Publications by authors named "Alexander Meves"

47 Publications

GAS7 Deficiency Promotes Metastasis in MYCN-driven Neuroblastoma.

Cancer Res 2021 Feb 18. Epub 2021 Feb 18.

Department of Biochemistry and Molecular Biology, Mayo Clinic

One of the greatest barriers to curative treatment of neuroblastoma (NB) is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the MYCN oncogene. However, only a limited number of regulatory proteins that contribute to this complex MYCN-mediated process have been elucidated. Here we show that the growth arrest-specific 7 (GAS7) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven NB. GAS7 expression was also suppressed in MYCN-amplified NB lacking 17p deletion. GAS7 deficiency led to accelerated metastasis in both zebrafish and mammalian models of NB with overexpression or amplification of MYCN. Analysis of expression profiles and the ultrastructure of zebrafish NB tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell-cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in NB metastasis in the context of MYCN overexpression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-1890DOI Listing
February 2021

ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL.

Nat Commun 2020 11 17;11(1):5865. Epub 2020 Nov 17.

Core Research Laboratory - Institute for Cancer Research and Prevention (ISPRO), Viale Pieraccini 6, 50139, Florence, Italy.

Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-19575-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673140PMC
November 2020

Identification of stage I/IIA melanoma patients at high risk for disease relapse using a clinicopathologic and gene expression model.

Eur J Cancer 2020 11 5;140:11-18. Epub 2020 Oct 5.

Mayo Clinic, Rochester, MN, USA. Electronic address:

Purpose: Patients with stage I/IIA cutaneous melanoma (CM) are currently not eligible for adjuvant therapies despite uncertainty in relapse risk. Here, we studied the ability of a recently developed model which combines clinicopathologic and gene expression variables (CP-GEP) to identify stage I/IIA melanoma patients who have a high risk for disease relapse.

Patients And Methods: Archival specimens from a cohort of 837 consecutive primary CMs were used for assessing the prognostic performance of CP-GEP. The CP-GEP model combines Breslow thickness and patient age, with the expression of eight genes in the primary tumour. Our specific patient group, represented by 580 stage I/IIA patients, was stratified based on their risk of relapse: CP-GEP High Risk and CP-GEP Low Risk. The main clinical end-point of this study was five-year relapse-free survival (RFS).

Results: Within the stage I/IIA melanoma group, CP-GEP identified a high-risk patient group (47% of total stage I/IIA patients) which had a considerably worse five-year RFS than the low-risk patient group; 74% (95% confidence interval [CI]: 67%-80%) versus 89% (95% CI: 84%-93%); hazard ratio [HR] = 2.98 (95% CI: 1.78-4.98); P < 0.0001. Of patients in the high-risk group, those who relapsed were most likely to do so within the first 3 years.

Conclusion: The CP-GEP model can be used to identify stage I/IIA patients who have a high risk for disease relapse. These patients may benefit from adjuvant therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655519PMC
November 2020

Reply to E. K. Bartlett et al and A. H. R. Varey et al.

JCO Precis Oncol 2020 3;4:992-994. Epub 2020 Sep 3.

Department of Dermatology, Mayo Clinic, Rochester, MN, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/po.20.00289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480899PMC
September 2020

Keloids: a review of therapeutic management.

Int J Dermatol 2020 Sep 9. Epub 2020 Sep 9.

Department of Dermatology, Mayo Clinic, Rochester, MN, USA.

Keloid scar formation arises from a disorganized fibroproliferative collagen response that extends beyond the original wound margins because of excessive production of extracellular matrix (ECM). Despite treatment options for keloid scars including medical and surgical therapies, such as intralesional steroid injection and surgical excision, the recurrence rate remains high. Herein we consolidate recently published narrative reviews, systematic reviews, and meta-analyses to provide an overview of updated treatment recommendations for keloidal scar formation. PubMed search engine was used to access the MEDLINE database to investigate updates regarding keloid incidence and treatment. More than 100 articles were reviewed. Keloid management remains a multimodal approach. There continues to be no gold standard of treatment that provides a consistently low recurrence rate; however, the increasing number of available treatments and synergistic combinations of these treatments (i.e., laser-based devices in combination with intralesional steroids, or 5-fluorouracil (5-FU) in combination with steroid therapy) is showing favorable results. Future studies could target the efficacy of novel treatment modalities (i.e., autologous fat grafting or stem cell-based therapies) for keloid management. This review article provides updated treatment guidelines for keloids and discusses insight into management to assist patient-focused, evidence-based clinical decision making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ijd.15159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940466PMC
September 2020

