Tackling Cancer with Yeast-Based Technologies

Ferreira, Raphael; Limeta, Angelo; Nielsen, Jens

doi:10.1016/j.tibtech.2018.11.013

Cited by 34 publications

(20 citation statements)

References 72 publications

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“…Several fungal species have been identified in the human gastrointestinal tract (17,18), representing 0.1-1.0% of the intestinal microbiota (commonly referred to as mycobiota). The fungal cells are outnumbered by the bacterial ones, but as eukaryotic organisms, fungi have substantially more diverse biochemical pathways than bacteria (19). Thus, when the bioactive capacity of the intestinal microbiota is considered, the role of mycobiota is of major importance with a remarkable potential to modulate host cellular functions.…”

Section: Introductionmentioning

confidence: 99%

Fungal Dysbiosis and Intestinal Inflammation in Children With Beta-Cell Autoimmunity

et al. 2020

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Although gut bacterial dysbiosis is recognized as a regulator of beta-cell autoimmunity, no data is available on fungal dysbiosis in the children at the risk of type 1 diabetes (T1D). We hypothesized that the co-occurrence of fungal and bacterial dysbiosis contributes to the intestinal inflammation and autoimmune destruction of insulin-producing beta-cells in T1D. Fecal and blood samples were collected from 26 children tested positive for at least one diabetes-associated autoantibody (IAA, GADA, IA-2A or ICA) and matched autoantibody-negative children with HLA-conferred susceptibility to T1D (matched for HLA-DQB1 haplotype, age, gender and early childhood nutrition). Bacterial 16S and fungal ITS2 sequencing, and analyses of the markers of intestinal inflammation, namely fecal human beta-defensin-2 (HBD2), calprotectin and secretory total IgA, were performed. Anti-Saccharomyces cerevisiae antibodies (ASCA) and circulating cytokines, IFNG, IL-17 and IL-22, were studied. After these analyses, the children were followed for development of clinical T1D (median 8 years and 8 months). Nine autoantibody positive children were diagnosed with T1D, whereas none of the autoantibody negative children developed T1D during the follow-up. Fungal dysbiosis, characterized by high abundance of fecal Saccharomyces and Candida, was found in the progressors, i.e., children with beta-cell autoimmunity who during the follow-up progressed to clinical T1D. These children showed also bacterial dysbiosis, i.e., increased Bacteroidales and Clostridiales ratio, which was, however, found also in the non-progressors, and is thus a common nominator in the children with beta-cell autoimmunity. Furthermore, the progressors showed markers of intestinal inflammation detected as increased levels of fecal HBD2 and ASCA IgG to fungal antigens. We conclude that the fungal and bacterial dysbiosis, and intestinal inflammation are associated with the development of T1D in children with beta-cell autoimmunity.

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Section: Introductionmentioning

confidence: 99%

Fungal Dysbiosis and Intestinal Inflammation in Children With Beta-Cell Autoimmunity

et al. 2020

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“…Yeast is a useful model organism for studying tumorigenic mechanisms [28] and for development of advanced technologies for drug discovery [29]. In particular, in BRCA2-expressing yeast cells, a high increase in both intra- and inter-recombination events occurs, and the expression of selected BRCA2 variants differentially affects yeast recombination [30], showing that BRCA2 function in homologous recombination-mediated DNA repair can be recapitulated in yeast.…”

