductive medicine. This study analyzed the immunohistochemical identification of TGFβ, HGF, FGF-2, FGFR1 and HoxB3 in placentas of various gestational ages. We found few (+) TGFβ, moderate (++) FGF-2 and numerous (+++) HGF and FGFR1 positive structures. Occasional (0/+) to numerous (+++) HoxB3-positive structures were detected in different types of placental cells specifically, cytotrophoblasts, syncytiotrophoblast, extravillous trophoblasts, and Höfbauer cells. Correlating the appearance of HoxB3 staining in placentas with neonatal parameters, we found a statistically significant negative correlation with ponderal index (r = −0.323, p = 0.018) and positive correlation with neonate body length (r = 0.541, p = 0.046). The number of HoxB3-positive cells did not correlate with growth factors and gestational age, but with neonatal anthropometrical parameters, indicating the role of HoxB3 not only in placental development, but also in the longitudinal growth of the fetus. TGFβ and FGF-2 did not play a significant role in the development of the placenta beyond 22nd week of pregnancy, while HGF and FGFR1 immunoreactive cells increased with advancing gestation, indicating increasingly evolving maturation (growth, proliferation) of the placenta, especially in the third trimester.
Collapse
|
|
39
|
Desole C, Gallo S, Vitacolonna A, Vigna E, Basilico C, Montarolo F, Zuppini F, Casanova E, Miggiano R, Ferraris DM, Bertolotto A, Comoglio PM, Crepaldi T. Engineering, Characterization, and Biological Evaluation of an Antibody Targeting the HGF Receptor. Front Immunol 2021; 12:775151. [PMID: 34925346 PMCID: PMC8679783 DOI: 10.3389/fimmu.2021.775151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 11/08/2021] [Indexed: 11/13/2022] Open
Abstract
The Hepatocyte growth factor (HGF) and its receptor (MET) promote several physiological activities such as tissue regeneration and protection from cell injury of epithelial, endothelial, neuronal and muscle cells. The therapeutic potential of MET activation has been scrutinized in the treatment of acute tissue injury, chronic inflammation, such as renal fibrosis and multiple sclerosis (MS), cardiovascular and neurodegenerative diseases. On the other hand, the HGF-MET signaling pathway may be caught by cancer cells and turned to work for invasion, metastasis, and drug resistance in the tumor microenvironment. Here, we engineered a recombinant antibody (RDO24) and two derived fragments, binding the extracellular domain (ECD) of the MET protein. The antibody binds with high affinity (8 nM) to MET ECD and does not cross-react with the closely related receptors RON nor with Semaphorin 4D. Deletion mapping studies and computational modeling show that RDO24 binds to the structure bent on the Plexin-Semaphorin-Integrin (PSI) domain, implicating the PSI domain in its binding to MET. The intact RDO24 antibody and the bivalent Fab2, but not the monovalent Fab induce MET auto-phosphorylation, mimicking the mechanism of action of HGF that activates the receptor by dimerization. Accordingly, the bivalent recombinant molecules induce HGF biological responses, such as cell migration and wound healing, behaving as MET agonists of therapeutic interest in regenerative medicine. In vivo administration of RDO24 in the murine model of MS, represented by experimental autoimmune encephalomyelitis (EAE), delays the EAE onset, mitigates the early clinical symptoms, and reduces inflammatory infiltrates. Altogether, these results suggest that engineered RDO24 antibody may be beneficial in multiple sclerosis and possibly other types of inflammatory disorders.
