| 1. |
- Gatto, Francesco, 1987, et al.
(författare)
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Flux balance analysis predicts essential genes in clear cell renal cell carcinoma metabolism
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 5, s. Art. no. 10738-
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Tidskriftsartikel (refereegranskat)abstract
- Flux balance analysis is the only modelling approach that is capable of producing genome-wide predictions of gene essentiality that may aid to unveil metabolic liabilities in cancer. Nevertheless, a systemic validation of gene essentiality predictions by flux balance analysis is currently missing. Here, we critically evaluated the accuracy of flux balance analysis in two cancer types, clear cell renal cell carcinoma (ccRCC) and prostate adenocarcinoma, by comparison with large-scale experiments of gene essentiality in vitro. We found that in ccRCC, but not in prostate adenocarcinoma, flux balance analysis could predict essential metabolic genes beyond random expectation. Five of the identified metabolic genes, AGPAT6, GALT, GCLC, GSS, and RRM2B, were predicted to be dispensable in normal cell metabolism. Hence, targeting these genes may selectively prevent ccRCC growth. Based on our analysis, we discuss the benefits and limitations of flux balance analysis for gene essentiality predictions in cancer metabolism, and its use for exposing metabolic liabilities in ccRCC, whose emergent metabolic network enforces outstanding anabolic requirements for cellular proliferation.
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| 2. |
- Gatto, Francesco, 1987
(författare)
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The origin of symmetry in the metabolism of cancer – From systems biology to translational medicine
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Why do not we have a cure for cancer yet? Cancer is the malady of the century, the most intensely studied disease of all time. The question is puzzling. It assumes that cancer is a single entity that we can target and eradicate. On the contrary, the current theory on the origin of cancer dictates that each patient bears a cancer that is an exquisite experiment of nature, in which a unique constellation of genetic aberrations confers the cell with malignant traits that enable it to proliferate and survive until death of the host. Nevertheless, the question is legitimate. Cancer is also a single entity because, in spite of the heterogeneity of origins, every individual cancer in its evolution ought to converge in the acquisition of the same malignant traits, e.g. abnormal proliferation and ability to metastasize. I define this phenomenon of convergent evolution as the symmetry of cancer and each of these traits as symmetric, reminiscent of the fact that as diverse as two individual cancers can be in its origin, they can be repositioned along the trait to be identical.This thesis is dedicated to understanding the origin of symmetry of cancer through systems biology. In particular, I focused my interest in a specific malignant trait, the reprogramming of cell metabolism. Metabolic reprogramming in cancer is associated with deregulation of anabolism and energy metabolism to foster rapid cell proliferation and plastic adaptation to enable cell survival. Human metabolism is a complex system, which consists of thousands of biochemical reactions that transform nutrients into energy, building blocks for cell growth (like membrane phospholipids), macromolecules with specialized functions (like hormones), and in general support life by maintaining whole body homeostasis. I sought to explore whether the transformation to cancer entailed some symmetric patterns of regulation of metabolism. In order to undertake an unbiased view of this complex system, I adopted a systems level perspective, in which genome-scale changes of gene and protein expression (so-called omics) attributable to cancer were bridged with the network of reactions that form the backbone of human metabolism. The results were two-fold. First, any cancer seemed to acquire a symmetric overexpression of nucleotide metabolism, regardless from where it originated (Paper I). However, the comparison was performed against the matched healthy tissues of origin, mostly composed of quiescent cells. Therefore we ascribed this symmetry to an adaptation to a metabolic requirement of cellular proliferation. In order to discern what regulatory patterns in metabolism are not adaptive but oncogenic, meaning an obligate metabolic reprogramming to foster evolution, we characterized those gene expression changes occurring in presence of an oncogenic mutation, again irrespective of the tissue of origin or other confounding factor (Paper II). This analysis revealed that oncogenic mutations independently converge on the deregulation of a sub-network revolving around the metabolism of arachidonic acid and xenobiotics mediated by glutathione and oxygen, which we termed AraX. Deregulation of AraX can be associated with a successful engagement of the immune system in tumor evolution, suggesting that the symmetry of cancer metabolism may exclusively rely on reprogramming fluxes to support pro-tumorigenic inflammation. Second, the symmetry of cancer metabolism broke with the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). We reported that a ccRCC-specific set of genetic aberrations is associated with the emergence of a uniquely compromised metabolic network (Paper I). These outstanding features of ccRCC metabolism provided an opportunity for translational medicine. We proved that it is possible to exploit ccRCC defective network to predict computationally metabolic liabilities that induce selective cell death in ccRCC (Paper III). Moreover, these changes in metabolic regulation unique to ccRCC can be distilled, through an algorithm of our creation, Kiwi (Paper V), in a coordinated regulation of glycosaminoglycan biosynthesis (GAGs) (Paper IV). This is mirrored by an altered profile of GAGs in kidney-proximal fluids, urine and blood, that we prove bearing a strong, accurate, and robust diagnostic value in metastatic ccRCC. The case of ccRCC and potential role of inflammation in AraX may raise more doubt than support on the existence of symmetry in the metabolic reprogramming in any cancer cell (Paper VI). Perhaps researchers are simply observing an enhanced plasticity in the adaptation to ever-changing conditions that is induced by mutations, but which is not symmetric under any specific trait and as such not essential to cancer. Yet, I argue that the quest for searching the symmetry in cancer should not be abandoned. This quest is in my opinion of paramount importance to unlock the discovery of a cure for cancer.
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| 3. |
- Mannello, F., et al.
(författare)
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Breast cyst fluid heparan sulphate is distinctively N-sulphated depending on apocrine or flattened type
- 2015
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Ingår i: Cell Biochemistry and Function. - : Wiley. - 0263-6484 .- 1099-0844. ; 33:3, s. 128-133
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Tidskriftsartikel (refereegranskat)abstract
- Breast cyst fluid (BCF) contained in gross cists is involved with its many biomolecules in different stages of breast cystic development. Type I apocrine and type II flattened cysts are classified based on biochemical, morphological and hormonal differences, and their different patterns of growth factors and active biocompounds may require different regulation. In a previous paper, hyaluronic acid in a very low content and chondroitin sulphate/dermatan sulphate were identified and characterized in BCF. In this new study, various apocrine and flattened BCFs were analyzed for HS concentration and disaccharide pattern. Apocrine HS was found specifically constituted of N-acetyl groups contrary to flattened HS richer in N-sulphate disaccharides with an overall N-acetylated/N-sulphated ratio significantly increased in apocrine compared with flattened (13.5 vs 3.7). Related to this different structural features, the charge density significantly decreased (-30%) in apocrine versus flattened BCFs. Finally, no significant differences were observed for HS amount (0.9-1.3 mu gml(-1)) between the two BCF types even if a greater content was determined for flattened samples. The specifically N-sulphated sequences in flattened BCF HS can exert biologic capacity by regulating growth factors activity. On the other hand, we cannot exclude a peculiar regulation of the activity of biomolecules in apocrine BCF by HS richer in N-acetylated disaccharides. In fact, the different patterns of growth factors and active biocompounds in the two types of cysts may require different regulation by specific sequences in the HS backbone possessing specific structural characteristics and distinctive chemical groups.
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