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Facultad de Biología. Universidad de Salamanca

Sábado, 16 Septiembre 2017 14:19

OFERTA TRABAJO DE FIN DE GRADO EN BIOLOGÍA/BIOTECNOLOGÍA

Se ofrece la posibilidad de realizar un TFG experimental en el curso 17/18 a través del Anexo I a estudiantes de Biología y Biotecnología.

Interesados contactar con el Dr. Miguel Vicente-Manzanares
Científico Titular Centro de Investigación del Cáncer/Instituto de Biologia Molecular y Celular del Cáncer

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Información sobre el Proyecto de investigación: Biophysics of melanoma-induced immunosuppression.

Cancer-induced mortality correlates with the migratory capability of tumor cells; and also their immunosuppressive ability. Melanoma is one of the deadliest forms of cancer, showing strong migratory and metastatic ability and triggering immunosuppression through a variety of mechanisms, including the generation of tolerogenic myeloid populations, macrophage polarization towards pro-tumor phenotypes and the induction of regulatory T cell populations. Drugs that target immune checkpoint proteins have shown promise in the treatment of melanoma. However, the molecular foundations of melanoma-induced immunosuppression remain elusive. Until now, immunosuppression has been attributed to the expression of immunosuppressive soluble factors, for example IL-10; or surface-membrane proteins, e.g. CTLA-4, or PD-1. Recent evidence emphasizes the role of mechanical changes in the aggressiveness of different types of cancer, e.g. breast cancer and glioblastoma. Based on preliminary evidence that manipulating key elements that determine the mechanical ability of melanoma cells changes the biophysical properties of their microenvironment, we will address how the biophysical changes involved in melanoma growth and metastatic capability also determine its immunosuppressive ability. The current project aims to determine the effect of the mechanical signature of melanoma malignant transformation in the immune function of myeloid cells involved in the anti-tumor immune response; we will also manipulate the mechanical signature of melanoma to improve the immune function of innate cells and thus enhance the anti-tumor immune response. Aim 1 will be carried out by inserting melanoma cells of well-characterized malignant ability (e.g. cell lines) in mechanically controlled microenvironments to study their immunosuppressive ability at two different levels: expression of immunosuppressive molecules, and modulation of tumor- myeloid cell membrane-to-membrane interactions. This effort will be carried out in two ways: in-depth study of specific molecules that control the mechanical signature of tumor cells in different contexts, e.g. molecular motors and their modulators; and large-scale proteomics and genomics approaches to determine whole-proteome/genome modifications in response to specific mechanical signatures. We will focus on the regulation of mechanosensitive transcription factors, e.g. Yap/Taz and Nkx2.5, and their relationship to cancer cell stemness. Aim 2 will be carried out by validating and targeting some of the molecules identified in Aim 1 to determine their specific function in immunosuppression. We are already carrying out a proof- of-concept approach by reintroducing myosin II-B (Myh10 gene) in melanoma cells. Myh10 RNA is downregulated in >10 human and mouse melanoma cell lines. We and other have reported its key role in mechanosensitive cell migration and cell polarization. By reintroducing its expression, we can study its role in melanoma development, metastatic growth and immunosuppression in vitro and in vivo. The mechanical modulation of the tumor microenvironment during malignant transformation is conducive to improved growing of tumor cells. Our preliminary data together with this hypothesis-driven proposal extend the effect of the mechanical alterations of the tumor microenvironment to enhanced immunosuppression. Thus, this proposal bears the potential to modify the landscape of cancer biology by integrating two major hallmarks of cancer (increased proliferation and immunosuppression) into a mechano-chemical model of cancer immunosuppression. In this model, the modulation of the mechanics of the tumor are directly related to their ability to inhibit immune responses by triggering “conventional” immunosuppression, i.e. driven by immunosuppressive molecules, as well as by altering the in situ interactions among tumor and immune myeloid cells. It also opens up a novel potential strategy of cancer treatment based on decreasing simultaneously the proliferative and immunosuppressive abilities of tumor cells. This strategy would be completely compatible with the molecular targeting of immune checkpoints and/or anti-proliferative approaches. 

Facultad de Biología

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Campus Miguel de Unamuno
C/ Donantes de sangre, s/n
37007 Salamanca, España

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