Collapse
Affiliation(s)
- Claudia Desole
- Department of Oncology, University of Turin, Candiolo, Italy
| | - Simona Gallo
- Department of Oncology, University of Turin, Candiolo, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Annapia Vitacolonna
- Department of Oncology, University of Turin, Candiolo, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Elisa Vigna
- Department of Oncology, University of Turin, Candiolo, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | | | - Francesca Montarolo
- Neuroscience Institute Cavalieri Ottolenghi (NICO), Orbassano, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy
| | | | | | - Riccardo Miggiano
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy.,IXTAL srl, Novara, Italy
| | - Davide Maria Ferraris
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy.,IXTAL srl, Novara, Italy
| | | | | | - Tiziana Crepaldi
- Department of Oncology, University of Turin, Candiolo, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| |
Collapse
|
|
40
|
Rahm JV, Malkusch S, Endesfelder U, Dietz MS, Heilemann M. Diffusion State Transitions in Single-Particle Trajectories of MET Receptor Tyrosine Kinase Measured in Live Cells. FRONTIERS IN COMPUTER SCIENCE 2021. [DOI: 10.3389/fcomp.2021.757653] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Single-particle tracking enables the analysis of the dynamics of biomolecules in living cells with nanometer spatial and millisecond temporal resolution. This technique reports on the mobility of membrane proteins and is sensitive to the molecular state of a biomolecule and to interactions with other biomolecules. Trajectories describe the mobility of single particles over time and provide information such as the diffusion coefficient and diffusion state. Changes in particle dynamics within single trajectories lead to segmentation, which allows to extract information on transitions of functional states of a biomolecule. Here, mean-squared displacement analysis is developed to classify trajectory segments into immobile, confined diffusing, and freely diffusing states, and to extract the occurrence of transitions between these modes. We applied this analysis to single-particle tracking data of the membrane receptor MET in live cells and analyzed state transitions in single trajectories of the un-activated receptor and the receptor bound to the ligand internalin B. We found that internalin B-bound MET shows an enhancement of transitions from freely and confined diffusing states into the immobile state as compared to un-activated MET. Confined diffusion acts as an intermediate state between immobile and free, as this state is most likely to change the diffusion state in the following segment. This analysis can be readily applied to single-particle tracking data of other membrane receptors and intracellular proteins under various conditions and contribute to the understanding of molecular states and signaling pathways.
Collapse
|
|
41
|
Li HJ, Ke FY, Lin CC, Lu MY, Kuo YH, Wang YP, Liang KH, Lin SC, Chang YH, Chen HY, Yang PC, Wu HC. ENO1 Promotes Lung Cancer Metastasis via HGFR and WNT Signaling-Driven Epithelial-to-Mesenchymal Transition. Cancer Res 2021; 81:4094-4109. [PMID: 34145039 DOI: 10.1158/0008-5472.can-20-3543] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/06/2021] [Accepted: 06/15/2021] [Indexed: 11/16/2022]
Abstract
ENO1 (α-enolase) expression is significantly correlated with reduced survival and poor prognosis in many cancer types, including lung cancer. However, the function of ENO1 in carcinogenesis remains elusive. In this study, we found that high expression of ENO1 is present in metastatic lung cancer cell lines and malignant tumors and is associated with poor overall survival of patients with lung cancer. Knockdown of ENO1 decreased cancer cell proliferation and invasiveness, whereas overexpression of ENO1 enhanced these processes. Moreover, ENO1 expression promoted tumor growth in orthotopic models and enhanced lung tumor metastasis in tail-vein injection models. These effects were mediated by upregulation of mesenchymal markers N-cadherin and vimentin and the epithelial-to-mesenchymal transition regulator SLUG, along with concurrent downregulation of E-cadherin. Mechanistically, ENO1 interacted with hepatocyte growth factor receptor (HGFR) and activated HGFR and Wnt signaling via increased phosphorylation of HGFR and the Wnt coreceptor LRP5/6. Activation of these signaling axes decreased GSK3β activity via Src-PI3K-AKT signaling and inactivation of the β-catenin destruction complex to ultimately upregulate SLUG and β-catenin. In addition, we generated a chimeric anti-ENO1 mAb (chENO1-22) that can decrease cancer cell proliferation and invasion. chENO1-22 attenuated cancer cell invasion by inhibiting ENO1-mediated GSK3β inactivation to promote SLUG protein ubiquitination and degradation. Moreover, chENO1-22 prevented lung tumor metastasis and prolonged survival in animal models. Taken together, these findings illuminate the molecular mechanisms underlying the function of ENO1 in lung cancer metastasis and support the therapeutic potential of a novel antibody targeting ENO1 for treating lung cancer. SIGNIFICANCE: This study shows that ENO1 promotes lung cancer metastasis via HGFR and WNT signaling and introduces a novel anti-ENO1 antibody for potential therapeutic use in lung cancer.