Rabgap1 promotes recycling of active β1 integrins to support effective cell migration.

J Cell Sci 2020 09 23;133(18). Epub 2020 Sep 23.

Department of Molecular Medicine, Max Planck Institute for Biochemistry, 82152 Martinsried, Germany

Integrin function depends on the continuous internalization of integrins and their subsequent endosomal recycling to the plasma membrane to drive adhesion dynamics, cell migration and invasion. Here we assign a pivotal role for Rabgap1 (GAPCenA) in the recycling of endocytosed active β1 integrins to the plasma membrane. The phosphotyrosine-binding (PTB) domain of Rabgap1 binds to the membrane-proximal NPxY motif in the cytoplasmic domain of β1 integrin subunits on endosomes. Silencing Rabgap1 in mouse fibroblasts leads to the intracellular accumulation of active β1 integrins, alters focal adhesion formation, and decreases cell migration and cancer cell invasion. Functionally, Rabgap1 facilitates active β1 integrin recycling to the plasma membrane through attenuation of Rab11 activity. Taken together, our results identify Rabgap1 as an important factor for conformation-specific integrin trafficking and define the role of Rabgap1 in β1-integrin-mediated cell migration in mouse fibroblasts and breast cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/jcs.243683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522031PMC
September 2020

Deselecting Melanoma Patients for Sentinel Lymph Node Biopsy During COVID-19: Clinical Utility of Tumor Molecular Profiling.

Mayo Clin Proc Innov Qual Outcomes 2020 Oct 17;4(5):586-587. Epub 2020 Jul 17.

Princess Máxima Center for Pediatric Oncology, Utrecht, NL.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mayocpiqo.2020.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367022PMC
October 2020

β3 integrin immunohistochemistry as a method to predict sentinel lymph node status in patients with primary cutaneous melanoma.

Int J Dermatol 2020 Oct 9;59(10):1241-1248. Epub 2020 Aug 9.

Department of Dermatology, Mayo Clinic, Rochester, MN, USA.

Background: Integrins are heterodimeric proteins composed of noncovalently linked ɑ and β subunits which are essential for a wide range of normal physiology and also play prominent roles in cancer. Here we tested whether integrin expression in diagnostic skin biopsies is associated with sentinel lymph node (SLN) metastasis.

Methods: We utilized a cohort of 854 consecutive patients with primary cutaneous melanoma to quantify the expression of β integrin subunits by reverse transcriptase quantitative PCR (RT-qPCR). In addition, we quantified the expression of β3 integrin by immunohistochemistry (IHC) in a subset of 271 patients by H score. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. Logistic regression analyses were used to develop models for the likelihood of SLN metastasis from molecular, clinical, and histologic variables.

Results: β3 integrin expression quantified by IHC or RT-qPCR was associated with SLN metastasis. β1, β5, β6, and β8 integrin expression was not associated with SLN metastasis. The incremental gain in performance of a predictive model which included β3 integrin expression as quantified by IHC in combination with established clinicopathologic variables (Breslow depth and patient age) was limited.

Conclusions: β3 integrin is the principal integrin subunit associated with sentinel lymph node biopsy (SLNb) metastasis in primary cutaneous melanoma. However, β3 integrin H score does not significantly improve models for the likelihood of SLN metastasis over Breslow depth and patient age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ijd.15125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722091PMC
October 2020

Deep Learning for Dermatologists: Part I Fundamental Concepts.

J Am Acad Dermatol 2020 May 17. Epub 2020 May 17.

