About 40% of Colorectal Cancer (CRC) patients with locally advanced disease show resistance to therapy and eventually develop metastasis. Current CRC staging based on histopathology and imaging has limited ability to predict disease progression or patient prognosis. A major advance has been the recent elaboration of molecular classifications based on global gene expression profiles, which have defined CRC subtypes displaying resistance to therapy and poor prognosis. In this work, we evaluated various molecular classifications and discovered that in all cases, their predictive power arises from genes expressed by cancer-associated fibroblasts (CAFs) rather than by tumor cells themselves. We found that such stromal gene program is driven by TGF-beta signaling and is expressed by virtually all poor prognosis CRCs. Functional dissection of CRC progression demonstrated that the presence of CAFs facilitates tumor initiation, an effect that is dramatically enhanced by transforming growth factor (TGF)-ß signaling. Using patient-derived tumor organoids and xenografts, we showed that the use of TGF-ß signaling inhibitors to block the cross-talk between cancer cells and the microenvironment prevented metastasis formation. Overall, our work reveals that CRC metastasis rely on a cancer cell non-autonomous program driven by TGF-ß in the tumor microenvironment. This dependency suggests that patients with advanced CRC cancers could benefit from the use TGF-ß signaling inhibitors. In addition, our work paves the way for new methods of patient classification based on the existence of distinct tumor microenvironments.
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 24 publications 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
The risk of metastatic disease in colorectal cancer is determined by a gene program expressed in the tumor stroma (2015)
Batlle Gómez, Eduard (IRB Barcelona)view details
A new light source with unprecedented sensitivity to molecular fingerprints of cancer cells (2015)
Biegert, Jens (ICFO)view details
Researchers from the Attoscience and Ultrafast Optics Group led by ICREA Prof. at ICFO Jens Biegert, in collaboration with the Laboratory for Attosecond Physics at the Max Planck Institute for Quantum Optics (MPQ) and the Ludwig-Maximilians-Universität (LMU) in Munich, have developed a worldwide unique broadband and coherent infrared light source. The record peak brilliance of the light source makes it an ultrasensitive detector for the infrared molecular fingerprint region, ideal to detect minute changes in the spectral features from cells or tissue which are telltale signs of DNA mutation or the presence of cellular malfunctions such as cancer.
Nucleosomes arrange in clutches along the chromatin fiber; a novel model of chromatin fiber organization (2015)
Cosma, Maria Pia (CRG)view details
García Parajo, Maria F. (ICFO)
The chromatin fiber is formed by wrapping of the DNA around the nucleosome octamers composed of H2A, H2B, H3 and H4 core histones (Luger et al., Nature, 1997). Using X-ray diffraction, the chromatin fiber was seen as assembled into a hierarchical structure with the DNA double helix of 10 nm diameter compacted into a higher ordered fiber of 30 nm with a solenoid or two-start helix spatial arrangement (Finch et al., Proc Natl Acad Sci U S A, 1976; Dorigo et al., Science, 2004). The existence of the 30 nm fibers has however been challenged and the 10 nm fiber was postulated to occasionally assemble in more condensed areas (Fussner et al., EMBO Rep, 2012). Computational modeling indicated that the 30 nm spatial assembly is not compatible with efficient packaging of the fiber into the nucleus (Tokuda et al., Biophys J, 2012).
Using quantitative super-resolution nanoscopy, we discovered that nucleosomes arrange in groups of various sizes along the chromatin fiber, which we named ‘nucleosome clutches’ (in analogy with clutches of eggs). Clutches are interspersed with nucleosome-free regions. Interestingly, we found that the median number of nucleosomes and their compaction inside the clutches is highly correlated with cellular state. Strikingly, ground-state pluripotent stem cells have, on average, clutches that are less dense and contain fewer nucleosomes. RNA polymerase II is associated with the smallest clutches, suggesting that small clutches are transcriptionally active. Moreover there is a high amount of linker histone H1 in the largest clutches, which form the heterochromatin.
Our super-resolution studies, which involve Prof. Melike Lakadamyali (ICFO) and two ICREA Professors, María García Parajo (ICFO) and Maria Pia Cosma (CRG), provide key structural and functional information on the chromatin fiber and reveal a novel and essential feature of stem cells.