Collapse
Affiliation(s)
- Hsin-Jung Li
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Feng-Yi Ke
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Chia-Ching Lin
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Mei-Yi Lu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Yi-Huei Kuo
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Yi-Ping Wang
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.,Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
| | - Kang-Hao Liang
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.,Biomedical Translation Research Center (BioTReC), Academia Sinica, Taipei, Taiwan
| | - Shin-Chang Lin
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.,Biomedical Translation Research Center (BioTReC), Academia Sinica, Taipei, Taiwan
| | - Ya-Hsuan Chang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Hsuan-Yu Chen
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Pan-Chyr Yang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Han-Chung Wu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan. .,Biomedical Translation Research Center (BioTReC), Academia Sinica, Taipei, Taiwan
| |
Collapse
|
|
42
|
Ogoke O, Yousef O, Ott C, Kalinousky A, Lin W, Shamul C, Ross S, Parashurama N. Modeling Liver Organogenesis by Recreating Three-Dimensional Collective Cell Migration: A Role for TGFβ Pathway. Front Bioeng Biotechnol 2021; 9:621286. [PMID: 34211963 PMCID: PMC8239196 DOI: 10.3389/fbioe.2021.621286] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 04/21/2021] [Indexed: 12/29/2022] Open
Abstract
Three-dimensional (3D) collective cell migration (CCM) is critical for improving liver cell therapies, eliciting mechanisms of liver disease, and modeling human liver development and organogenesis. Mechanisms of CCM differ in 2D vs. 3D systems, and existing models are limited to 2D or transwell-based systems, suggesting there is a need for improved 3D models of CCM. To recreate liver 3D CCM, we engineered in vitro 3D models based upon a morphogenetic transition that occurs during liver organogenesis, which occurs rapidly between E8.5 and E9.5 (mouse). During this morphogenetic transition, 3D CCM exhibits co-migration (multiple cell types), thick-strand interactions with surrounding septum transversum mesenchyme (STM), branching morphogenesis, and 3D interstitial migration. Here, we engineer several 3D in vitro culture systems, each of which mimics one of these processes in vitro. In mixed spheroids bearing both liver cells and uniquely MRC-5 (fetal lung) fibroblasts, we observed evidence of co-migration, and a significant increase in length and number of liver spheroid protrusions, which was highly sensitive to transforming growth factor beta 1 (TGFβ1) stimulation. In MRC-5-conditioned medium (M-CM) experiments, we observed dose-dependent branching morphogenesis associated with an upregulation of Twist1, which was inhibited by a broad TGFβ inhibitor. In models in which liver spheroids and MRC-5 spheroids were co-cultured, we observed complex strand morphogenesis, whereby thin, linear, 3D liver cell strands attach to the MRC-5 spheroid, anchor and thicken to form permanent and thick anchoring contacts between the two spheroids. In these spheroid co-culture models, we also observed spheroid fusion and strong evidence for interstitial migration. In conclusion, we present several novel cultivation systems that recreate distinct features of liver 3D CCM. These methodologies will greatly improve our molecular, cellular, and tissue-scale understanding of liver organogenesis, liver diseases like cancer, and liver cell therapy, and will also serve as a tool to bridge conventional 2D studies and preclinical in vivo studies.