Department of Dermatology, Mayo Clinic, Rochester, Minnesota; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Mayo Clinic Office of Artificial Intelligence in Dermatology (AIDE).

Artificial intelligence (AI) is generating substantial interest in the field of medicine. One form of artificial intelligence, deep learning, has led to rapid advances in automated image analysis. In 2017, an algorithm demonstrated the ability to diagnose certain skin cancers from clinical photographs with the accuracy of an expert dermatologist. Subsequently, deep learning has been applied to a range of dermatology applications. Though experts will never be replaced by AI, it will certainly impact the specialty of dermatology. In this first article of a two-part series, the basic concepts of deep learning will be reviewed with the goal of laying the groundwork for effective communication between clinicians and technical colleagues. In part two of the series, the clinical applications of deep learning in dermatology will be reviewed considering limitations and opportunities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2020.05.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669702PMC
May 2020

Deep learning for dermatologists: Part II. Current applications.

J Am Acad Dermatol 2020 May 16. Epub 2020 May 16.

Mayo Clinic Office of Artificial Intelligence in Dermatology, Rochester, Minnesota; Department of Health Sciences Research, Division of Digital Health Sciences, Mayo Clinic, Rochester, Minnesota.

Because of a convergence of the availability of large data sets, graphics-specific computer hardware, and important theoretical advancements, artificial intelligence has recently contributed to dramatic progress in medicine. One type of artificial intelligence known as deep learning has been particularly impactful for medical image analysis. Deep learning applications have shown promising results in dermatology and other specialties, including radiology, cardiology, and ophthalmology. The modern clinician will benefit from an understanding of the basic features of deep learning to effectively use new applications and to better gauge their utility and limitations. In this second article of a 2-part series, we review the existing and emerging clinical applications of deep learning in dermatology and discuss future opportunities and limitations. Part 1 of this series offered an introduction to the basic concepts of deep learning to facilitate effective communication between clinicians and technical experts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2020.05.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669658PMC
May 2020

Model Combining Tumor Molecular and Clinicopathologic Risk Factors Predicts Sentinel Lymph Node Metastasis in Primary Cutaneous Melanoma.

JCO Precis Oncol 2020 14;4:319-334. Epub 2020 Apr 14.

Mayo Clinic, Rochester, MN, USA.

Purpose: More than 80% of patients who undergo sentinel lymph node (SLN) biopsy have no nodal metastasis. Here we describe a model that combines clinicopathologic and molecular variables to identify patients with thin and intermediate thickness melanomas who may forgo the SLN biopsy procedure due to their low risk of nodal metastasis.

Patients And Methods: Genes with functional roles in melanoma metastasis were discovered by analysis of next generation sequencing data and case control studies. We then used PCR to quantify gene expression in diagnostic biopsy tissue across a prospectively designed archival cohort of 754 consecutive thin and intermediate thickness primary cutaneous melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. A penalized maximum likelihood estimation algorithm was used to train logistic regression models in a repeated cross validation scheme to predict the presence of SLN metastasis from molecular, clinical and histologic variables.

Results: Expression of genes with roles in epithelial-to-mesenchymal transition (glia derived nexin, growth differentiation factor 15, integrin β3, interleukin 8, lysyl oxidase homolog 4, TGFβ receptor type 1 and tissue-type plasminogen activator) and melanosome function (melanoma antigen recognized by T cells 1) were associated with SLN metastasis. The predictive ability of a model that only considered clinicopathologic or gene expression variables was outperformed by a model which included molecular variables in combination with the clinicopathologic predictors Breslow thickness and patient age; AUC, 0.82; 95% CI, 0.78-0.86; SLN biopsy reduction rate of 42% at a negative predictive value of 96%.

Conclusion: A combined model including clinicopathologic and gene expression variables improved the identification of melanoma patients who may forgo the SLN biopsy procedure due to their low risk of nodal metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/po.19.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220172PMC
April 2020

The role of integrins in melanoma: a review.

Int J Dermatol 2020 May 10;59(5):525-534. Epub 2020 Mar 10.

