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Julie S. Di Martino

New York Medical College

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Jose Javier Bravo‐Cordero

Icahn School of Medicine at Mount Sinai

Chandrani Mondal

Visva-Bharati University

Nathaniel R. Campbell

Johns Hopkins University

Charlotte E. Ariyan

Memorial Sloan Kettering Cancer Center

Jedd D. Wolchok

Cornell University

Theresa Simon-Vermot

Memorial Sloan Kettering Cancer Center

Katherine S. Panageas

Memorial Sloan Kettering Cancer Center

Taha Merghoub

Swim Across America

Travis J. Hollmann

Memorial Sloan Kettering Cancer Center

Sanjeethan C. Baksh

Memorial Sloan Kettering Cancer Center

Cooperative Institutions

Icahn School of Medicine at Mount Sinai

Inserm

Université de Bordeaux

Memorial Sloan Kettering Cancer Center

Centre National de la Recherche Scientifique

Bordeaux Population Health

Cornell University

Spanish National Cancer Research Centre

Kettering University

Translational Research in Oncology

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2D and 3D Matrices to Study Linear Invadosome Formation and Activity

Journal of Visualized Experiments (2017)

Julie S. Di Martino Elodie Henriet Zakaria Ezzoukhry Chandrani Mondal Jose Javier Bravo‐Cordero

Cell adhesion, migration, and invasion are involved in many physiological and pathological processes. For example, during metastasis formation, tumor cells have to cross anatomical barriers to invade and migrate through the surrounding tissue in order to reach blood or lymphatic vessels. This requires the interaction between cells and the extracellular matrix (ECM). At the cellular level, many cells, including the majority of cancer cells, are able to form invadosomes, which are F-actin-based structures capable of degrading ECM. Invadosomes are protrusive actin structures that recruit and activate matrix metalloproteinases (MMPs). The molecular composition, density, organization, and stiffness of the ECM are crucial in regulating invadosome formation and activation. In vitro, a gelatin assay is the standard assay used to observe and quantify invadosome degradation activity. However, gelatin, which is denatured collagen I, is not a physiological matrix element. A novel assay using type I collagen fibrils was developed and used to demonstrate that this physiological matrix is a potent inducer of invadosomes. Invadosomes that form along the collagen fibrils are known as linear invadosomes due to their linear organization on the fibers. Moreover, molecular analysis of linear invadosomes showed that the discoidin domain receptor 1 (DDR1) is the receptor involved in their formation. These data clearly demonstrate the importance of using a physiologically relevant matrix in order to understand the complex interactions between cells and the ECM.

DDR1

Discoidin domain

Matrix (chemical analysis)

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Citations (15)

Supplemental Table 5 from Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins

Maomao Zhang Julie S. Di Martino Robert L. Bowman Nathaniel R. Campbell Sanjeethan C. Baksh

<p>ZMEL in vivo lipidomics</p>

Table (database)

10.1158/2159-8290.22532410

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ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency

PLoS ONE (2017)

Philippe Joly Hélène Vignaud Julie S. Di Martino Mathias Ruiz Roman Garin

The most common and severe disease causing allele of Alpha 1-Antitrypsin Deficiency (1ATD) is Z-1AT. This protein aggregates in the endoplasmic reticulum, which is the main cause of liver disease in childhood. Based on recent evidences and on the frequency of liver disease occurrence in Z-1AT patients, it seems that liver disease progression is linked to still unknown genetic factors.We used an innovative approach combining yeast genetic screens with next generation exome sequencing to identify and functionally characterize the genes involved in 1ATD associated liver disease.Using yeast genetic screens, we identified HRD1, an Endoplasmic Reticulum Associated Degradation (ERAD) associated protein, as an inducer of Z-mediated toxicity. Whole exome sequencing of 1ATD patients resulted in the identification of two variants associated with liver damages in Z-1AT homozygous cases: HFE H63D and HERPUD1 R50H. Functional characterization in Z-1AT model cell lines demonstrated that impairment of the ERAD machinery combined with the HFE H63D variant expression decreased both cell proliferation and cell viability, while Unfolded Protein Response (UPR)-mediated cell death was hyperstimulated.This powerful experimental pipeline allowed us to identify and functionally validate two genes involved in Z-1AT-mediated severe liver toxicity. This pilot study moves forward our understanding on genetic modifiers involved in 1ATD and highlights the UPR pathway as a target for the treatment of liver diseases associated with 1ATD. Finally, these findings support a larger scale screening for HERPUD1 R50H and HFE H63D variants in the sub-group of 1ATD patients developing significant chronic hepatic injuries (hepatomegaly, chronic cholestasis, elevated liver enzymes) and at risk developing liver cirrhosis.

