John Condeelis

Albert Einstein Medical Center, Filadelfia, Pennsylvania, United States

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Publications (301)2149.46 Total impact

  • Cancer Research 08/2015; 75(15 Supplement):4112-4112. DOI:10.1158/1538-7445.AM2015-4112 · 9.28 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):4034-4034. DOI:10.1158/1538-7445.AM2015-4034 · 9.28 Impact Factor
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    ABSTRACT: Context .- Head and neck squamous cell carcinoma (HNSCC) is a highly invasive cancer with an association with locoregional recurrence and lymph node metastasis. We have previously reported that low microRNA-375 (miR-375) expression levels correlate with poor patient survival, increased locoregional recurrence, and distant metastasis. Increasing miR-375 expression in HNSCC cell lines to levels found in normal cells results in suppressed invasive properties. HNSCC invasion is mediated in part by invadopodia-associated degradation of the extracellular matrix. Objective .- To determine whether elevated miR-375 expression in HNSCC cell lines also affects invadopodia formation and activity. Design .- For evaluation of the matrix degradation properties of the HNSCC lines, an invadopodial matrix degradation assay was used. The total protein levels of invadopodia-associated proteins were measured by Western blot analyses. Immunoprecipitation experiments were conducted to evaluate the tyrosine phosphorylation state of cortactin. Human Protease Arrays were used for the detection of the secreted proteases. Quantitative real time-polymerase chain reaction measurements were used to evaluate the messenger RNA (mRNA) expression of the commonly regulated proteases. Results .- Increased miR-375 expression in HNSCC cells suppresses extracellular matrix degradation and reduces the number of mature invadopodia. Higher miR-375 expression does not reduce cellular levels of selected invadopodia-associated proteins, nor is tyrosine phosphorylation of cortactin altered. However, HNSCC cells with higher miR-375 expression had significant reductions in the mRNA expression levels and secreted levels of specific proteases. Conclusions .- MicroRNA-375 regulates invadopodia maturation and function potentially by suppressing the expression and secretion of proteases.
    Archives of pathology & laboratory medicine 07/2015; 75(15 Supplement). DOI:10.5858/arpa.2014-0471-OA · 2.88 Impact Factor
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    ABSTRACT: Mena(calc) is an immunofluorescence-based, quantitative method in which expression of the non-invasive Mena protein isoform (Mena11a) is subtracted from total Mena protein expression. Previous work has found a significant positive association between Mena(calc) and risk of death from breast cancer. Our goal was to determine if Mena(calc) could be used as an independent prognostic marker for axillary node-negative (ANN) breast cancer. Analysis of the association of Mena(calc) with overall survival (death from any cause) was performed for 403 ANN tumors using Kaplan Meier survival curves and the univariate Cox proportional hazards (PH) model with the log-rank or the likelihood ratio test. Cox PH models were used to estimate hazard ratios (HRs) for the association of Mena(calc) with risk of death after adjustment for HER2 status and clinicopathological tumor features. High Mena(calc) was associated with increased risk of death from any cause (P = 0.0199, HR (CI) = 2.18 (1.19, 4.00)). A similarly elevated risk of death was found in the subset of the Mena(calc) cohort which did not receive hormone or chemotherapy (n = 142) (P = 0.0052, HR (CI) = 3.80 (1.58, 9.97)). There was a trend toward increased risk of death with relatively high Mena(calc) in the HER2, basal and luminal molecular subtypes. Mena(calc) may serve as an independent prognostic biomarker for the ANN breast cancer patient population.
    BMC Cancer 06/2015; 15(1):483. DOI:10.1186/s12885-015-1468-6 · 3.32 Impact Factor
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    ABSTRACT: The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Ultrastructural, biochemical, and proteomic analysis indicates a loss of matrix proteins, and smooth muscle cells in aged collectors resulting in a decrease in contraction frequency, systolic lymph flow velocity, and pumping activity, as measured in vivo in lymphatic collectors. Functionally, this impairment also translated into a reduced ability for in vivo bacterial transport as determined by time-lapse microscopy. Ultrastructural and proteomic analysis also indicates a decrease in the thickness of the endothelial cell glycocalyx and loss of gap junction proteins in aged lymph collectors. Redox proteomic analysis mapped an aging-related increase in the glycation and carboxylation of lymphatic's endothelial cell and matrix proteins. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Altogether, our data provide a mechanistic analysis of how the anatomical and biochemical changes, occurring in aged lymphatic vessels, compromise lymph flow, tissue fluid homeostasis, and pathogen transport.