Department of Dermatology, Mayo Clinic, Rochester, MN, USA.

Integrins are the major family of cell adhesion receptors in humans and essential for a wide range of normal physiology, including formation and maintenance of tissue structure integrity, cell migration, proliferation, and differentiation. Integrins also play a prominent role in tumor growth and metastasis. Translational research has tried to define the contribution of integrins to the phenotypic aggressiveness of melanoma because such knowledge is clinically useful. For example, differential expression of integrins in primary cutaneous melanoma can be used to distinguish indolent from aggressive, prometastatic melanoma. Recent studies have shown that gene expression-based testing of patient-derived melanoma tissue is feasible, and molecular tests may fully replace interventional surgical methods such as sentinel lymph node biopsies in the future. Because of their central role in mediating invasion and metastasis, integrins are likely to be useful biomarkers. Integrins are also attractive candidate targets for interventional therapy. This article focuses on the role of integrins in melanoma and highlights recent advances in the field of translational research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ijd.14850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167356PMC
May 2020

Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.

EMBO J 2019 12 21;38(23):e101982. Epub 2019 Oct 21.

Ageing Research Laboratories, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.

Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16 during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/embj.2019101982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885734PMC
December 2019

Clinical and histopathologic manifestations of solid organ transplantation-associated graft-versus-host disease involving the skin: A single-center retrospective study.

J Cutan Pathol 2018 Nov 19;45(11):817-823. Epub 2018 Aug 19.

Department of Dermatology, Mayo Clinic, Rochester, Minnesota.

Background: Graft-versus-host disease (GVHD) following solid organ transplantation (SOT) is extremely rare and infrequently described in the dermatologic literature.

Methods: We performed a retrospective clinicopathologic review of our institution's experience with patients diagnosed with SOT-associated GVHD (SOT GVHD) (May 1, 1996 to September 1, 2017).

Results: Of nine patients with SOT GVHD, seven had undergone liver transplantation, while two had undergone lung transplantation. All presented initially with a skin eruption, which developed an average of 63 days (range: 11-162 days) post transplant. The average time to diagnosis following the onset of the skin eruption was 12 days (range: 0-54 days). Diagnosis was often delayed because of a competing diagnosis of drug reaction. Frequent skin findings included pruritic erythematous to violaceous macules and papules with desquamation. Histopathology showed vacuolar interface dermatitis in 12 of 15 cases (80.0%). Of the 11 specimens in which a hair follicle was present for evaluation, vacuolar interface changes around the hair follicle were present in eight (72.7%) cases. Seven patients (77.8%) died from complications during the follow-up period.

Conclusions: SOT GVHD presents initially with skin involvement, is associated with vacuolar interface changes on skin biopsy, and is associated with a high mortality rate. Clinicopathologic correlation is required for accurate diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cup.13326DOI Listing
November 2018

FAK auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis.

PLoS One 2018 12;13(7):e0200558. Epub 2018 Jul 12.

Department of Dermatology, Mayo Clinic, Rochester, Minnesota, United States of America.

Focal adhesion kinase (FAK) is an intensely studied non-receptor tyrosine kinase with roles in cancer and other common human diseases. Despite the large interest in FAK, the in vivo contribution of FAK auto-phosphorylation site tyrosine (Y) 397 to FAK function is incompletely understood. To study FAK Y397 in vivo we analyzed mice with 'non-phosphorylatable' Y-to-phenylalanine (F) and 'phospho-mimicking' Y-to-glutamate (E) mutations in the germline. We found that FAK Y397F mice die early during embryogenesis with abnormal angiogenesis like FAK kinase-dead mice. When Y397 is mutated to a glutamate mice survive beyond mid-gestation like mice where Y397 is lost by deletion of FAK exon 15. In culture, defects in proliferation, invasion and gene expression were more severe with the FAK Y397F than with the FAK Y397E mutation despite the inability of FAK Y397E to bind SRC. Conditional expression of FAK Y397F or Y397E in unchallenged avascular epidermis, however, resulted in no appreciable phenotype. We conclude that FAK Y397 is required for the highly dynamic tissue remodeling during development but dispensable for normal homeostasis of avascular epidermis. In contrast to the Y397F mutation, FAK Y397E retains sufficient biological activity to allow for development beyond mid-gestation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200558PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042779PMC
January 2019

Dermatologic manifestations of solid organ transplantation-associated graft-versus-host disease: A systematic review.

