Brittany Carson

Bio: Brittany Carson is an academic researcher from Karolinska Institutet. The author has contributed to research in topics: Ribosome biogenesis & Population. The author has an hindex of 6, co-authored 7 publications receiving 398 citations. Previous affiliations of Brittany Carson include Cornell University.

An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway

Abstract: Misregulated β-catenin responsive transcription (CRT) has been implicated in the genesis of various malignancies, including colorectal carcinomas, and it is a key therapeutic target in combating various cancers. Despite significant effort, successful clinical implementation of CRT inhibitory therapeutics remains a challenging goal. This is, in part, because of the challenge of identifying inhibitory compounds that specifically modulate the nuclear transcriptional activity of β-catenin while not affecting its cytoskeletal function in stabilizing adherens junctions at the cell membrane. Here, we report an RNAi-based modifier screening strategy for the identification of CRT inhibitors. Our data provide support for the specificity of these inhibitory compounds in antagonizing the transcriptional function of nuclear β-catenin. We show that these inhibitors efficiently block Wnt/β-catenin–induced target genes and phenotypes in various mammalian and cancer cell lines. Importantly, these Wnt inhibitors are specifically cytotoxic to human colon tumor biopsy cultures as well as colon cancer cell lines that exhibit deregulated Wnt signaling.

Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease.

Abstract: Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ERα) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.

To give is better than to receive: compliance with WHO guidelines for drug donations during 2000-2008.

Abstract: OBJECTIVE: To assess drug donations in terms of their adherence to the drug donation guidelines put forth by the World Health Organization (WHO). METHODS: In 2009 we searched the academic and lay literature - journal articles, media articles and industry and donor web sites - to identify reports about drug donations made from 2000 to 2008. Publications focusing on molecular mechanisms of drug action, general descriptions of guidelines or specific one-time drug donations before 2000 were excluded. For cases with sufficient information, we assessed compliance with each of the 12 articles of WHO's guidelines. FINDINGS: We found 95 articles describing 96 incidents of drug donations between 2000 and 2008. Of these, 50 were made in response to disaster situations, 43 involved the long-term donation of a drug to treat a specific disease and 3 were drug recycling cases. Disaster-related donations were less likely to comply with the guidelines, particularly in terms of meeting the recipient's needs, quality assurance and shelf-life, packaging and labelling, and information management. Recipient countries were burdened with the costs of destroying the drugs received through inappropriate donations. Although long-term donations were more likely to comply with WHO guidelines related to quality assurance and labelling, they did not consistently meet the needs of the recipients. Furthermore, they discouraged local drug production and development. CONCLUSION: Drug donations can do more harm than good for the recipient countries. Strengthening the structures and systems for coordinating and monitoring drug donations and ensuring that these are driven by recipient needs will improve adherence to the drug donation guidelines set forth by WHO.

To Give Is Better Than to Receive: Compliance with WHO Guidelines for Drug Donations during 2000-2008/mieux Vaut Donner Que Recevoir: Conformite Avec Les Directives De l'OMS En Matiere De Dons De Medicaments Sur la Periode 2000-2008/dar Es Mejor Que Recibir: Cumplimiento De Las Directrices De la OMS Sobre Las Donaciones De Medicamentos Entre 2000 V 2008

Abstract: Introduction Drug donations are pharmaceutical agents given to countries or health facilities at no cost by nongovernmental organizations (NGOs), other countries, private corporations of groups of donors. The donations may be made for different purposes, such as providing assistance during emergency situations, supplying specific medicines over the long term or recycling drugs (e.g. donating leftover drugs just before they expire if a clinic purchased more than it actually needed). Although the sources and reasons for drug donations differ, the same basic guidelines apply to drug donations of all types. (1,2) Drug donations are intended to provide the medicines needed to alleviate suffering, yet drug donations often generate problems. (2) For example, the donated drugs may not meet the needs of the recipient and donor agencies may fall to comply with local procedures for approving, labelling, storing or inventorying medicines. The donated drugs are often also labelled in a language foreign to the recipient population, they may fail to meet the quality standards established by the recipient country or they may even have expired. Lastly, drug donations can be a financial burden on the recipient country. If the donated drugs have a high declared value, import taxes and overhead costs may be high; if the quantity of the donation is larger than required to meet the recipient's needs, the recipient may have to bear the cost of properly disposing of the excess. In 1996, the World Health Organization (WHO), in collaboration with major international agencies active in humanitarian relief, issued guidelines aimed at reducing the problems that are often linked with drug donations.' Following review, the guidelines were revised and reissued in 1999. (2) Because the guidelines were developed from the standpoint of providing aid to countries who are in need of drugs, the donations are guided by four core principles: They must be: (i) of maximum benefit to the recipient; (ii) given with respect for the recipient's wishes and authority; (iii) free from any double standards in product quality; and (iv)provided through effective communication between donor and recipient. The 12 articles of the guidelines on drug donations are based on these four principles. The guidelines are applicable to both emergency and long-term donations. The objective of this study was to assess the level of adherence to the 1999 edition of the WHO Guidelines for drug donations (2) by reviewing all the drug donation cases that have occurred from 2000 to 2008. Methods In 2009 we searched the academic and lay literature to identify reports about drug donations from 2000 to 2008. We searched PubMed and Google Scholar using the terms "drug donation(s)" and "program(s)(me)(mes)" and performed snowball searches based on the names of specific products, companies or events associated with drug donations as we found them. For example, when we found an article mentioning drug donations in response to an earthquake in Gujarat, we specifically searched for articles on this event (earthquake) in that location (Gujarat). We also searched the WHO Library (www.who. int/library/en/), Intranet (www.who.int/ en/), Internet (www.who.int/en/) and Essential Medicines and Pharmaceutical Policy (http://www.who.int/medicines/ en/) using derivatives of the phrase "drug donation". A snowball search of web sites mentioned in these initial searches, including web sites of pharmaceutical companies and NGOs, was conducted. We also posted a request for any relevant articles on eDrug (www.essentialdrugs. org), an electronic information source on essential drugs. When particular cases were identified, we queried for more information on them by using keywords that were specific to each event. AI1 case studies, news reports, journal articles and company reports that were available were considered for inclusion. Publications about the molecular mechanisms of drug action or general descriptions of guidelines were excluded. …

Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses.

Abstract: Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstream signaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na+, which compromised Na+-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas. Cancer Res; 77(7); 1741-52. ©2017 AACR.

WNT signalling pathways as therapeutic targets in cancer

Abstract: Since the initial discovery of the oncogenic activity of WNT1 in mouse mammary glands, our appreciation for the complex roles for WNT signalling pathways in cancer has increased dramatically. WNTs and their downstream effectors regulate various processes that are important for cancer progression, including tumour initiation, tumour growth, cell senescence, cell death, differentiation and metastasis. Although WNT signalling pathways have been difficult to target, improved drug-discovery platforms and new technologies have facilitated the discovery of agents that can alter WNT signalling in preclinical models, thus setting the stage for clinical trials in humans.

Can we safely target the WNT pathway

Abstract: WNT–β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.

Tackling the cancer stem cells — what challenges do they pose?

Abstract: Since their identification in 1994, cancer stem cells (CSCs) have been objects of intensive study. Their properties and mechanisms of formation have become a major focus of current cancer research, in part because of their enhanced ability to initiate and drive tumour growth and their intrinsic resistance to conventional therapeutics. The discovery that activation of the epithelial-to-mesenchymal transition (EMT) programme in carcinoma cells can give rise to cells with stem-like properties has provided one possible mechanism explaining how CSCs arise and presents a possible avenue for their therapeutic manipulation. Here we address recent developments in CSC research, focusing on carcinomas that are able to undergo EMT. We discuss the signalling pathways that create these cells, cell-intrinsic mechanisms that could be exploited for selective elimination or induction of their differentiation, and the role of the tumour microenvironment in sustaining them. Finally, we propose ways to use our current knowledge of the complex biology of CSCs to design novel therapies to eliminate them.

Mechanical strain induces E-cadherin–dependent Yap1 and β-catenin activation to drive cell cycle entry

Abstract: Mechanical strain regulates the development, organization, and function of multicellular tissues, but mechanisms linking mechanical strain and cell-cell junction proteins to cellular responses are poorly understood. Here, we showed that mechanical strain applied to quiescent epithelial cells induced rapid cell cycle reentry, mediated by independent nuclear accumulation and transcriptional activity of first Yap1 and then β-catenin. Inhibition of Yap1- and β-catenin-mediated transcription blocked cell cycle reentry and progression through G1 into S phase, respectively. Maintenance of quiescence, Yap1 nuclear exclusion, and β-catenin transcriptional responses to mechanical strain required E-cadherin extracellular engagement. Thus, activation of Yap1 and β-catenin may represent a master regulator of mechanical strain-induced cell proliferation, and cadherins provide signaling centers required for cellular responses to externally applied force.

Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms.

Abstract: The evolutionarily conserved Wnt signaling pathway plays essential roles during embryonic development and tissue homeostasis. Notably, comprehensive genetic studies in Drosophila and mice in the past decades have demonstrated the crucial role of Wnt signaling in intestinal stem cell maintenance by regulating proliferation, differentiation, and cell-fate decisions. Wnt signaling has also been implicated in a variety of cancers and other diseases. Loss of the Wnt pathway negative regulator adenomatous polyposis coli (APC) is the hallmark of human colorectal cancers (CRC). Recent advances in high-throughput sequencing further reveal many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations in CRC. Despite attractive strategies to develop drugs for Wnt signaling, major hurdles in therapeutic intervention of the pathway persist. Here we discuss the Wnt-activating mechanisms in CRC and review the current advances and challenges in drug discovery.