Collapse
Affiliation(s)
- Ogechi Ogoke
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, NY, United States
| | - Osama Yousef
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, NY, United States
| | - Cortney Ott
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, NY, United States
| | - Allison Kalinousky
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, NY, United States
| | - Wayne Lin
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, NY, United States
| | - Claire Shamul
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, NY, United States
| | - Shatoni Ross
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, NY, United States
| | - Natesh Parashurama
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Buffalo, NY, United States.,Department of Biomedical Engineering, University at Buffalo (State University of New York), Buffalo, NY, United States.,Clinical and Translational Research Center, University at Buffalo (State University of New York), Buffalo, NY, United States
| |
Collapse
|
|
43
|
Desole C, Gallo S, Vitacolonna A, Montarolo F, Bertolotto A, Vivien D, Comoglio P, Crepaldi T. HGF and MET: From Brain Development to Neurological Disorders. Front Cell Dev Biol 2021; 9:683609. [PMID: 34179015 PMCID: PMC8220160 DOI: 10.3389/fcell.2021.683609] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 04/30/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatocyte growth factor (HGF) and its tyrosine kinase receptor, encoded by the MET cellular proto-oncogene, are expressed in the nervous system from pre-natal development to adult life, where they are involved in neuronal growth and survival. In this review, we highlight, beyond the neurotrophic action, novel roles of HGF-MET in synaptogenesis during post-natal brain development and the connection between deregulation of MET expression and developmental disorders such as autism spectrum disorder (ASD). On the pharmacology side, HGF-induced MET activation exerts beneficial neuroprotective effects also in adulthood, specifically in neurodegenerative disease, and in preclinical models of cerebral ischemia, spinal cord injuries, and neurological pathologies, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). HGF is a key factor preventing neuronal death and promoting survival through pro-angiogenic, anti-inflammatory, and immune-modulatory mechanisms. Recent evidence suggests that HGF acts on neural stem cells to enhance neuroregeneration. The possible therapeutic application of HGF and HGF mimetics for the treatment of neurological disorders is discussed.
Collapse
Affiliation(s)
- Claudia Desole
- Department of Oncology, University of Turin, Turin, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Simona Gallo
- Department of Oncology, University of Turin, Turin, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Annapia Vitacolonna
- Department of Oncology, University of Turin, Turin, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Francesca Montarolo
- Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy.,Neurobiology Unit, Neurology, CReSM (Regional Referring Center of Multiple Sclerosis), San Luigi Gonzaga University Hospital, Orbassano, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Antonio Bertolotto
- Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy.,Neurobiology Unit, Neurology, CReSM (Regional Referring Center of Multiple Sclerosis), San Luigi Gonzaga University Hospital, Orbassano, Italy
| | - Denis Vivien
- INSERM U1237, University of Caen, Gyp Cyceron, Caen, France.,Department of Clinical Research, Caen-Normandie University Hospital, Caen, France
| | - Paolo Comoglio
- IFOM, FIRC Institute for Molecular Oncology, Milan, Italy
| | - Tiziana Crepaldi
- Department of Oncology, University of Turin, Turin, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| |
Collapse
|
|
44
|
When the MET receptor kicks in to resist targeted therapies. Oncogene 2021; 40:4061-4078. [PMID: 34031544 DOI: 10.1038/s41388-021-01835-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/26/2021] [Accepted: 05/07/2021] [Indexed: 02/04/2023]
Abstract
Although targeted therapies have increased the life expectancy of patients with druggable molecular alterations directly involved in tumor development, the efficacy of these therapies is limited by acquired resistances leading to treatment failure. Most targeted therapies, including ones exploiting therapeutic antibodies and kinase inhibitors, are directed against receptor tyrosine kinases (RTKs) or major signaling hubs. Resistances to these therapies arise when inhibition of these targets is bypassed through activation of alternative signaling pathways. In recent years, activation of the receptor tyrosine kinase MET has been shown to promote resistance to various targeted therapies. This casts MET as important actor in resistance. In this review, we describe how the MET receptor triggers resistance to targeted therapies against RTKs such as EGFR, VEGFR, and HER2 and against signaling hubs such as BRAF. We also describe how MET can be its own resistance factor, as illustrated by on-target resistance of lung tumors harboring activating mutations causing MET exon 14 skipping. Interestingly, investigation of all these situations reveals functional physiological relationships between MET and the target of the therapy to which the cancer becomes resistant, suggesting that resistance stems from preexisting mechanisms. Identification of MET as a resistance factor opens the way to co-treatment strategies that are being tested in current clinical trials.