J Am Acad Dermatol 2018 Jun 27;78(6):1097-1101.e1. Epub 2017 Dec 27.

Department of Dermatology, Mayo Clinic, Rochester, Minnesota; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background: Graft-versus-host-disease (GVHD) after solid organ transplantation (SOT) is extremely rare.

Objective: To investigate the dermatologic manifestations and clinical outcomes of SOT GVHD.

Methods: Systematic literature review of SOT GVHD.

Results: After full-text article review, we included 61 articles, representing 115 patients and 126 transplanted organs. The most commonly transplanted organ was the liver (n = 81). Among 115 patients, 101 (87.8%) developed skin involvement. The eruption appeared an average of 48.3 days (range, 3-243 days) posttransplant and was pruritic in 5 of 101 (4.9%) cases. The eruption was described as morbilliform in 2 patients (1.9%), confluent in 6 (5.9%), and desquamative in 4 (3.9%) cases. In many cases, specific dermatologic descriptions were lacking. The mortality rate was 72.2%. Relative time of death was reported in 23 patients who died during the follow-up period. These patients died an average of 99.2 days (range, 22-270 days) posttransplant, or 50.9 days after the appearance of dermatologic symptoms. Frequent causes of death were sepsis and multiorgan failure.

Limitations: Incomplete descriptions of skin findings and potential publication bias resulting in publication of only the most severe cases.

Conclusions: GVHD is a potentially fatal condition that can occur after SOT and often presents with a skin rash. We recommend that dermatologists have a low threshold to consider and pursue this diagnosis in the setting of post-SOT skin eruption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2017.12.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167008PMC
June 2018

LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis.

Cancer Cell 2017 09 31;32(3):310-323.e5. Epub 2017 Aug 31.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

A genome-wide association study identified LMO1, which encodes an LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dβh promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3, and itga5. Our results provide in vivo validation of LMO1 as an important oncogene that promotes neuroblastoma initiation, progression, and widespread metastatic dissemination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2017.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605802PMC
September 2017

Myosin-1E interacts with FAK proline-rich region 1 to induce fibronectin-type matrix.

Proc Natl Acad Sci U S A 2017 04 27;114(15):3933-3938. Epub 2017 Mar 27.

Department of Dermatology, Mayo Clinic, Rochester, MN 55905;

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in development and human disease, including cancer. It is currently thought that the four-point one, ezrin, radixin, moesin (FERM)-kinase domain linker, which contains autophosphorylation site tyrosine (Y) 397, is not required for in vivo FAK function until late midgestation. Here, we directly tested this hypothesis by generating mice with FAK Y397-to-phenylalanine (F) mutations in the germline. We found that Y397F embryos exhibited reduced mesodermal fibronectin (FN) and osteopontin expression and died during mesoderm development akin to FAK kinase-dead mice. We identified myosin-1E (MYO1E), an actin-dependent molecular motor, to interact directly with the FAK FERM-kinase linker and induce FAK kinase activity and Y397 phosphorylation. Active FAK in turn accumulated in the nucleus where it led to the expression of osteopontin and other FN-type matrix in both mouse embryonic fibroblasts and human melanoma. Our data support a model in which FAK Y397 autophosphorylation is required for FAK function in vivo and is positively regulated by MYO1E.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1614894114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393228PMC
April 2017

Critical Role for GAB2 in Neuroblastoma Pathogenesis through the Promotion of SHP2/MYCN Cooperation.

