Highlights

Every year, a committee of experts sits down with a tough job to do: from among all ICREA publications, they must find a handful that stand out from all the others. This is indeed a challenge. The debates are sometimes heated and always difficult but, in the end, a shortlist of  the most outstanding publications of the year is produced. No prize is awarded, and the only additional acknowledge is the honour of being chosen and highlighted by ICREA. Each piece has something unique about it, whether it be a particularly elegant solution, the huge impact it has in the media or the sheer fascination it generates as a truly new idea. For whatever the reason, these are the best of the best and, as such, we are proud to share them here.

LIST OF SCIENTIFIC HIGHLIGHTS

Format: yyyy

  • Crosstalk between Non-coding RNAs in Cancer Cells (2014)

    Esteller Badosa, Manel (IDIBELL)

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    Crosstalk between Non-coding RNAs in Cancer Cells

    When we talk about genetic material, we are usually referring to the DNA (deoxyribonucleic acid) that we inherit from our parents. This DNA is the factory where is built a similar molecule called RNA (ribonucleic acid) which produces our proteins, such as hemoglobin or insulin , allowing the lives of our cells. But there is a special group called non-coding RNA that has a more enigmatic function. The best known are microRNAs, tiny molecules that are responsible for turning on or off our genome like an electrical current switch. The article published in the prestigious journal Molecular Cell by Manel Esteller, Director of Epigenetics and Cancer Biology Program of the Bellvitge Biomedical Research Institute (IDIBELL), ICREA researcher and Professor of Genetics at the University of Barcelona, provides a twist over this mystery. Research shows that there is a second type of non-coding RNA, called ultra-conserved RNA that acts as switches switch, ie, controls the activity of microRNAs."Who watches the watchers? This was one of the issues that the researchers set at the beginning of the research. They found that special molecules called ultra-conserved RNA were not produced in human tumors and this contributed to their growth, but we knew nothing about this mechanism. It should be an important role because these molecules are highly conserved in evolution and there is no variation from chickens to humans. The researchers realized ultraconservated RNAs attached to the other family of non-coding RNAs, microRNAs, as a magnet and prevented its function. That is, they are the police internal affairs officers who supervise the battle soldiers in healthy cells. If a cell fails to produce the ultraconserved RNA, microRNA gets altered and hundreds of genes that should maintain cellular balance become disrupted, and thus contributes to the formation of human tumors.The results obtained by the group of Dr. Esteller in the Molecular Cell article are very important for understanding the function of the dark genome. Deciphering encrypted codes of cellular activity in these sequences of our DNA represents one of the most exciting challenges of modern biology. This cutting edge research is beginning to bear its first fruits in the field of medical research such as that described ultraconservated RNA is related with cancer development. 

  • The advantages of order in Biology: Cell membranes exploit hierarchical order to efficiently internalize pathogens (2014)

    García Parajo, Maria F. (ICFO)

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    The advantages of order in Biology: Cell membranes exploit hierarchical order to efficiently internalize pathogens

    Dendritic cells are the first line of fighters in our body against infections and foreign pathogens. These cells are equipped with a battery of receptors designed to recognize and uptake pathogens for further degradation. Amongst them, the pathogen recognition receptor DC-SIGN does this job with amazing efficiency and versatility. Previous work from our group found that organization of this receptor in small nanoclusters on the cell surface of dendritic cells was crucial for binding DC-SIGN to viruses, including HIV. Other molecules called glycans (sugars with different branching structures) which are ubiquitously present in the cell membrane, have the potential to interact with glycosylated proteins such as DC-SIGN, but until now their role on DC-SIGN was completely unknown. Using a combination of super-resolution imaging techniques and dual-color single-particle tracking, we visualized the organization of DC-SIGN on cells of the immune system at multiple spatial and temporal scales. Our study revealed that DC-SIGN organizes in a highly hierarchical fashion on cell the membrane (from the nano- to the meso-scale) exploring regions that are enriched with sites for endocytosis. Intriguingly, extracellular glycans micro-patterned the receptor in regions of around 1 μm in size. In turn, this micro-patterning corralled DC-SIGN into clathrin active regions (the primary internalization pathway in mammalian cells). This preferred organization increases the probability of internalizing virus pathogens for subsequent processing and degradation by dendritic cells. This work, carried out in collaboration with a team of scientists from the Radboud University Medical Center in Nijmegen, the Netherlands, has been published in PNAS this year and recommended by the Faculty of 1000 as an important paper that provides new findings in biology by means of technically advanced imaging instrumentation. Understanding how the cells of our immune system recognize and fight against pathogens is of key importance to human health. This work demonstrates that efficient pathogen binding and uptake crucially depends on how receptors organize on the cell membrane, providing clear guidelines for the design of new therapeutic drugs against infections. It is also a clear example on how Nature has devised strategies to optimize cellular function using concepts of compartmentalization and molecular modularity.

