Our group studies the mechanisms contributing to the progression of chronic lymphocytic leukemia (CLL), the most common leukemia in Western countries. We focus on molecules involved in cell adhesion, migration, and survival, particularly matrix metalloproteinase-9 (MMP-9). MMP-9 binds to CLL cells via α4β1 integrin and CD44v. We have identified two sequences (P3 and P6, Fig.1) within the hemopexin domain of MMP-9 (PEX9), responsible for MMP-9 interaction with these cell receptors. Using xenograft models in mice, we have also found that overexpression of MMP-9 in CLL cells leads to modulation of several migration regulatory pathways and impairment of in vivo homing to bone marrow and spleen. MMP-9 (abundant in these organs) may thus contribute to the retention of CLL cells in niches, favoring malignant cell survival and drug resistance. Indeed, MMP-9 induces CLL cell resistance to arsenic trioxide and fludarabine by modulating proteins of the Bcl-2 family and upregulating the corresponding anti-apoptotic/pro-apoptotic ratios (Fig. 2). Our results establish that targeting MMP-9 in combined therapies may thus improve CLL response to treatment. Our current studies include non-catalytic MMP-9 functions that also contribute to malignancy. Multiple myeloma (MM) is also a common B-cell malignancy, where plasma cells accumulate in the bone marrow and induce osteolytic bone lesions and immunodeficiency. In collaboration with Dr. Joaquín Teixidó we are using in vivo imaging approaches to examine the molecular mechanisms governing the initial MM cell attachment to the bone marrow endothelium. We have found a critical role for the α4β1 integrin and selectin ligands in this process. A better knowledge of these mechanisms should help design new appropriate targets for myeloma.
Gutiérrez-González A, Martinez-Moreno M, Samaniego R, Arellano-Sánchez N, Relloso M, Valeri A, Martinez-López J, Corbí A, Hidalgo A, García-Pardo A, Teixidó J and Sánchez-Mateos P. . Evaluation of the potential therapeutic benefits of macrophage reprogramming in Multiple Myeloma. Blood, 128(18): 2241-2252. PMID 27625360.
Martínez-Moreno M, Leiva M, Aguilera-Montilla N, Sevilla-Movilla S, Isern de Val S, Arellano-Sánchez N, Gutiérrez NC, Maldonado R, Martínez-López J, Buño I, García-Marco JA, Sánchez-Mateos P, Hidalgo A, García-Pardo A, Teixidó J. 2016. . In vivo adhesion of malignant B cells to bone marrow microvasculature is regulated by α4β1 cytoplasmic-binding proteins. Leukemia, 30(4): 861-872. doi: 10.1038/leu.2015.332.
Amigo-Jiménez I*, Bailón E*, Aguilera-Montilla N, García-Marco JA, García-Pardo A. 2016. *equal contribution . Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget doi: 10.18632/oncotarget.13091.
Ugarte-Berzal E, Vandooren J, Bailón E, Opdenakker G, García-Pardo A. . Inhibition of MMP-9-dependent degradation of gelatin, but not other MMP-9 substrates, by the MMP-9 hemopexin domain blades 1 and 4. J Biol Chem 291(22): 11751-11760. doi: 10.1074/jbc.M115.708438.
Amigo-Jiménez I, Bailón E., Aguilera-Montilla N, Terol MJ, García-Marco JA, García-Pardo A. . Bone marrow stroma-induced resistance of chronic lymphocytic leukemia cells to arsenic trioxide involves Mcl-1 upregulation and is overcome by inhibiting the PI3Kδ or PKCβ signaling pathways. Oncotarget, 6: 44832-44848. doi: 10.18632/oncotarget.6265.
Lozano-Santos C*, Amigo-Jiménez I*, Nova-Gurumeta S, Pérez-Sanz N, García-Pardo, A**, García-Marco, J.A**. *equal contribution; **corresponding authors. . Arsenic trioxide synergistically potentiates the cytotoxic effect of fludarabine in chronic lymphocytic leukemia cells by further inactivating the Akt and ERK signaling pathways. Biochem. Biophys. Res. Comm. 461: 243-248. doi: 10.1016/j.bbrc.2015.04.007.
García-Pardo A, Opdenakker G. . Nonproteolytic functions of matrix metalloproteinases in pathology and insights for the development of novel therapeutic inhibitors. Metalloproteinases in Medicine, 2: 19-28.
Vandooren J, Born B, Solomonov I, Zajac E, Saldova R, Senske M, Ugarte-Berzal E, Martens E, Van den Steen PE, Van Damme J, Garcia-Pardo A, Froeyen M, Deryugina EI, Quigley JP, Moestrup SK, Rudd PM, Sagi I, Opdenakker G. . Circular trimers of gelatinase B/matrix metalloproteinase-9 constitute a distinct population of functional enzyme molecules differentially regulated by tissue inhibitor of metalloproteinases-1. Biochem J 465(2): 259-270. doi: 10.1042/BJ20140418.
Rey-Barroso J, Coló GP, Alvarez-Barrientos A, Redondo-Muñoz J, Carvajal-González JM, Mulero-Navarro S, García-Pardo A, Teixidó J, Fernández-Salguero PM. . The dioxin receptor controls β1 integrin activation in fibroblasts through a Cbp-Csk-Src pathway. Cell. Signaling 25(4): 848-859. doi: 10.1016/j.cellsig.2013.01.010
Amigo-Jiménez I, Bailón E, Ugarte-Berzal E, Aguilera-Montilla N, García-Marco JA and García-Pardo A . Matrix metalloproteinase-9 is involved in chronic lymphocytic leukemia cell response to fludarabine and arsenic trioxide. Plos One 9(6): e99993. doi: 10.1371/journal.pone.0099993
- SAF2009-07035 (2010-2012)
- S2010/BMD-2314 (2012-2015)
- SAF2012-31613 (2013-2016)
- RD06/0020/0011 (2013-2015)
- RD12/0036/0061 (2015-2016)
- SAF2015-69180R (2016-2018)