Cell Rep 2017 03;18(12):2932-2942

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA. Electronic address:

Growing evidence suggests a major role for Src-homology-2-domain-containing phosphatase 2 (SHP2/PTPN11) in MYCN-driven high-risk neuroblastoma, although biologic confirmation and a plausible mechanism for this contribution are lacking. Using a zebrafish model of MYCN-overexpressing neuroblastoma, we demonstrate that mutant ptpn11 expression in the adrenal gland analog of MYCN transgenic fish promotes the proliferation of hyperplastic neuroblasts, accelerates neuroblastomagenesis, and increases tumor penetrance. We identify a similar mechanism in tumors with wild-type ptpn11 and dysregulated Gab2, which encodes a Shp2 activator that is overexpressed in human neuroblastomas. In MYCN transgenic fish, Gab2 overexpression activated the Shp2-Ras-Erk pathway, enhanced neuroblastoma induction, and increased tumor penetrance. We conclude that MYCN cooperates with either GAB2-activated or mutant SHP2 in human neuroblastomagenesis. Our findings further suggest that combined inhibition of MYCN and the SHP2-RAS-ERK pathway could provide effective targeted therapy for high-risk neuroblastoma patients with MYCN amplification and aberrant SHP2 activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2017.02.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393048PMC
March 2017

Expanded traditional melanoma FISH testing versus CAP-QPCR to identify high-risk melanocytic lesions.

Int J Dermatol 2017 09 20;56(9):e182-e184. Epub 2017 Mar 20.

Department of Dermatology, Mayo Clinic, Rochester, MN, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ijd.13596DOI Listing
September 2017

Cell adhesion phenotyping by quantitative polymerase chain reaction in melanoma: Clarifying misconceptions.

J Am Acad Dermatol 2017 Jan;76(1):e23

Department of Dermatology, Mayo Clinic, Rochester, MN. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2016.09.001DOI Listing
January 2017

Bullous Pemphigoid, Neurodegenerative Disease, and Hippocampal BP180 Expression: A Retrospective Postmortem Neuropathologic Study.

J Invest Dermatol 2016 10 24;136(10):2090-2092. Epub 2016 Jun 24.

Department of Dermatology, Mayo Clinic, Rochester, Minnesota, USA; Division of Dermatopathology and Cutaneous Immunopathology, Mayo Clinic, Rochester, Minnesota, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2016.06.015DOI Listing
October 2016

Hepatic adenomas with synchronous or metachronous fibrolamellar carcinomas: both are characterized by LFABP loss.

Mod Pathol 2016 06 25;29(6):607-15. Epub 2016 Mar 25.

Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.

Rare hepatic adenomas are associated with synchronous or metachronous fibrolamellar carcinomas. The morphology of these adenomas has not been well described and they have not been subclassifed using the current molecular classification schema. We examined four hepatic adenomas co-occurring with or preceding a diagnosis of fibrolamellar carcinoma in three patients. On histological examination, three of the adenomas showed the typical morphology of HNF1-α inactivated adenomas, whereas one showed a myxoid adenoma morphology. All of the adenomas were negative for PRKACA rearrangements by Fluorescence in situ Hybridization (FISH) analysis. All four of the adenomas showed complete loss or significant reduction of liver fatty acid binding protein (LFABP) expression by immunohistochemistry. Interestingly, the fibrolamellar carcinomas in each case also showed loss of LFABP by immunohistochemistry. One of the fibrolamellar carcinomas was negative for PRKACA rearrangements by FISH, whereas the others were positive. To investigate if LFBAP loss is typical of fibrolamellar carcinomas in general, an additional cohort of tumors was studied (n=19). All 19 fibrolamellar carcinomas showed the expected PRKACA rearrangements and immunostains showed loss of LFABP in each case, consistent with HNF1-α inactivation. To validate this observation, mass spectrometry-based proteomics was performed on tumor-normal pairs of six fibrolamellar carcinomas and showed an average 10-fold reduction in LFABP protein levels, compared with matched normal liver tissue. In conclusion, hepatic adenomas co-occurring with fibrolamellar carcinomas show LFABP loss and are negative for PRKACA rearrangements, indicating they are genetically distinct lesions. These data also demonstrate that LFABP loss, which characterizes HNF1-α inactivation, is a consistent feature of fibrolamellar carcinoma, indicating HNF1-α inactivation is an important event in fibrolamellar carcinoma pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/modpathol.2016.59DOI Listing
June 2016

Tumor Cell Adhesion As a Risk Factor for Sentinel Lymph Node Metastasis in Primary Cutaneous Melanoma.