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    ABSTRACT: The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Ultrastructural, biochemical, and proteomic analysis indicates a loss of matrix proteins, and smooth muscle cells in aged collectors resulting in a decrease in contraction frequency, systolic lymph flow velocity, and pumping activity, as measured in vivo in lymphatic collectors. Functionally, this impairment also translated into a reduced ability for in vivo bacterial transport as determined by time-lapse microscopy. Ultrastructural and proteomic analysis also indicates a decrease in the thickness of the endothelial cell glycocalyx and loss of gap junction proteins in aged lymph collectors. Redox proteomic analysis mapped an aging-related increase in the glycation and carboxylation of lymphatic's endothelial cell and matrix proteins. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Altogether, our data provide a mechanistic analysis of how the anatomical and biochemical changes, occurring in aged lymphatic vessels, compromise lymph flow, tissue fluid homeostasis, and pathogen transport.
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    ABSTRACT: Metastasis is a complex, multistep process of cancer progression that has few treatment options. A critical event is the invasion of cancer cells into blood vessels (intravasation), through which cancer cells disseminate to distant organs. Breast cancer cells with increased abundance of Mena [an epidermal growth factor (EGF)–responsive cell migration protein] are present with macrophages at sites of intravasation, called TMEM sites (for tumor microenvironment of metastasis), in patient tumor samples. Furthermore, the density of these intravasation sites correlates with metastatic risk in patients. We found that intravasation of breast cancer cells may be prevented by blocking the signaling between cancer cells and macrophages. We obtained invasive breast ductal carcinoma cells of various subtypes by fine-needle aspiration (FNA) biopsies from patients and found that, in an in vitro transendothelial migration assay, cells that migrated through a layer of human endothelial cells were enriched for the transcript encoding Mena[superscript INV], an invasive isoform of Mena. This enhanced transendothelial migration required macrophages and occurred with all of the breast cancer subtypes. Using mouse macrophages and the human cancer cells from the FNAs, we identified paracrine and autocrine activation of colony-stimulating factor-1 receptor (CSF-1R). The paracrine or autocrine nature of the signal depended on the breast cancer cell subtype. Knocking down Mena[superscript INV] or adding an antibody that blocks CSF-1R function prevented transendothelial migration. Our findings indicate that Mena[superscript INV] and TMEM frequency are correlated prognostic markers and CSF-1 and Mena[superscript INV] may be therapeutic targets to prevent metastasis of multiple breast cancer subtypes.
  • Nature Cell Biology 03/2015; 17(3):350-350. DOI:10.1038/ncb3123 · 20.06 Impact Factor
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    ABSTRACT: Invadopodia are actin-driven membrane protrusions that show oscillatory assembly and disassembly causing matrix degradation to support invasion and dissemination of cancer cells in vitro and in vivo. Profilin1, an actin and phosphoinositide binding protein, is downregulated in several adenocarcinomas and it is been shown that its depletion enhances invasiveness and motility of breast cancer cells by increasing PI(3,4)P2 levels at the leading edge. In this study, we show for the first time that depletion of profilin1 leads to an increase in the number of mature invadopodia and these assemble and disassemble more rapidly than in control cells. Previous work by Sharma et al. (2013a), has shown that the binding of the protein Tks5 with PI(3,4)P2 confers stability to the invadopodium precursor causing it to mature into a degradation-competent structure. We found that loss of profilin1 expression increases the levels of PI(3,4)P2 at the invadopodium and as a result, enhances recruitment of the interacting adaptor Tks5. The increased PI(3,4)P2-Tks5 interaction accelerates the rate of invadopodium anchorage, maturation, and turnover. Our results indicate that profilin1 acts as a molecular regulator of the levels of PI(3,4)P2 and Tks5 recruitment in invadopodia to control the invasion efficiency of invadopodia. Copyright © 2015 Elsevier GmbH. All rights reserved.
