Doctor en Ciencias mención Biología Molecular, Celular y Neurociencias / Cell adhesion to the extracellular matrix (ECM) is key to the regulation of cellular
processes such as proliferation, survival, and migration. Mesenchymal cell adhesion
requires the formation of focal adhesions, defined as multiprotein complexes that allow
cell binding to the ECM. Focal adhesions involve the congregation of more than 150
proteins, which include integrins, the main ECM receptors, and the Focal Adhesion
Kinase (FAK), which has as a fundamental role in the turnover of focal adhesions.
Formation and disassembly of focal adhesions are dynamically regulated during
cell migration, and numerous studies show that increased expression or activity of focal
adhesion proteins is associated with many human diseases. For example, increased levels
and/or activities of FAK have been associated with oncogenic transformation in a variety
of tissues and organs. Aside the roles commonly described for FAK in activating integrins,
such as integrin β1 (ITGB1), and modulating integrin downstream signaling, this kinase
has been shown to behave as an intracellular effector of multiple signaling pathways,
including Neogenin-1 (NEO1). NEO1 is a transmembrane receptor involved in tissue
growth during embryogenesis, although it is also broadly expressed in adulthood. More
recently, overexpression of NEO1 has been observed in a wide variety of human cancers
including those of the breast, pancreas, cervix, colon and medulloblastoma. Despite the
latter, its role in tumorigenesis is still controversial and remains to be elucidated.
In the context of neural development NEO1 promotes neuronal migration and
axonal guidance through interaction with the extracellular Netrin (NTN) ligand family.
Interestingly, NEO1 is strongly expressed in neuroblastoma (NB), a cancer derived from
neural progenitors of the sympathoadrenal lineage. Therefore, it will be relevant
xii
determining if NEO1, by interacting with NTNs, could promote the migration and
metastasis of NB cells, and if this phenomenon is mediated through the activation of FAK,
thus promoting the intracellular activation of the ITGB1.
It was shown that both the NEO1 receptor and its main NTN ligands family
members, Netrin-1 (NTN1) and Netrin-4 (NTN4), are expressed in NB patient samples.
We reveal that NEO1, in addition to promoting chemotactic migration in association with
NTN4 in vitro, promotes metastasis in vivo, as demonstrated in the chicken embryo model.
Recent data from the literature supports our results and allow us to suggest that the
interaction between NTN4 and NEO1 might not be direct, but rather mediated by a
signaling complex also made up by laminin g1 and ITGB1. NTN1, on the other hand, acts
as a chemoattractant molecule and binds directly to NEO1. In addition, we show that FAK
is an downstream effector of NEO1, and that the NTN1/ NEO1 signaling complex
interacts with ITGB1, in the SK-N-SH NB cells. Thus, our results suggest that NTN1/
NEO1 promotes the activation of ITGB1 through FAK, most likely through the formation
of a macromolecular complex, driving cell migration. All these results are consistent with
our in vivo observations, which show that NEO1 promotes the metastasis of SK-N-SH
cells in an immunodeficient mouse model.
In summary, this thesis shows that NEO1 promotes the migration of NB cells and
that its mechanism of action is via interaction with ITGB1, with FAK being an
intracellular mediator of this signaling pathway. NEO1, by promoting cell migration,
could play a key role in the process of NB metastasis. Therefore, the signaling complex
xiii
conformed by NTNs / NEO1 is proposed as a possible prognostic marker of the
progression of NB.
| Identifer | oai:union.ndltd.org:UCHILE/oai:repositorio.uchile.cl:2250/151941 |
| Date | 09 1900 |
| Creators | Villanueva Arros, Andrea Marisol. |
| Contributors | Palma Contreras, Verónica, Torres, Vicente, Universidad de Chile. Facultad de Ciencias. Escuela de Posgrado |
| Source Sets | Universidad de Chile |
| Language | English |
| Detected Language | English |
| Type | Tesis |
| Rights | Attribution-NonCommercial-NoDerivs 3.0 Chile, http://creativecommons.org/licenses/by-nc-nd/3.0/cl/ |
Page generated in 0.0016 seconds