  • Electrically tunable nonlinear plasmonics in graphene nanoislands (2014)

    García de Abajo, Francisco Javier (ICFO)

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    Electrically tunable nonlinear plasmonics in graphene nanoislands

    Nonlinear optical processes rely on the intrinsically weak interactions between photons enabled by their coupling with matter. Unfortunately, many applications in nonlinear optics are severely hindered by the small response of conventional materials. Metallic nanostructures partially alleviate this situation, as the large light enhancement associated with their localized plasmons amplifies their nonlinear response to record high levels. Graphene hosts long-lived, electrically tunable plasmons that also interact strongly with light. Here we show that the nonlinear polarizabilities of graphene nanoislands can be electrically tuned to surpass by several orders of magnitude those of metal nanoparticles of similar size. This extraordinary behaviour extends over the visible and near-infrared spectrum for islands consisting of hundreds of carbon atoms doped with moderate carrier densities. Our quantum- mechanical simulations of the plasmon-enhanced optical response of nanographene reveal this material as an ideal platform for the development of electrically tunable nonlinear optical nanodevices. 

  • Prediction of tunable plasmons in atomically thin gold nanodisks (2014)

    García de Abajo, Francisco Javier (ICFO)

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    Prediction of tunable plasmons in atomically thin gold nanodisks

    The ability to modulate light at high speeds is of paramount importance for telecommunications, information processing and medical imaging technologies. This has stimulated intense efforts to master optoelectronic switching at visible and near-infrared frequencies, although coping with current computer speeds in integrated architectures still remains a major challenge. As a partial success, mid-infrared light modulation has been recently achieved through gating patterned graphene. Here we show that atomically thin noble metal nanoislands can extend optical modulation to the visible and near-infrared spectral range. We find plasmons in thin metal nanodisks to produce similar absorption cross-sections as spherical particles of the same diameter. Using realistic levels of electrical doping, plasmons are shifted by about half their width, thus leading to a factor-of-two change in light absorption. These results, which we substantiate on microscopic quantum theory of the optical response, hold great potential for the development of electrical visible and near-infrared light modulation in integrable, nanoscale devices. 

  • Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signaling and PTHLH (2014)

    Gomis, Roger (IRB Barcelona)

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    Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signaling and PTHLH

    Despite improvements in diagnosis and treatment of early colorectal cancer (CRC), both first and subsequent relapse in liver and lung remain common. Patients with metastasis are treated with systemic chemotherapy, mostly in a palliative manner. Nevertheless, in selected patients with isolated liver metastasis, increased 5 year survival can be achieved by multimodal treatment that includes combination of surgery with modern chemotherapy. However, only about 25% of patients can benefit from this type of treatment and the presence of metastases in other organs is, in most cases, a contraindication for resection. Lung is the most frequently involved organ, which highlights the need to understand mechanisms of CRC lung metastasis to further improve disease control.In this manuscript, we have identified for the first time the signaling pathway mediators and effectors that drive lung metastasis from previously established liver metastasis in colon cancer. We report a set of genes whose expression supports colonization by KRASmut colorectal cancer cells and that are associated with metastasis relapse in patients with colon cancer. We have also found enhanced ERK2 activity levels both in the metastatic cell populations and in tumors from colon cancer patients with metastasis. Downregulation of ERK2 does not affect the proliferation of colon cancer cells but attenuates their ability to form liver metastasis in mice. Interestingly, ERK2 downregulation did not affect the ability of colon cancer cells to colonize the lungs, but we provide clinical and molecular evidence indicating that p38 MAPK activity is involved. In particular, we show that induction of the cytokine PTHLH, as a consequence of p38 MAPK attenuation, facilitates the seeding of the lungs by colon cancer cells growing in liver metastatic lesions facilitating the extravasation process. Altogether, our results dissect colorectal cancer metastasis mechanisms into consecutive steps of liver and lung colonization, which involve specific alterations in MAPK signaling, and highlight the implications of metastatic lesions as a platform for further dissemination.The observation that liver and lung seeding is linked to tumor-specific or circulating cell-specific factors may create opportunities for the development of targeted therapies to prevent disease dissemination from the colon to the liver, and subsequently to the lungs.

  • The first light-operated drugs for most common target proteins (2014)

    Gorostiza Langa, Pau (IBEC)

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    The first light-operated drugs for most common target proteins

    We have developed Alloswitch-1, the first light-controlled therapeutic agent whose effects focus specifically on the largest, most important class of drug target proteins – G protein-coupled receptors. Controlling drug activity with light means that the therapeutic effects can be accurately delivered locally, thus reducing their effect on other areas and the resultant side effects, and helps reduce the dosage required. Alloswitch-1 targets the metabotropic glutamate receptor mGlu5 specifically at the allosteric site of the protein. Allosteric modulators have a number of advantages over traditional drugs, offering higher selectivity of target receptors, tunable release according to whether the undesirable protein receptor activity is present, and lower potential for toxic effects. Building a photocontrolled modulator of a G protein-coupled receptor required developing a new chemical design concept in which the photoswitch is not tethered to the drug but inserted within the pharmacophore, which is the group of atoms in the molecule of a drug responsible for its action. The compound turned out to be one of the most potent and selective allosteric modulators in its class. The effects of this ‘optopharmacological’ compound can be remotely controlled in space and time in living, wildtype organisms. This is an advantage over optogenetic manipulations, which require gene overexpression using viruses, for example. Small molecule therapeutic agents as Alloswitch-1, if they can be made available orally, could offer a competitive advantage over traditional drugs, which often affect off-target tissues and organs, leading to unwanted consequences and compromising their beneficial effects.

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