    European Journal of Cell Biology 12/2014; 94(2). DOI:10.1016/j.ejcb.2014.12.002 · 3.70 Impact Factor
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    ABSTRACT: Breast cancer heterogeneity demands that prognostic models must be biologically driven and recent clinical evidence indicates that future prognostic signatures need evaluation in the context of early compared with late metastatic risk prediction. In pre-clinical studies, we and others have shown that various protein-protein interactions, pertaining to the actin microfilament-associated proteins, ezrin and cofilin, mediate breast cancer cell migration, a prerequisite for cancer metastasis. Moreover, as a direct substrate for protein kinase Cα, ezrin has been shown to be a determinant of cancer metastasis for a variety of tumour types, besides breast cancer; and has been described as a pivotal regulator of metastasis by linking the plasma membrane to the actin cytoskeleton. In the present article, we demonstrate that our tissue imaging-derived parameters that pertain to or are a consequence of the PKC-ezrin interaction can be used for breast cancer prognostication, with inter-cohort reproducibility. The application of fluorescence lifetime imaging microscopy (FLIM) in formalin-fixed paraffin-embedded patient samples to probe protein proximity within the typically <10 nm range to address the oncological challenge of tumour heterogeneity, is discussed.
    Biochemical Society Transactions 12/2014; 42(6):1498-505. DOI:10.1042/BST20140165 · 3.24 Impact Factor
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    ABSTRACT: The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Ultrastructural, biochemical, and proteomic analysis indicates a loss of matrix proteins, and smooth muscle cells in aged collectors resulting in a decrease in contraction frequency, systolic lymph flow velocity, and pumping activity, as measured in vivo in lymphatic collectors. Functionally, this impairment also translated into a reduced ability for in vivo bacterial transport as determined by time-lapse microscopy. Ultrastructural and proteomic analysis also indicates a decrease in the thickness of the endothelial cell glycocalyx and loss of gap junction proteins in aged lymph collectors. Redox proteomic analysis mapped an aging-related increase in the glycation and carboxylation of lymphatic's endothelial cell and matrix proteins. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Altogether, our data provide a mechanistic analysis of how the anatomical and biochemical changes, occurring in aged lymphatic vessels, compromise lymph flow, tissue fluid homeostasis, and pathogen transport. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging Cell 12/2014; 14(4). DOI:10.1111/acel.12330 · 5.71 Impact Factor
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    Bojana Gligorijevic · Aviv Bergman · John Condeelis
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    ABSTRACT: Metastasis is a complex, multistep process of cancer progression that has few treatment options. A critical event is the invasion of cancer cells into blood vessels (intravasation), through which cancer cells disseminate to distant organs. Breast cancer cells with increased abundance of Mena [an epidermal growth factor (EGF)-responsive cell migration protein] are present with macrophages at sites of intravasation, called TMEM sites (for tumor microenvironment of metastasis), in patient tumor samples. Furthermore, the density of these intravasation sites correlates with metastatic risk in patients. We found that intravasation of breast cancer cells may be prevented by blocking the signaling between cancer cells and macrophages. We obtained invasive breast ductal carcinoma cells of various subtypes by fine-needle aspiration (FNA) biopsies from patients and found that, in an in vitro transendothelial migration assay, cells that migrated through a layer of human endothelial cells were enriched for the transcript encoding Mena(INV), an invasive isoform of Mena. This enhanced transendothelial migration required macrophages and occurred with all of the breast cancer subtypes. Using mouse macrophages and the human cancer cells from the FNAs, we identified paracrine and autocrine activation of colony-stimulating factor-1 receptor (CSF-1R). The paracrine or autocrine nature of the signal depended on the breast cancer cell subtype. Knocking down Mena(INV) or adding an antibody that blocks CSF-1R function prevented transendothelial migration. Our findings indicate that Mena(INV) and TMEM frequency are correlated prognostic markers and CSF-1 and Mena(INV) may be therapeutic targets to prevent metastasis of multiple breast cancer subtypes. Copyright © 2014, American Association for the Advancement of Science.