Section: Introductionmentioning

confidence: 99%

6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner

Laera

Guaragnella

Giannattasio

et al. 2019

Cancers

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Background: Mutations in the oncosuppressor gene BReast CAncer susceptibility gene 2 (BRCA2) predispose to aggressive forms of prostate cancer which show poor response to taxane-based therapy, the standard treatment for castration-resistant, aggressive prostate cancer. Herein, we addressed the question whether changes in BRCA2 expression, a potential surrogate marker for BRCA2 activity, may affect the response of castration-resistant prostate cancer cells to 6-thioguanine (6-TG), a thiopurine used in the treatment of haematological malignancies. Methods: Yeast, normal prostate cells and castration-resistant prostate cancer cells were treated with 6-TG or its analogues, in presence or absence of paclitaxel, or with olaparib, a poly-(ADP-ribose) polymerase (PARP) inhibitor currently in clinical trials for treatment of metastatic castration-resistant prostate cancer, and cell proliferation, apoptosis and androgen receptor (AR) levels were measured. Results: 6-TG inhibited cell proliferation in yeast, normal and castration-resistant prostate cancer cells but promoted apoptosis only in cancer cells. Suppression of BRCA2 expression by siRNA or shRNA increased the sensitivity to 6-TG- and olaparib-induced apoptosis but did not affect cancer cell response to taxane. Intriguingly, 6-TG reduced AR expression levels independently on BRCA2 expression. Instead, olaparib decreased AR levels only in BRCA2-knockdown prostate cancer cells. Notably, overexpression of BRCA2 resulted in resistance of castration-resistant prostate cancer cells to 6-TG-, taxane- and olaparib-based treatment but promoted sensitivity to apoptosis induced by 2-amino-6-bromopurine and 2,6–dithiopurine, two 6-TG analogues. Conclusions: Our results provide a pre-clinical rationale for the use of 6-TG in the treatment of BRCA2-deficient castration-resistant prostate cancers, and of certain 6-TG analogues for treatment of BRCA2-proficient prostate cancers.

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“…Due to its endogenous glycosylation machinery lacking specific terminal mannose glycopeptides known to be clinically incompatible for human administration (Hamilton and Gerngross, 2007), studies of antibody production in yeast have predominantly been conducted in K. phaffii (Spadiut et al, 2014). Several glycoengineering approaches provided valuable insights into the glycosylation machinery of K. phaffii and enabled the production of proteins with human linked glycans causing only mild to low antigenicity in humans (reviewed by Ferreira et al, 2019).…”

Section: Protein Secretion and Unfolded Protein Responsementioning

confidence: 99%

Komagataella phaffii as Emerging Model Organism in Fundamental Research

et al. 2021

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Komagataella phaffii (Pichia pastoris) is one of the most extensively applied yeast species in pharmaceutical and biotechnological industries, and, therefore, also called the biotech yeast. However, thanks to more advanced strain engineering techniques, it recently started to gain attention as model organism in fundamental research. So far, the most studied model yeast is its distant cousin, Saccharomyces cerevisiae. While these data are of great importance, they limit our knowledge to one organism only. Since the divergence of the two species 250 million years ago, K. phaffii appears to have evolved less rapidly than S. cerevisiae, which is why it remains more characteristic of the common ancient yeast ancestors and shares more features with metazoan cells. This makes K. phaffii a valuable model organism for research on eukaryotic molecular cell biology, a potential we are only beginning to fully exploit. As methylotrophic yeast, K. phaffii has the intriguing property of being able to efficiently assimilate methanol as a sole source of carbon and energy. Therefore, major efforts have been made using K. phaffii as model organism to study methanol assimilation, peroxisome biogenesis and pexophagy. Other research topics covered in this review range from yeast genetics including mating and sporulation behavior to other cellular processes such as protein secretion, lipid biosynthesis and cell wall biogenesis. In this review article, we compare data obtained from K. phaffii with S. cerevisiae and other yeasts whenever relevant, elucidate major differences, and, most importantly, highlight the big potential of using K. phaffii in fundamental research.

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Tackling Cancer with Yeast-Based Technologies

Cited by 34 publications

References 72 publications

Fungal Dysbiosis and Intestinal Inflammation in Children With Beta-Cell Autoimmunity

Fungal Dysbiosis and Intestinal Inflammation in Children With Beta-Cell Autoimmunity

6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner

Komagataella phaffii as Emerging Model Organism in Fundamental Research

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