Projects: Nanomedicine

Research Projects of the Nanomedicine Group

26

Sep 2017

Impact of dietary intervention on tumour immunity-DIgesT

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Disease progression can be controlled in cancer patients through the administration of immune checkpoint inhibitors (ICIs). But, ICIs mainly show efficacy in subsets of patients and treatment costs are very high. Here, we use a dietary intervention to counteract cancer-related immune suppression through interfering with metabolic pathways. DIgesT will enable the exciting possibility of integrating cancer therapy with a dietary approach that is inherently low-risk and non-toxic, will encounter little regulatory barriers and
is highly cost-effective. Given the effects of metabolic pathways on immune responses, we hypothesize that a fasting-mimicking diet (FMD) diet will reduce proinflammatory and immunosuppressive responses, that are influenced by glucose and lipid metabolism, to restore effective antitumor immunity.

DIgesT aims to:

- Determine if FMD modulates immune cell profiles in cancer patients and tilts the balance from immunosuppressive to antitumor immune responses
- Evaluate in mouse models if FMD improves antitumor immune response, alone or combined with ICIs
- Clarify the molecular mechanisms underlying FMD-induced immune modifications
- Analyze the effect of FMD on gut microbiota, as a possible link to systemic immune modulation

Two parallel approaches will be used: 1) Investigating FMD immune effects on tumour immunity in clinical setting (breast cancer and melanoma) and 2) Investigating FMD immune effects on tumour immununity in murine cancer models. DIgesT results and expected impacts:
• Knowledge on the immune effects of FMD in preclinical and clinical settings
• Preclinical evidence of FMD potentiating effects on immunotherapy (ICIs)
• Improving cancer treatment strategies and survival rates, and quality of life
• Creating networking infrastructures and databases, international sharing of data and knowledge

Funding:

Funding

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22

Mar 2016

The DNA hydroxymethylomes of colorectal cancer

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Colorectal cancer (CRC) continues to be one of the main health problems world-wide. Its high mortality rates are linked to late diagnosis and, therefore, the development of useful biomarkers to aid in earlier detection is a priority in this disease setting. Epigenetic alterations are key processes both in initiation and progression of this disease. In this context, 5-hydroxymethyl cytosine (5hmC) recent discovery is changing our views about DNA genomic methylomas in cancer. In this project, we propose whole hydroxymethylomas determination in CRC; evaluation of the alterations found as a source of clinical markers; and the functional role of these alterations. For these purposes we will use DNA oxidation techniques, recently added to the portfolio of our lab, that allow 5hmC discrimination from 5-methylcytosine (5mC); DNA next-generation sequencing; and methylation arrays. Identified genes will be validated by bisulfate pyrosequencing, in independent patient’s cohorts. For several of these candidate genes, we will study the effect of the 5hmC changes found on gene expression, as well as their functional consequences on the tumoral process both in vitro and in vivo. Finally, we will study plasma DNA from CRC patients and from healthy individuals to determine if the molecular markers, identified in tumor samples, are also detectable in peripheral blood. Would this be the case, the method’s utility in clinical practice would be enhanced, mainly due to an easier use.

Funding:

LOGO FEDER_ISCIII

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25

Aug 2015

Crosstalk between DNA methylomes and H4K16 acetylomes in acute myeloid leukemia

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Aberrant DNA methylation is a hallmark of cancer. We previously showed that other epigenetic mark, H4K16ac is also frequently altered in hematopoietic tumors. Our two previous FIS projects allowed the identification of specific enzymes underlying this epigenetic alteration and the mapping of the affected chromatin regions. New preliminary data from our laboratory suggest that the alteration of H4K16ac in cancer is highly tumor-type dependent and that it is tightly coordinated with genome-wide DNA methylation. To study these issues in more detail, in this project we propose to use chromatin inmunoprecipitation and ultra deep sequencing technologies to analyze in parallel the genome-wide patterns of H4K16ac and DNA methylation in individual samples obtained from 40 patients with acute mielocitic leukemia (AML). In addition, to determine the functional role of H4K16ac in blood tumors, we will generate a drug-inducible and blood compartment-conditional mice deficient for Myst1, the H4K16-specific histone acetyltranferase (HAT). We will assess the clinical implications of our results at two different levels: i) if they corroborate that H4K16ac is tumor-type dependent we will study the potential of this histone posttranslational modification as a bona fide clinical marker and, ii) if the conditional Myst1 KO mice are more prone to develop blood tumors, we will evaluate the potential of this HAT as a target in cancer therapy.    

Funding:

LOGO FEDER_ISCIII

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25

Aug 2015

Genome-wide changes of hydroxymethylcytosie during aging in adult stem cells

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To investigate the epigenetic alterations during aging in adult stem cells, we recently finalized a study (Fernandez et al. 2015, Genome Res) in which we used Illumina methylation arrays (Illumina Infinium® Human Methylation 450K BeadChip) to analyze the genome-wide DNA methylation patterns of bone marrow mesenchymal stem cells (MSCs) obtained from individuals of different ages. However, the recent discovery of the 5-hydroxymethylcytosisne (5hmC), suggests that this new epigenetic modification may play an important role on the previously observed changes of DNA methylation. Thus, in this project we aim to determine the role of 5hmC in bone marrow mesenchymal stem cells during aging and the effect, if any, on adipocytes, a cell type derived form MSCs.

Funding:  Logo GRUPIN014

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