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Alejandro Pablo P Adam , PhD
Assistant Professor


2007 - PhD from Roffo Institute of Oncology, University of Buenos Aires

Current Research

Multicellular organisms depend on strong, stable intercellular adhesion structures to maintain a cohesive state, but also on mechanisms to allow the separation of cells when required. Many fundamental cellular processes in multicellular organisms, such as embryonic development, organ regeneration, immune surveillance, and blood vessels permeability, require a transient inhibition of intercellular adhesion. Cells are held together by distinct cellular junctions, consisting of protein complexes that confer them with particular characteristics, such as protection against mechanical stress, barrier function, and cell-cell communication. These are the tight junction, the adherens junction (AJ), and the desmosome.

The endothelial adherens junction structure
Endothelial cells (ECs) regulate the passage of fluids, macromolecules, and cells from the blood stream to the surrounding tissues. Endothelial permeability and transendothelial migration (TEM) are critical during acute and chronic inflammation, shock (septic, anaphylactic or cardiogenic), atherosclerosis, acute lung distress syndrome, and primary tumor growth and metastasis. The EC is not only centrally involved in this process, but also readily exposed to circulating drugs and humanized antibodies, thus making it a perfect target for novel drug development. Hence, it is essential to understand its mechanisms of regulation in order to design better therapeutic strategies. Endothelial intercellular adhesion, and thus permeability, is tightly regulated by a number of vasoactive factors and is critical to determine the onset and extent of an inflammatory response. The endothelial AJ is comprised of the classical cadherin VE-cadherin and the catenins p120, β-catenin and plakoglobin. ECs contain AJ complexes along the cell-cell border in close association with a cortical actin ring, supporting strong cell-cell adhesion and resistance to the shear stress induced by the blood flow. Endothelial AJ can form very distinct structures within the cells, and their relative composition and function is currently unknown. Essentially, while we know the molecular The endothelial adherens junction structurepartners of stable adherens junctions, little is known about the dynamic formation of these structures and why endothelial cells may show different AJ structures. The classical structure, termed here “linear” junction, is observed along the lines of cell-cell interactions in close association with the cortical actin ring. Linear junctions may occur together with “reticular” junctions, which are observed at regions of cell-cell overlap. These junctions are named after the distinct network of cadherins and catenins observed throughout the overlapping region. Linear AJ colocalize with tight junction markers, while reticular AJ do not. Further, linear junctions are less mobile than reticular junctions, suggesting that linear AJ may be more mature, stronger adhesion sites. Determining quantitatively the molecular composition of each structure is critical to be able to understand how endothelial cells interact and what is the role for each adherens junction structure.
Signaling in inflammation
Signaling in inflammationIt has long been known that many vasoactive mediators can induce phosphorylation of proteins in the adherens junction in cultured endothelial cells. Src family kinases (SFK) inhibitors not only block the AJ proteins' phosphorylation, but also protect from increased permeability, suggesting that SFK activity plays a critical role in regulating endothelial barrier function. However, we previously reported that activation of endogenous SFKs by removing Csk-mediated repression of SFK activity through expression of a dominant negative form of Csk (DN-Csk) is not sufficient to induce a loss of barrier function in human dermal microvascular endothelial cells, despite a strong phosphorylation of VE-cadherin and several other SFK target proteins. Moreover, we did not observe a reduction in VE-cadherin binding to either p120 or β-catenin upon SFK activation. Our previous results support a model in which other signaling molecules need to act concurrently with SFK activation in order to promote endothelial permeability. More recently, we found that tumor necrosis factor alpha (TNF-a) and SFKs act synergistically to increase endothelial permeability. TNF-a is a potent proinflammatory cytokine critically involved in vascular permeability and transendothelial migration (TEM). By using techniques that allowed us to activate individual signaling pathways independent of mediator induced receptor activation, we have demonstrated that SFKs can cooperate with low levels of p38 activation, similar to those induced by low levels of TNF-a to disrupt endothelial barrier function.
The role of the cytoskeleton
TNF-a alone induces only a mild formation of actin stress fibers and does not result in a loss of peripheral actin. In turn, activation of endogenous SFKs do not induce actin stress fiber The role of the cytoskeletonformation. In this case, actin is observed in the cell periphery and active SFKs (labeled using an anti- pY419 Src antibody) co-localizes with actin at the cell-cell junctions. Dual TNF-a and DN-Csk treatment, however, induces a dramatic change in actin configuration and the localization of phospho-SFKs. Cells show short and thick bundles of F-actin with large paxillin-containing adhesion sites at the ends of these actin bundles. Additionally, active (pY419) Src also localizes to these adhesion structures, as well as several other markers of focal adhesions, such as vinculin, FAK, PYK2 and b3 integrin, many of which were in a hyperphosphorylated state. In addition to the changes in actin, VE-cadherin is also disrupted following dual treatment but not with either TNF-a or DN-Csk alone. While induction of SFK activity alone by DN-Csk expression promotes cell-cell overlap and an increase in reticular VE-cadherin staining, treatment with both TNF-a and DN-Csk reduces the extent of this overlap and induces the appearance of large gaps in the monolayer.
Molecular mechanisms of rosacea
Multiple lines of evidence indicate that rosacea is associated with vascular hyperreactivity and instability. In fact, several vascular abnormalities have been reported in facial rosacea, including hyperpermeability, angiogenesis, and lymphangiogenesis. Additionally, a class of antimicrobial compounds called cathelicidins that are increased in rosacea yield multiple angiogenic effects and induce vascular endothelial changes. Nonetheless, our previous investigation into the molecular biology of the ocular variant of this disorder did not demonstrate any enrichment of vascular endothelial growth factor in cutaneous biopsies, as compared with normal eyelid skin, and the signaling mechanisms by which the vascular phenomena associated with ocular rosacea develop are unknown.Molecular mechanisms of rosacea
 Several therapeutic interventions have been proposed to address ocular rosacea, including topical treatments, systemic medications, laser and light-based modalities, and surgical therapies. Nonetheless, our current treatment options are largely ineffective, and ocular rosacea remains an incurable disorder.
Very recently we found that CD31 staining (a marker for the presence of blood vessels) does not demonstrate any statistically significant differences between control eyelid biopsies and those taken from patients with ocular rosacea, suggesting that the total number of vessels are not different in this disorder as compared to normal eyelid skin. Nonetheless, CD105 and ICAM staining is enhanced in specimens of ocular rosacea. In essence, this disorder does not represent an increase in the number of blood vessels, but the vascular phenomena inherent to this disease instead reflects pathologic inflammation and weakness of the existing vasculature. Furthermore, no statistically significant differences were identified at the levels of the venules or lymphatics, suggesting that aberrancies in the arterioles may be a specific culprit in the pathogenesis of ocular rosacea.
Future directions
My goal is to understand the mechanisms that regulate endothelial permeability in inflammation. My research is focused on several key aspects: 1) the synergistic effects of tyrosine kinases and serine/threonine kinases that result in endothelial permeability; 2) the role of integrins in permeability and TEM; 3) the structural and functional differences between the cortical, reticular, and discontinuous adherens junctions; 4) the molecular mechanisms of the inflammation observed in rosacea, studying not only the endothelium, but also the leukocytes present and the neighboring keratinocytes. 