    Science Signaling 11/2014; 7(353):ra112. DOI:10.1126/scisignal.2005329 · 7.65 Impact Factor
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    Bojana Gligorijevic · Aviv Bergman · John Condeelis
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    ABSTRACT: While it has been established that a number of microenvironment components can affect the likelihood of metastasis, the link between microenvironment and tumor cell phenotypes is poorly understood. Here we have examined microenvironment control over two different tumor cell motility phenotypes required for metastasis. By high-resolution multiphoton microscopy of mammary carcinoma in mice, we detected two phenotypes of motile tumor cells, different in locomotion speed. Only slower tumor cells exhibited protrusions with molecular, morphological, and functional characteristics associated with invadopodia. Each region in the primary tumor exhibited either fast- or slow-locomotion. To understand how the tumor microenvironment controls invadopodium formation and tumor cell locomotion, we systematically analyzed components of the microenvironment previously associated with cell invasion and migration. No single microenvironmental property was able to predict the locations of tumor cell phenotypes in the tumor if used in isolation or combined linearly. To solve this, we utilized the support vector machine (SVM) algorithm to classify phenotypes in a nonlinear fashion. This approach identified conditions that promoted either motility phenotype. We then demonstrated that varying one of the conditions may change tumor cell behavior only in a context-dependent manner. In addition, to establish the link between phenotypes and cell fates, we photoconverted and monitored the fate of tumor cells in different microenvironments, finding that only tumor cells in the invadopodium-rich microenvironments degraded extracellular matrix (ECM) and disseminated. The number of invadopodia positively correlated with degradation, while the inhibiting metalloproteases eliminated degradation and lung metastasis, consistent with a direct link among invadopodia, ECM degradation, and metastasis. We have detected and characterized two phenotypes of motile tumor cells in vivo, which occurred in spatially distinct microenvironments of primary tumors. We show how machine-learning analysis can classify heterogeneous microenvironments in vivo to enable prediction of motility phenotypes and tumor cell fate. The ability to predict the locations of tumor cell behavior leading to metastasis in breast cancer models may lead towards understanding the heterogeneity of response to treatment.
    PLoS Biology 11/2014; 12(11):e1001995. DOI:10.1371/journal.pbio.1001995 · 11.77 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):3593-3593. DOI:10.1158/1538-7445.AM2014-3593 · 9.28 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):1452-1452. DOI:10.1158/1538-7445.AM2014-1452 · 9.28 Impact Factor
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    Brian T. Beaty · John Condeelis
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    ABSTRACT: Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for penetration through the basement membrane, stromal invasion and intravasation. Invadopodia are enriched in actin regulators, such as cortactin, cofilin, N-WASp, Arp2/3 and fascin. Much of the work to date has centered around identifying the proteins involved in regulating actin polymerization and matrix degradation. Recently, there have been significant advances in characterization of the very early stages of invadopodium precursor assembly and the role of adhesion proteins, such as β1 integrin, talin, FAK and Hic-5, in promoting invadopodium maturation. This review summarizes these findings in the context of our current model of invadopodial function and highlights some of the important unanswered questions in the field.
