INFLUENCE OF THYMIC STROMAL CELLS AND CHEMOKINE SIGNALING IN ACUTE T-CELL LEUKEMIA DEVELOPMENT

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Context-dependent roles for lymphotoxin-beta receptor signaling in cancer development

Publication . Fernandes, Mónica T.; Dejardin, Emmanuel; Rodrigues Dos Santos, Nuno

The LT alpha(1)beta(2) and LIGHT TNF superfamily cytokines exert pleiotropic physiological functions through the activation of their cognate lymphotoxin-beta receptor (LT beta R). Interestingly, since the discovery of these proteins, accumulating evidence has pinpointed a role for LT beta R signaling in carcinogenesis. Early studies have shown a potential anti-tumoral role in a subset of solid cancers either by triggering apoptosis in malignant cells or by eliciting an anti-tumor immune response. However, more recent studies provided robust evidence that LT beta R signaling is also involved in diverse cell-intrinsic and microenvironment-dependent pro-oncogenic mechanisms, affecting several solid and hematological malignancies. Consequently, the usefulness of LT beta R signaling axis blockade has been investigated as a potential therapeutic approach for cancer. Considering the seemingly opposite roles of LT beta R signaling in diverse cancer types and their key implications for therapy, we here extensively review the different mechanisms by which LT beta R activation affects carcinogenesis, focusing on the diverse contexts and different models assessed. (C) 2016 Elsevier B.V. All rights reserved.

2016-04Journal article

Open Access

Thymic stromal factors promoting t-cell leukemia

Publication . Ghezzo, Marinella Nobre; Santos, Nuno R. dos

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of T cell precursors that affects mainly children and young adults, disseminates throughout the body invading several organs, and fatal without early diagnosis and appropriate therapy. It is thought that T-ALL arises from the malignant transformation of T-cell precursors or thymocytes, as denoted by similar immunophenotypic, genotypic and transcriptomic profile of T-ALL cases and particular stages of intra-thymic T-cell differentiation. Thymocyte development is achieved through a close bidirectional communication between stromal cells and the developing thymocytes. These interactions trigger changes in the thymic stromal microenvironment that are essential for thymocyte migration, differentiation and selection of functional mature T cells tolerant to self-antigens. During the intra-thymic development and differentiation process of thymocytes, transformation events lead to the expression of certain oncogenes. Several genetic alterations result in the activation of signaling pathways commonly involved in cancer, any of which can be activated by microenvironmental cell-derived ligands. The cancer microenvironment is crucial for tumorigenesis, yet relatively little is known about the microenvironmental factors contributing to T-ALL. The identification of thymic stromal cell molecular factors that participate in T-ALL is important for a better understanding of T-ALL pathogenesis. The molecular and cellular players involved in stromal support of thymocyte leukemogenesis have only recently began to be explored. Our group has reported that inactivation in stromal cells of the RelB transcription factor and the lymphotoxin-β receptor (LTβR) delayed leukemia development in the TEL-JAK2 transgenic mouse model of thymic T-ALL development. In this work, we characterized the thymic stromal alteration in various stages of disease and found that thymic leukemogenesis was associated with an expansion of medullary thymic epithelial cells (TEC) and reduction of cortical TECs. More importantly, we found that haploinsufficiency of the Foxn1 gene, an essential master regulator of TEC differentiation, delayed thymic leukemogenesis.

2017-06-27Doctoral thesis

Open Access