Metabostemness: metaboloepigenetic reprogramming of cancer stem-cell functions

Cancer researchers are currently embarking on one of their field’s biggest challenges, namely the understanding of how cellular metabolism or certain classes of elite metabolites (e.g., oncometabolites) can directly influence chromatin structure and the functioning of epi-transcriptional circuits to causally drive tumour formation. We here propose that refining the inherent cell attractor nature of nuclear reprogramming phenomena by adding the under-appreciated capacity of metabolism to naturally reshape the Waddingtonian landscape’s topography provides a new integrative metabolo-epigenetic model of the cancer stem cell (CSC) theory

CSR and Deregulation : Social Responsibility and Competitive Advantage

Bakgrund: Den statliga utredningen En framtida spelreglering presenterades under december 2008. Ett förslag i utredningen är att delar av monopolet på den svenska spelmarknaden i framtiden kan komma att konkurrensutsättas. Syfte: Denna studie syftar till att undersöka hur det sociala ansvarstagandet påverkas och i vilken omfattning CSR kan utgöra en konkurrensfördel på en avreglerad marknad. Genomförande: Vi har använt oss av en kvalitativ undersökningsmetod där Svenska Spel, Ladbrokes och Betssons CSR - arbete studeras. Utöver sekundärdata har det empiriska materialet kompletterats genom intervjuer med varje företag. Resultat: En avreglerad marknad behöver inte innebära att företagens sociala ansvarstagande minskar i samhället. Att integrera CSR i företagsstrategin är ett viktigt led i att nå acceptans bland intressenterna på marknaden. För ett lyckat CSR – arbete menar vi att företagens interna resurser måste användas med hänsyn till flertalet faktorer i den omgivande miljön.Background: During the end of 2008 the Swedish government published a submission for comment regarding the future legislation of the Swedish gambling industry. The investigation suggests that new entrants may be allowed to enter the Swedish market. Aim: The purpose of this thesis is to determine if and how the social responsibility is affected when a market is deregulated, and if CSR is a possible tool for creating competitive advantage. Completion: The study is based on a qualitative method and examines the gambling companies Svenska Spel, Ladbrokes and Betsson. We conducted questionnaire studies among the examined gambling companies to enhance the secondary data. Findings: Our findings suggest that there is a good possibility for social responsibility to maintain a strong position in a deregulated market. CSR integration with the corporate strategy is an important step concerning acceptance among the company’s stakeholders

Oncometabolic nuclear reprogramming of cancer stemness

By impairing histone demethylation and locking cells into a reprogramming-prone state, oncometabolites can partially mimic the process of induced pluripotent stem cell generation. Using a systems biology approach, combining mathematical modeling, computation, and proof-of-concept studies with live cells, we found that an oncometabolite-driven pathological version of nuclear reprogramming increases the speed and efficiency of dedifferentiating committed epithelial cells into stem-like states with only a minimal core of stemness transcription factors. Our biomathematical model, which introduces nucleosome modification and epigenetic regulation of cell differentiation genes to account for the direct effects of oncometabolites on nuclear reprogramming, demonstrates that oncometabolites markedly lower the “energy barriers” separating non-stem and stem cell attractors, diminishes the average time of nuclear reprogramming, and increases the size of the basin of attraction of the macrostate occupied by stem cells. These findings establish the concept of oncometabolic nuclear reprogramming of stemness as a bona fide metabolo-epigenetic mechanism for generation of cancer stem-like cells

Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer

The correction of specific signaling defects can reverse the oncogenic phenotype of tumor cells by acting in a dominant manner over the cancer genome. Unfortunately, there have been very few successful attempts at identifying the primary cues that could redirect malignant tissues to a normal phenotype. Here we show that suppression of the lipogenic enzyme fatty acid synthase (FASN) leads to stable reversion of the malignant phenotype and normalizes differentiation in a model of breast cancer (BC) progression. FASN knockdown dramatically reduced tumorigenicity of BC cells and restored tissue architecture, which was reminiscent of normal ductal-like structures in the mammary gland. Loss of FASN signaling was sufficient to direct tumors to a reversed phenotype that was near normal when considering the development of polarized growth-arrested acinar-like structure similar to those formed by nonmalignant breast cells in a 3D reconstituted basement membrane in vitro. This process, in vivo, resulted in a low proliferation index, mesenchymal-epithelial transition, and shut-off of the angiogenic switch in FASN-depleted BC cells orthotopically implanted into mammary fat pads. The role of FASN as a negative regulator of correct breast tissue architecture and terminal epithelial cell differentiation was dominant over the malignant phenotype of tumor cells possessing multiple cancer-driving genetic lesions as it remained stable during the course of serial in vivo passage of orthotopic tumor-derived cells. Transient knockdown of FASN suppressed hallmark structural and cytosolic/secretive proteins (vimentin, N-cadherin, fibronectin) in a model of EMT-induced cancer stem cells (CSC). Indirect pharmacological inhibition of FASN promoted a phenotypic switch from basal- to luminal-like tumorsphere architectures with reduced intrasphere heterogeneity. The fact that sole correction of exacerbated lipogenesis can stably reprogram cancer cells back to normal-like tissue architectures might open a new avenue to chronically restrain BC progression by using FASN-based differentiation therapies

Silibinin meglumine, a water-soluble form of milk thistle silymarin, is an orally active anti-cancer agent that impedes the epithelial-to-mesenchymal transition (EMT) in EGFR-mutant non-small-cell lung carcinoma cells.

10.1016/j.fct.2013.07.063Silibinin is the primary active constituent of a crude extract (silymarin) from milk thistle plant (Silybum marianum) seeds. We explored the ability of an oral milk thistle extract formulation that was enriched with a water-soluble form of silibinin complexed with the amino-sugar meglumine to inhibit the growth of non-small-cell lung carcinoma (NSCLC) mouse xenografts. As a single agent, oral silibinin meglumine notably decreased the overall volumes of NSCLC tumors as efficiently as did the EGFR tyrosine kinase inhibitor (TKI) gefitinib. Concurrent treatment with silibinin meglumine impeded the regrowth of gefitinib-unresponsive tumors, resulting in drastic tumor growth prevention. Because the epithelial-to-mesenchymal transition (EMT) is required by a multiplicity of mechanisms of resistance to EGFR TKIs, we evaluated the ability of silibinin meglumine to impede the EMT in vitro and in vivo. Silibinin-meglumine efficiently prevented the loss of markers associated with a polarized epithelial phenotype as well as the de novo synthesis of proteins associated with the mesenchymal morphology of transitioning cells. Our current findings with this non-toxic, orally active, and water-soluble silibinin formulation might facilitate the design of clinical trials to test the administration of silibinin meglumine-containing injections, granules, or beverages in combination with EGFR TKIs in patients with EGFR-mutated NSCLC