A human antibody alters memory and behavior (2015)
Dalmau, Josep (IDIBAPS)view details
In 2007 we discovered a human brain disease mediated by antibodies against the NMDA glutamate receptor (NMDAR). This disorder (named anti-NMDAR encephalitis) was the first of a new category of neuropsychiatric diseases mediated by antibodies against synaptic neurotransmitter receptors. The concept that an antibody could directly alter memory, behavior, cognition, and cause psychosis was novel, and changed the landscape of diagnostic and treatment approaches in neurology and psychiatry. Today, anti-NMDAR encephalitis is considered the most common antibody-mediated CNS disease, ranking in frequency above most viral encephalitis. Over the years, a pathogenic effect of the antibodies had been suggested in studies of cultured neurons and other in vitro models. This year, we reported an animal model that definitively established that patients’ antibodies alter memory and behavior. In this model patient antibodies were continuously infused over 14 days into the cerebroventricular system of mice using catheters connected to osmotic pumps. During and after the infusion multiple memory and behavioral tests were performed. The studies showed that patients’ NMDAR antibodies led to progressive memory impairment, anhedonia and depressive-like behaviors. Molecular studies in the hippocampus of the mice showed a decrease of clusters of total and synaptic NMDAR. These molecular effects, which paralleled behavioral symptoms, gradually reversed after the end of the antibody infusion. This model establishes a link between memory and behavioral deficits and antibody-mediated reduction of NMDAR, provides the biological basis by which removal of antibodies and antibody-producing cells improve neurological function, and offers a model for testing experimental therapies in this and similar disorders. The work was summarized on the cover of Brain: A Journal of Neurology (Jan 2015).
Graphene enables all-electrical control of energy flow from light emitters (2015)
de Riedmatten, Hugues (ICFO)view details
Garcia de Abajo, Francisco Javier (ICFO)
Koppens, Frank (ICFO)
At the heart of lasers, displays and other light-emitting devices lies the emission of photons. Electrically controlled modulation of this emission is of great importance in applications such as optical communication, sensors and displays. Moreover, electrical control of the light emission pathways opens up the possibility of novel types of nano-photonics devices, based on active plasmonics.
A collaboration between the groups of ICREA professors at ICFO Frank Koppens, Javier García de Abajo and Hugues de Riedmatten, as well as scientists from MIT, CNRS, CNISM and Graphenea have now demonstrated active, in-situ electrical control of the energy flow from erbium ions into photons and plasmons. The experiment was implemented by placing the erbium emitters a few tens of nanometers away from the graphene sheet, whose carrier density (Fermi energy) is electrically controlled. Partially funded by the EC Graphene Flagship, this study entitled “Electrical control of optical emitter relaxation pathways enabled by graphene”, has been published in Nature Physics.
Erbium ions are essentially used for optical amplifiers and emit light at a wavelength of 1.5 micrometers, the so called third telecom window. This is an important window for optical telecommunications because there is very little energy loss in this range, and thus highly efficient information transmission.
The study has shown that the energy flow from erbium into photons or plasmons can be controlled simply by applying a small electrical voltage. The plasmons in graphene are rather unique, as they are very strongly confined, with a plasmon wavelength that is two orders of magnitude smaller than the wavelength of the emitted photons. As the Fermi energy of the graphene sheet was gradually increased, the erbium emitters went from exciting electrons in the graphene sheet, to emitting photons or plasmons. The experiments revealed the long-sought-after graphene plasmons at near-infrared frequencies, relevant for these telecommunications applications. In addition, the strong concentration of optical energy offers new possibilities for data storage and manipulation through active plasmonic networks.
Progress in a New Paradigm to Explain the Magnitude of the Electroweak Scale (2015)
Espinosa Sedano, José Ramón (IFAE)view details
Our understanding of Nature is based on the empirical evidence that natural phenomena taking place at different energy/distance scales do not influence each other. The parameters of an effective theory are natural if they do not require any special tuning of the parameters of the theory at higher energies. Wilson and 't Hooft gave a quantitative meaning to this naturalness principle by demanding that all dimensionless parameters controlling the different effective theories should be of order unity unless they are associated to the breaking of a symmetry. The Higgs boson mass and the value of the cosmological constant have been long recognized as two notorious challengers of this naturalness principle. Supersymmetry or Higgs compositeness are two prime examples of models trying to associate the Higgs mass to a small symmetry breaking. Recently, however, a radically new approach to explain the smallness of the Higgs mass has been proposed by Graham, Kaplan and Rajendran (Phys. Rev. Lett. 115 (2015) 22, 221801), in reminiscence of the relaxation mechanism of Abbott proposed for explaining the smallness of the cosmological constant.
Technically, the relaxation mechanism exploits the coupling of the Higgs boson to an axionlike field and a long era in the early Universe where the axion unchains a dynamical screening of the Higgs mass. We present a new realization of this idea with the new and outstanding feature that it leaves no sign of new physics at the electroweak scale, and up to a rather large scale, 109 GeV, except for two very light and weakly coupled axionlike states. One of the scalars can be a viable dark matter candidate. Such a cosmological Higgs-axion interplay could be tested with a number of experimental strategies.
The relaxion idea pursued here represent a new twist in the long and fruitful history of the interplay between particle physics and cosmology. While in the past particle physics has been a crucial ingredient to understand the cosmological history of our universe, if these new ideas were correct, cosmological evolution would be a crucial ingredient in the understanding of some key parameters of particle physics.