J Clin Oncol 2015 Aug 6;33(23):2509-15. Epub 2015 Jul 6.

Alexander Meves, Ekaterina Nikolova, Joel B. Heim, Edwin J. Squirewell, Clark C. Otley, Louis A. Schenck, Amy L. Weaver, and Vera J. Suman, Mayo Clinic, Rochester, MN; Mark A. Cappel, Mayo Clinic, Jacksonville, FL; Mark R. Pittelkow, Mayo Clinic, Scottsdale, AZ; and Nille Behrendt, Ditte M. Saunte, and Jorgen Lock-Andersen, Hospital Roskilde, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Purpose: Less than 20% of patients with melanoma who undergo sentinel lymph node (SLN) biopsy based on American Society of Clinical Oncology/Society of Surgical Oncology recommendations are SLN positive. We present a multi-institutional study to discover new molecular risk factors associated with SLN positivity in thin and intermediate-thickness melanoma.

Patients And Methods: Gene clusters with functional roles in melanoma metastasis were discovered by next-generation sequencing and validated by quantitative polymerase chain reaction using a discovery set of 73 benign nevi, 76 primary cutaneous melanoma, and 11 in-transit melanoma metastases. We then used polymerase chain reaction to quantify gene expression in a model development cohort of 360 consecutive thin and intermediate-thickness melanomas and a validation cohort of 146 melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. Logic and logistic regression analyses were used to develop a model for the likelihood of SLN metastasis from molecular, clinical, and histologic variables.

Results: ITGB3, LAMB1, PLAT, and TP53 expression were associated with SLN metastasis. The predictive ability of a model that included these molecular variables in combination with clinicopathologic variables (patient age, Breslow depth, and tumor ulceration) was significantly greater than a model that only considered clinicopathologic variables and also performed well in the validation cohort (area under the curve, 0.93; 95% CI, 0.87 to 0.97; false-positive and false-negative rates of 22% and 0%, respectively, using a 10% cutoff for predicted SLN metastasis risk).

Conclusion: The addition of cell adhesion-linked gene expression variables to clinicopathologic variables improves the identification of patients with SLN metastases within 90 days of melanoma diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2014.60.7002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979232PMC
August 2015

Sorting nexin 31 binds multiple β integrin cytoplasmic domains and regulates β1 integrin surface levels and stability.

J Mol Biol 2014 Sep 11;426(18):3180-3194. Epub 2014 Jul 11.

Department of Molecular Medicine, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. Electronic address:

Trafficking of α5β1 integrin to lysosomes and its subsequent degradation is influenced by ligand occupancy and the binding of SNX17 via its protein 4.1, ezrin, radixin, moesin (FERM) domain to the membrane-distal NPxY motif in the cytoplasmic domain of β1 integrin in early endosomes. Two other sorting nexin (SNX) family members, namely SNX27 and SNX31, share with SNX17 next to their obligate phox domain a FERM domain, which may enable them to bind β integrin tails. Here we report that, in addition to SNX17, SNX31 but not SNX27 binds several β integrin tails in early endosomes in a PI3 (phosphatidylinositide 3)-kinase-dependent manner. Similarly like SNX17, binding of SNX31 with β1 integrin tails in early endosomes occurs between the FERM domain and the membrane-distal NPxY motif in the β1 integrin cytoplasmic domain. Furthermore, expression of SNX31 rescues β1 integrin surface levels and stability in SNX17-depleted cells. In contrast to SNX17, expression of SNX31 is restricted and found highly expressed in bladder and melanoma tissue. Altogether, these results demonstrate that SNX31 is an endosomal regulator of β integrins with a restricted expression pattern.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmb.2014.07.003DOI Listing
September 2014