Endoplasmic-reticulum-associated protein degradation

Liver disease

Alpha 1-antitrypsin deficiency

10.1371/journal.pone.0179369

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Supplementary figures from Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins

Maomao Zhang Julie S. Di Martino Robert L. Bowman Nathaniel R. Campbell Sanjeethan C. Baksh

<p>Supplementary Figure S1: RNA-seq analysis of human A375 melanoma cells in co-culture with adipocytes compared to monoculture controls Supplementary Figure S2: Lipid transfer and melanoma cell uptake of long chain fatty acids Supplementary Figure S3: Adipocytes do not increase glycolysis in melanoma cells Supplementary Figure S4: Endogenous FATP expression in control tissues and patient-derived xenografts Supplementary Figure S5: Absence of lipid-laden tumor cells in in vivo setting devoid of adipocytes Supplementary Figure S6: Lipidomics reveals specific lipid species transferred from adipocytes to melanoma cells Supplementary Figure S7: FATP1 expression and survival Supplementary Figure S8: Validation of FATP1 knockdown Supplementary Figure S9: Lipofermata targets FATP1 Supplementary Figure S10: Compounds that are structurally similar to Lipofermata do not cause decreases in lipid uptake or increased cell death Supplementary Figure S11: Measurement of apoptosis in Lipofermata-treated cells</p>

Lipid droplet

10.1158/2159-8290.22532404.v1

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Cell Adhesion & Migration (2014)

Julie S. Di Martino Lisa Paysan Caroline Gest Valérie Lagrée Amélie Juin

Invadosomes are actin-based structures involved in extracellular-matrix degradation. Invadosomes, either known as podosomes or invadopodia, are found in an increasing number of cell types. Moreover, their overall organization and molecular composition may vary from one cell type to the other. Some are constitutive such as podosomes in hematopoietic cells whereas others are inducible. However, they share the same feature, their ability to interact and to degrade the extracellular matrix. Based on the literature and our own experiments, the aim of this study was to establish a minimal molecular definition of active invadosomes. We first highlighted that Cdc42 is the key RhoGTPase involved in invadosome formation in all described models. Using different cellular models, such as NIH-3T3, HeLa, and endothelial cells, we demonstrated that overexpression of an active form of Cdc42 is sufficient to form invadosome actin cores. Therefore, active Cdc42 must be considered not only as an inducer of filopodia, but also as an inducer of invadosomes. Depending on the expression level of Tks5, these Cdc42-dependent actin cores were endowed or not with a proteolytic activity. In fact, Tks5 overexpression rescued this activity in Tks5 low expressing cells. We thus described the adaptor protein Tks5 as a major actor of the invadosome degradation function. Surprisingly, we found that Src kinases are not always required for invadosome formation and function. These data suggest that even if Src family members are the principal kinases involved in the majority of invadosomes, it cannot be considered as a common element for all invadosome structures. We thus define a minimal and universal molecular signature of invadosome that includes Cdc42 activity and Tks5 presence in order to drive the actin machinery and the proteolytic activity of these invasive structures.

Invadopodia

Podosome

CDC42

Filopodia

10.4161/cam.28833

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Abstract 5663: Collagen COL26A1 correlates with poor papillary thyroid cancer prognosis and in vitro characteristics of metastasis indicating a potential role as a biomarker or therapeutic target

Cancer Research (2024)

Michelle Carnazza Danielle Quaranto Nicole R. DeSouza Sina Dadafarin Augustine Moscatello