PubMed Publications

  1. Ladeda V*, Adam A*, Puricelli L, Bal de Kier Joffé E Apoptotic cell death is prevented by soluble factors present in the target organ of metastasis. Breast Cancer Res Treat 69:39-51 (2001). (*equal contribution)

  2. Bal de Kier Joffé E, Adam A. Transformación celular y mecanismos de sobrevida regulados por la GTPasa RalA. Medicina 61:658-663 (2001).

  3. Mazzoni E, Adam A, Bal de Kier Joffé E, Aguirre-Ghiso J. Immortalized mammary epithelial cells overexpressing PKCgamma acquire a malignant phenotype and become tumorigenic in vivo. Mol Cancer Res 1:776-787 (2003).

  4. Ranganathan A, Zhang L, Adam A, Aguirre-Ghiso J. Functional Coupling of p38-Induced Up-regulation of BiP and Activation of RNA-Dependent Protein Kinase–Like Endoplasmic Reticulum Kinase to Drug Resistance of Dormant Carcinoma Cells. Cancer Res 66:1702-1711 (2006).

  5. Ranganathan A*, Adam A*, Zhang L, Aguirre-Ghiso J. Tumor Cell Dormancy Induced by p38SAPK and ER-Stress Signaling. An Adaptive Advantage for Metastatic Cells? Cancer Biol & Therapy 5:729-735 (2006). (*equal contribution)

  6. Ranganathan A*, Adam A*, Aguirre-Ghiso J. Opposing Roles of Mitogenic and Stress Signaling Pathways in the Induction of Cancer Dormancy. Cell Cycle 5:1799-1807 (2006). (*equal contribution)

  7. Sequeira S, Ranganathan A, Adam A, Iglesias B, Farias E, Aguirre-Ghiso J., Inhibition of Proliferation by PERK Regulates Mammary Acinar Morphogenesis and Tumor Formation. PlosONE 2:e615 (2007).

  8. Adam AP, George A, Schewe D, Bragado P, Iglesias BV, Ranganathan AC, Kourtidis A, Conklin DS, Aguirre-Ghiso JA. Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence. Cancer Res 69:5664-5672 (2009).

  9. Bajaj A, Zheng Q, Adam A, Vincent P, Pumiglia K. Activation of endothelial ras signaling bypasses senescence and causes abnormal vascular morphogenesis. Cancer Res 70:3803-3812 (2010).

  10. Adam AP, Sharenko AL, Pumiglia K, Vincent PA. Src-induced tyrosine phosphorylation of VE-cadherin is not sufficient to decrease barrier function of endothelial monolayers. J Biol Chem 285:7045-7055 (2010).

  11. Wladis EJ, Iglesias BV, Adam AP, and Gosselin EJ. Molecular Biologic Assessment of Cutaneous Specimens of Ocular Rosacea. Ophthal Plast Reconstr Surg 28:246-250 (2012).

  12. Wladis EJ, Iglesias BV, Adam AP, Nazeer T, and Gosselin EJ. Toll-like Receptors in Idiopathic Orbital Inflammation. Ophthal Plast Reconstr Surg 28:273-276 (2012).

  13. Alcaide P, Martinelli R, Newton G, Williams MR, Adam A, Vincent PA, Luscinskas FW. p120-catenin prevents neutrophil transmigration independently of Rho A inhibition by impairing Src dependent VE-cadherin phosphorylation. Am J Physiol: Cell Physiology 303: C385-C395 (2012).