Collapse
|
|
45
|
Differential roles of factors IX and XI in murine placenta and hemostasis under conditions of low tissue factor. Blood Adv 2021; 4:207-216. [PMID: 31935292 DOI: 10.1182/bloodadvances.2019000921] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 10/28/2019] [Indexed: 01/31/2023] Open
Abstract
The intrinsic tenase complex (FIXa-FVIIIa) of the intrinsic coagulation pathway and, to a lesser extent, thrombin-mediated activation of FXI, are necessary to amplify tissue factor (TF)-FVIIa-initiated thrombin generation. In this study, we determined the contribution of murine FIX and FXI to TF-dependent thrombin generation in vitro. We further investigated TF-dependent FIX activation in mice and the contribution of this pathway to hemostasis. Thrombin generation was decreased in FIX- but not in FXI-deficient mouse plasma. Furthermore, injection of TF increased levels of FIXa-antithrombin complexes in both wild-type and FXI-/- mice. Genetic studies were used to determine the effect of complete deficiencies of either FIX or FXI on the survival of mice expressing low levels of TF. Low-TF;FIX-/y male mice were born at the expected frequency, but none survived to wean. In contrast, low-TF;FXI-/- mice were generated at the expected frequency at wean and had a 6-month survival equivalent to that of low-TF mice. Surprisingly, a deficiency of FXI, but not FIX, exacerbated the size of blood pools in low-TF placentas and led to acute hemorrhage and death of some pregnant dams. Our data indicate that FIX, but not FXI, is essential for survival of low-TF mice after birth. This finding suggests that TF-FVIIa-mediated activation of FIX plays a critical role in murine hemostasis. In contrast, FXI deficiency, but not FIX deficiency, exacerbated blood pooling in low-TF placentas, indicating a tissue-specific requirement for FXI in the murine placenta under conditions of low TF.
Collapse
|
|
46
|
Wang S, Ma H, Yan Y, Chen Y, Fu S, Wang J, Wang Y, Chen H, Liu J. cMET promotes metastasis and epithelial-mesenchymal transition in colorectal carcinoma by repressing RKIP. J Cell Physiol 2021; 236:3963-3978. [PMID: 33151569 DOI: 10.1002/jcp.30142] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 10/01/2020] [Accepted: 10/23/2020] [Indexed: 02/05/2023]
Abstract
Increasing evidence indicates that c-mesenchymal-epithelial transition factor (cMET) plays an important role in the malignant progression of colorectal cancer (CRC). However, the underlying mechanism is not fully understood. As a metastasis suppressor, raf kinase inhibitory protein (RKIP) loss has been reported in many cancer types. In this study, the expression levels of cMET and RKIP in CRC tissues and cell lines were determined, and their crosstalk and potential biological effects were explored in vitro and in vivo. Our results showed that cMET was inversely correlated with RKIP. Both cMET upregulation and RKIP downregulation indicated poor clinical outcomes. Moreover, the MAPK/ERK signaling pathway was implicated in the regulation of cMET and RKIP. Overexpression of cMET promoted tumor cell epithelial-mesenchymal transition, invasion, migration, and chemoresistance, whereas the effects could be efficiently inhibited by increased RKIP. Notably, small hairpin RNA-mediated cMET knockdown dramatically suppressed cell proliferation, although no RKIP-induced influence on cell growth was observed in CRC. Altogether, cMET overexpression may contribute to tumor progression by inhibiting the antioncogene RKIP, providing preclinical justification for targeting RKIP to treat cMET-induced metastasis of CRC.
Collapse
Affiliation(s)
- Siyun Wang
- Department of PET Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Haiqing Ma
- Department of Oncology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Yan Yan
- Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Yu Chen
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Sirui Fu
- Department of Interventional Therapy, Zhuhai Interventional Medical Center, Zhuhai City People's Hospital/Zhuhai Hospital of Jinan University, Zhuhai, Guangdong, China
| | - Junjiang Wang
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Ying Wang
- Department of Oncology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Hao Chen
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Jianhua Liu
- Department of Oncology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
- Southern Medical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
47
|
Ma Y, Yu X, Li YX, Wang YL. HGF/c-Met signaling regulates early differentiation of placental trophoblast cells. J Reprod Dev 2021; 67:89-97. [PMID: 33455972 PMCID: PMC8075731 DOI: 10.1262/jrd.2020-107] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Depletion of hepatocyte growth factor (HGF) or mesenchymal-epithelial transition factor (c-Met) in mice leads to fetal lethality and placental maldevelopment.
