RESERACH SUMMARY

Our main research interest is to understand how chemokines mediate the interaction between tumour cells and their microenvironment, and how they participate in the control of tumour growth and progression. We study the contribution of chemokine receptors to cancer cell physiology, and evaluate their potential as antitumor targets.

Chemokines are small proteins that bind to G protein-coupled receptors and regulate leukocyte migration during homeostasis, inflammation and infection. Chemokine action extend to all cell types, however, and appears to be important in defining organ-specific metastatic destinations during cancer spread. In some solid tumors, levels of the chemokine receptors CCR7 and CXCR4 correlate with cell dissemination in lymph nodes or other sites; CCR6 and CX3CR1 expression is related to cancer cell homing to specific organs, suggesting chemokine receptors as promising therapeutic targets. The chemokine receptor CCR9 is expressed primarily on thymocytes and in a small subset of intraepithelial lymphocytes; its only natural ligand, CCL25, is expressed mainly in thymus and by the small bowel. Recent reports showed that CCR9 overexpression increases the migratory and invasive capacity of prostate cancer cells, directs ovarian cancer and melanoma cell metastases to the small intestine, and increases proliferation of and resistance to apoptosis by acute lymphoblastic leukemia-derived cell lines. CCR9-mediated intracellular signaling activates the anti-apoptotic PI3K, Akt, PTEN, mTOR, ERK1/2 and GSK-3 pathways, and downregulates activation of caspase-3, leading to survival and increased cell proliferation.

Our group is interested in determining the role of CCR9 in tumor physiopathology. We have generated anti-human CCR9 monoclonal antibodies (mAb) to characterize and follow CCR9 expression by flow cytometry, Western blot and immunomicroscopy, and for blocking receptor signaling. Our neutralizing anti-CCR9 mAb are being evaluated in tumor cell cycling, survival, migratory and invasiveness using human tumor lines, and in tumor progression and metastasis in xenogeneic mouse models. We use quantitative real-time PCR and immunohistochemistry to determine whether antibody action produces changes in mRNA and protein levels. CCR9-expressing human carcinoma cell lines and RNA interference approaches are also used to study the molecular mechanisms that underlie CCR9-mediated effects. In addition, we will test the usefulnes of these mAb for diagnostic imaging and for antagonist screening of low molecular weight compounds for drug development.

We work in collaboration with Drs. Laura Carramolino (CNIC), Gabriel Márquez (Genetrix), Joaquín Teixido (CIB/CSIC), Julio Gutiérrez (CNB), Ricardo Villares (CNB), Carlos Martínez-A (CNB) and Elena Fernandez-Ruiz (Hospital La Princesa, Madrid).