    European Journal of Cell Biology 10/2014; 93(10-12). DOI:10.1016/j.ejcb.2014.07.003 · 3.70 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):4940-4940. DOI:10.1158/1538-7445.AM2014-4940 · 9.28 Impact Factor
  • A Patsialou · Y Wang · J Pignatelli · X Chen · D Entenberg · M Oktay · J S Condeelis
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    ABSTRACT: Patient data suggest that colony-stimulating factor-1 (CSF1) and its receptor (CSF1R) have critical roles during breast cancer progression. We have previously shown that in human breast tumors expressing both CSF1 and CSF1R, invasion in vivo is dependent both on a paracrine interaction with tumor-associated macrophages and an autocrine regulation of CSF1R in the tumor cells themselves. Although the role of the paracrine interaction between tumor cells and macrophages has been extensively studied, very little is known about the mechanism by which the autocrine CSF1R signaling contributes to tumor progression. We show here that breast cancer patients of the claudin-low subtype have significantly increased expression of CSF1R. Using a panel of breast cancer cell lines, we confirm that CSF1R expression is elevated and regulated by TGFβ specifically in claudin-low cell lines. Abrogation of autocrine CSF1R signaling in MDA-MB-231 xenografts (a claudin-low cell line) leads to increased tumor size by enhanced proliferation, but significantly reduced invasion, dissemination and metastasis. Indeed, we show that proliferation and invasion are oppositely regulated by CSF1R downstream of TGFβ only in claudin-low cell lines. Intravital multiphoton imaging revealed that inhibition of CSF1R in the tumor cells leads to decreased in vivo motility and a more cohesive morphology. We show that, both in vitro and in vivo, CSF1R inhibition results in a reversal of claudin-low marker expression by significant upregulation of luminal keratins and tight-junction proteins such as claudins. Finally, we show that artificial overexpression of claudins in MDA-MB-231 cells is sufficient to tip the cells from an invasive state to a proliferative state. Our results suggest that autocrine CSF1R signaling is essential in maintaining low claudin expression and that it mediates a switch between the proliferative and the invasive state in claudin-low tumor cells downstream of TGFβ.
    Oncogene 08/2014; 34(21). DOI:10.1038/onc.2014.226 · 8.56 Impact Factor
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    ABSTRACT: Background Tumor microenvironment of metastasis (TMEM), consisting of direct contact between a macrophage, an endothelial cell, and a tumor cell, has been associated with metastasis in both rodent mammary tumors and human breast cancer. We prospectively examined the association between TMEM score and risk of distant metastasis and compared risk associated with TMEM score with that associated with IHC4. Methods We conducted a case-control study nested within a cohort of 3760 patients with invasive ductal breast carcinoma diagnosed between 1980 and 2000 and followed through 2010. Case patients were women who developed a subsequent distant metastasis; control subjects were matched (1: 1) on age at and calendar year of primary diagnosis. TMEM was assessed by triple immunostain and IHC4 by standard methods; slides were read by pathologists blinded to outcome. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusted for clinical variables. A Receiver Operating Characteristic analysis was performed, and the area under the curve was estimated. All statistical tests were two-sided. Results TMEM score was associated with increased risk of distant metastasis in estrogen receptor (ER)(+)/human epidermal growth factor receptor (HER2)-tumors (multivariable OR (high vs low tertile) = 2.70; 95% CI = 1.39 to 5.26; P-trend = .004), whereas IHC4 score had a borderline positive association (OR10 unit increase = 1.06; 95% CI = 1.00 to 1.13); the association for TMEM score persisted after adjustment for IHC4 score. The area under the curve for TMEM, adjusted for clinical variables, was 0.78. Neither TMEM score nor IHC4 score was independently associated with metastatic risk overall or in the triple negative or HER2(+) subgroups. Conclusions TMEM score predicted risk of distant metastasis in ER+/HER2-breast cancer independently of IHC4 score and classical clinicopathologic features.
    JNCI Journal of the National Cancer Institute 08/2014; 106(8). DOI:10.1093/jnci/dju136 · 15.16 Impact Factor

Publication Stats

19k Citations
2,149.46 Total Impact Points

Institutions

  • 2014
    • Albert Einstein Medical Center
      Filadelfia, Pennsylvania, United States
  • 1992–2014
    • Yeshiva University
      • • Department of Anatomy and Structural Biology
      • • Department of Biology
      • • Albert Einstein College of Medicine
      New York, New York, United States
  • 1980–2014
    • Albert Einstein College of Medicine
      • Department of Anatomy and Structural Biology
      New York, New York, United States
  • 2012
    • Montefiore Medical Center
      • Department of Pathology
      New York City, NY, United States
  • 1977–2012
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2003
    • Imperial College London
      Londinium, England, United Kingdom
  • 1990
    • University of Iowa
      • Department of Biology
      Iowa City, IA, United States
  • 1986
    • The Rockefeller University
      • Laboratory of Cellular Physiology and Immunology
      New York, New York, United States
  • 1973–1977
    • University at Albany, The State University of New York
      • Department of Biological Sciences
      New York City, New York, United States
  • 1976
    • Marine Biological Laboratory
      Falmouth, Massachusetts, United States