Delivery of transcription factors as modulators of cell differentiation

Rilo-Alvarez, Héctor; Ledo, Adriana M.; Vidal, Anxo; García-Fuentes, Marcos

doi:10.1007/s13346-021-00931-8

Cited by 11 publications

(4 citation statements)

References 150 publications

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“…Given the role of transcription factors as master regulators of cell fate, their pharmacological modulation has been widely studied, including the inhibition of DNA binding or protein interaction using small molecules ( 194 ). To increase the activity, transcription factors themselves can be used as drugs, in either their protein form or encoded in suitable gene vectors ( 195 ). These successful efforts have debunked the previous view that transcriptional factors are undruggable.…”

Section: Discussionmentioning

confidence: 99%

The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis

Igarashi

Nishizawa

Saiki

et al. 2021

Journal of Biological Chemistry

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The progression of cancer involves not only the gradual evolution of cells by mutations in DNA but also alterations in the gene expression induced by those mutations and input from the surrounding microenvironment. Such alterations contribute to cancer cells' abilities to reprogram metabolic pathways and undergo epithelial-to-mesenchymal transition (EMT), which facilitate the survival of cancer cells and their metastasis to other organs. Recently, BTB and CNC homology 1 (BACH1), a heme-regulated transcription factor that represses genes involved in iron and heme metabolism in normal cells, was shown to shape the metabolism and metastatic potential of cancer cells. The growing list of BACH1 target genes in cancer cells reveals that BACH1 promotes metastasis by regulating various sets of genes beyond iron metabolism. BACH1 represses the expression of genes that mediate cell–cell adhesion and oxidative phosphorylation but activates the expression of genes required for glycolysis, cell motility, and matrix protein degradation. Furthermore, BACH1 represses FOXA1 gene encoding an activator of epithelial genes and activates SNAI2 encoding a repressor of epithelial genes, forming a feedforward loop of EMT. By synthesizing these observations, we propose a “two-faced BACH1 model”, which accounts for the dynamic switching between metastasis and stress resistance along with cancer progression. We discuss here the possibility that BACH1-mediated promotion of cancer also brings increased sensitivity to iron-dependent cell death (ferroptosis) through crosstalk of BACH1 target genes, imposing programmed vulnerability upon cancer cells. We also discuss the future directions of this field, including the dynamics and plasticity of EMT.

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Section: Discussionmentioning

confidence: 99%

The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis

Igarashi

Nishizawa

Saiki

et al. 2021

Journal of Biological Chemistry

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“…In the therapies mentioned above, bacteria have been used to deliver a variety of therapeutic molecules including checkpoint inhibitors, nanobodies, or epitopes for vaccines, and have even been used to cause tumor cell lysis as a way of altering the tumor microenvironment (TME) or to activate immune cells [71][72][73]75,82 . TFs regulate genes that control cellular fates [97][98][99][100] and thus TFs are being evaluated in clinical trials to treat cancer, and chronic wounds, as well as guide tissue regeneration and modulate immune responsesresponses 101 . Previously, we engineered B. subtilis LLO strains to express and deliver signal transducer and activator of transcription 1 (STAT-1) together with Krüppel-like factor 6 (KLF6) for polarization towards a pro-inflammatory phenotype, and Krüppel-like factor 4 (KLF4) together with GATA binding protein 3 (GATA-3) to polarize macrophages toward an anti-inflammatory phenotype [102][103][104][105][106] .…”

Section: Introductionmentioning

confidence: 99%

Engineered endosymbionts that modulate primary macrophage function and attenuate tumor growth by shifting the tumor microenvironment

Madsen,

Makela,

Maduka

et al. 2024

Preprint

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Modulating gene expression in macrophages can be used to improve tissue regeneration and to redirect tumor microenvironments (TME) toward positive therapeutic outcomes. We have developed Bacillus subtilis as an engineered endosymbiont (EES) capable of residing inside the eukaryotic host cell cytoplasm and controlling the fate of macrophages. Secretion of mammalian transcription factors (TFs) from B. subtilis that expresses listeriolysin O (LLO; allowing the EES to escape destruction by the macrophage) modulated expression of surface markers, cytokines and chemokines, indicating functional changes in a macrophage/monocyte cell line. The engineered B. subtilis LLO TF strains were evaluated in murine bone marrow-derived macrophages (BMDMs) by flow cytometry, chemokine/cytokine profiling, metabolic assays and RNA-Seq. Delivery of TFs by the EES shifted BMDM gene expression, production of cytokine and chemokines and metabolic patterns, indicating that the TF strains could guide primary macrophage function. Thereafter, the ability of the TF strains to alter the TME was characterized in vivo, in an orthotopic murine model of triple-negative breast cancer to assess therapeutic effects. The TF strains altered the TME by shifting immune cell composition and attenuating tumor growth. Additionally, multiple doses of the TF strains were well-tolerated by the mice. The use of B. subtilis LLO TF strains as EES showed promise as a unique cancer immunotherapy by directing immune function intracellularly. The uses of EES could be expanded to modulate other mammalian cells over a range of biomedical applications.

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“…For instance, delivery of Cas9 protein through NILVs vectors resulted in efficient DNA breakage and genome correction in sickle cell disease (SCD) ( Uchida et al, 2021 ). In addition to their relevance in infectious and genetic diseases, NILVs vectors are being used in many clinical applications, including vaccination, cell type differentiation, and site-directed integration ( Rilo-Alvarez et al, 2021 ; Gurumoorthy et al, 2022 ). Hence, the transient expression nature of NILVs in dividing cells, combined with their low immunogenicity makes them the most promising vector candidates to be used in clinical applications ( Luis, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Viral Vectors for the in Vivo Delivery of CRISPR Components: Advances and Challenges

Mengstie

2022

Front. Bioeng. Biotechnol.

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The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) and its accompanying protein (Cas9) are now the most effective, efficient, and precise genome editing techniques. Two essential components of the CRISPR/Cas9 system are guide RNA (gRNA) and CRISPR-associated (Cas9) proteins. Choosing and implementing safe and effective delivery systems in the therapeutic application of CRISPR/Cas9 has proven to be a significant problem. For in vivo CRISPR/Cas9 delivery, viral vectors are the natural specialists. Due to their higher delivery effectiveness than other delivery methods, vectors such as adenoviral vectors (AdVs), adeno-associated viruses (AAVs), and lentivirus vectors (LVs) are now commonly employed as delivery methods. This review thoroughly examined recent achievements in using a variety of viral vectors as a means of CRISPR/Cas9 delivery, as well as the benefits and limitations of each viral vector. Future thoughts for overcoming the current restrictions and adapting the technology are also discussed.

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Delivery of transcription factors as modulators of cell differentiation

Cited by 11 publications

References 150 publications

The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis

The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis

Engineered endosymbionts that modulate primary macrophage function and attenuate tumor growth by shifting the tumor microenvironment

Viral Vectors for the in Vivo Delivery of CRISPR Components: Advances and Challenges

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