Abstract Papillary thyroid cancer (PTC) is the most common cancer in young women and is increasing 3% annually in incidence. While PTC is often slow-growing and surgically resectable, recurrence years to decades later occurs in 20% of patients (now only in their 40s/50s), decreasing survival by ~60%. The identification of prognostic biomarkers and actionable therapeutic targets for high-risk PTC is critically important and an unmet need. RNASeq analysis of our repository of PTC and matched normal tissues identified collagen 26A1 (COL26A1) as significantly upregulated in patients with extrathyroidal extension (ETE), lymph node metastasis, and multifocal tumors, indicative of high-risk for recurrence. Correspondingly, survival curves of The Cancer Genome Atlas (TCGA) demonstrated increased COL26A1 expression decreases survival probability by 25% (p=0.0086) and correlated with MACIS score (q=0.001), differentiation score (q=0.025), tumor stage (q=0.025), and ETE (p=0.0038). COL26A1 expression was increased in PTC cell lines K1 (3-fold) and TPC1 (5-fold) compared to “normal” thyroid epithelial cells, NThy-ori-3-1. CRISPR knockdown of COL26A1 repressed RNA (50%) and protein (70%) expression. COL26A1 repression decreased known cancer-promoting activities of collagens, including proliferation (30%), clonogenicity (33%), anchorage-independent growth (37%), cell motility (43%), Matrigel invasion (30%), in situ gelatin degradation (70%), and migration (33%). Cell-to-cell adhesion and cell-matrix adhesion also decreased (36% and 25%, respectively). This coincided with reduced anoikis resistance (31%), increased MMP expression (50%), and reductions in mesenchymal markers (30%) and increases in epithelial markers (3-fold). Evidence that COL26A1 is a secreted protein was validated by conditioned media isolations whereby expression was decreased in knockdowns compared to control cells (70%). Preliminary data indicate the control cells’ conditioned media can restore the aggressive phenotypes, including cell motility (51%). Qiagen Ingenuity Pathway Analysis (IPA) elucidated the potential role of androgen receptor (AR) in linking COL26A1 with PTC, coinciding with the known effects of sex hormones on collagen expression and organization, and the sex disparity in PTC. Preliminary data indicate that physiologic levels of androgen decrease COL26A1 RNA (46%) and protein (45%) expression in K1 cells expressing the androgen receptor. Thus, COL26A1 may serve as a prognostic marker and actionable target for small molecule inhibitors in high-risk PTC. Citation Format: Michelle Carnazza, Danielle Quaranto, Nicole DeSouza, Sina Dadafarin, Augustine Moscatello, Humayun K. Islam, Julie S. Di Martino, Raj K. Tiwari, Jan Geliebter. Collagen COL26A1 correlates with poor papillary thyroid cancer prognosis and in vitro characteristics of metastasis indicating a potential role as a biomarker or therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5663.

Distant metastasis

10.1158/1538-7445.am2024-5663

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Supplemental Table 2 from Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins

Maomao Zhang Julie S. Di Martino Robert L. Bowman Nathaniel R. Campbell Sanjeethan C. Baksh

<p>ZMEL RNAseq table S2</p>

Table (database)

10.1158/2159-8290.22532419

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The microenvironment controls invadosome plasticity

Journal of Cell Science (2016)

Julie S. Di Martino Elodie Henriet Zakaria Ezzoukhry Jacky G. Goetz Violaine Moreau

ABSTRACT Invadosomes are actin-based structures involved in extracellular matrix degradation. Invadosomes is a term that includes podosomes and invadopodia, which decorate normal and tumour cells, respectively. They are mainly organised into dots or rosettes, and podosomes and invadopodia are often compared and contrasted. Various internal or external stimuli have been shown to induce their formation and/or activity. In this Commentary, we address the impact of the microenvironment and the role of matrix receptors on the formation, and dynamic and degradative activities of invadosomes. In particular, we highlight recent findings regarding the role of type I collagen fibrils in inducing the formation of a new linear organisation of invadosomes. We will also discuss invadosome plasticity more generally and emphasise its physio-pathological relevance.

Invadopodia

Podosome

Matrix (chemical analysis)

10.1242/jcs.182329

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Citations (67)

Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine

David Olmeda Daniela Cerezo‐Wallis Erica Riveiro‐Falkenbach Paula Comune Pennacchi Marta Contreras-Alcalde

Lymphangiogenesis

Midkine

10.1038/nature22977

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Citations (146)

Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition

Bram Priem Mandy M. T. van Leent Abraham J. P. Teunissen Alexandros Marios Sofias Vera P. Mourits

10.1016/j.cell.2020.09.059

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Citations (137)