However, the dynamic change pattern of HGF/c-Met signaling during placental development and its involvement in the early differentiation of trophoblasts remain
to be elucidated. In this study, using in situ hybridization assay, we elaborately demonstrated the spatial-temporal expression of
Hgf and c-Met in mouse placenta from E5.5, the very early stage after embryonic implantation, to E12.5, when the placental
structure is well developed. The concentration of the soluble form of c-Met (sMet) in maternal circulation peaked at E10.5. By utilizing the induced
differentiation model of mouse trophoblast stem cells (mTSCs), we found that HGF significantly promoted mTSC differentiation into syncytiotrophoblasts (STBs)
and invasive parietal trophoblast giant cells (PTGCs). Interestingly, sMet efficiently reversed the effect of HGF on mTSC differentiation. These findings
indicate that HGF/c-Met signaling participates in regulating placental trophoblast cell fate at the early differentiation stage and that sMet acts as an
endogenous antagonist in this aspect.
Collapse
Affiliation(s)
- Yeling Ma
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xin Yu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yu-Xia Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yan-Ling Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| |
Collapse
|
|
48
|
Yılmaz Y, Batur T, Korhan P, Öztürk M, Atabey N. Targeting c-Met and AXL Crosstalk for the Treatment of Hepatocellular Carcinoma. LIVER CANCER IN THE MIDDLE EAST 2021:333-364. [DOI: 10.1007/978-3-030-78737-0_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
49
|
HGF/MET Signaling in Malignant Brain Tumors. Int J Mol Sci 2020; 21:ijms21207546. [PMID: 33066121 PMCID: PMC7590206 DOI: 10.3390/ijms21207546] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/08/2020] [Accepted: 10/11/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocyte growth factor (HGF) ligand and its receptor tyrosine kinase (RTK) mesenchymal-epithelial transition factor (MET) are important regulators of cellular processes such as proliferation, motility, angiogenesis, and tissue regeneration. In healthy adult somatic cells, this ligand and receptor pair is expressed at low levels and has little activity except when tissue injuries arise. In cancer cells, HGF/MET are often overexpressed, and this overexpression is found to correlate with tumorigenesis, metastasis, and poorer overall prognosis. This review focuses on the signaling of these molecules in the context of malignant brain tumors. RTK signaling pathways are among the most common and universally dysregulated pathways in gliomas. We focus on the role of HGF/MET in the following primary malignant brain tumors: astrocytomas, glioblastomas, oligodendrogliomas, ependymomas, and embryonal central nervous system tumors (including medulloblastomas and others). Brain metastasis, as well as current advances in targeted therapies, are also discussed.
Collapse
|
|
50
|
Yu J, Chen GG, Lai PBS. Targeting hepatocyte growth factor/c-mesenchymal-epithelial transition factor axis in hepatocellular carcinoma: Rationale and therapeutic strategies. Med Res Rev 2020; 41:507-524. [PMID: 33026703 DOI: 10.1002/med.21738] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/27/2020] [Accepted: 09/27/2020] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. The outcome of current standard treatments, as well as targeted therapies in advanced stages, are still unsatisfactory. Attention has been drawn to novel strategies for better treatment efficacy. Hepatocyte growth factor/c-mesenchymal-epithelial transition factor (HGF/c-Met) axis has been known as an essential element in the regulation of liver diseases and as an oncogenic factor in HCC. In this review, we collected the evidence of HGF/c-Met as a tumor progression and prognostic marker, discussed the anti-c-Met therapy in vitro, summarized the outcome of c-Met inhibitors in clinical trials, and identified potential impetus for future anti-c-Met treatments. We also analyzed the inconsistency of HGF/c-Met from various publications and offered reasonable explanations based on the current understanding in this area. In conclusion, HGF/c-Met plays a crucial role in the progression and growth of HCC, and the strategies to inhibit this pathway may facilitate the development of new and effective treatments for HCC patients.
Collapse
Affiliation(s)
- Jianqing Yu
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - George G Chen
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Paul B S Lai
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| |
Collapse
|