Cancer STEM cells and skin cancer

Cancer STEM cells and skin cancer

Dr. Weeks’ Comment: Skin cancer – like all cancer – spreads via inflammatory mechanisms which is why anyone with skin cancer needs to take safe and effective anti-inflammatory agents.  Topical SOUL – a drink made from WHOLE seeds with anti-inflammatory properties is appreciated many people suffering with cancer.

“…Twist1, a well-known regulator of , is necessary for , regulation of cancer stem cell function and malignant progression…”

“…Twist1 expression in different fat depots and cellular components of AT and to discuss the potential mechanisms suggesting a role for Twist1 in AT metabolism, inflammation and remodeling…”

New mechanism involved in skin cancer initiation, growth and progression

New mechanism involved in skin cancer initiation, growth and progression
Credit: C. Blanpain
Squamous cell carcinoma (SCC) represents the second most frequent skin cancer with more than half million new patients affected every year in the world. Cancer stem cells (CSCs), a population of cancer cells that have been described in many different cancers including skin SCCs and that feed tumor growth, could be resistant to therapy, thus being responsible for tumor relapse after therapy. However, very little is yet known about the mechanisms that regulate CSCs functions.

In a new study featured on the cover of Cell Stem Cell, researchers led by Pr. Cédric Blanpain, MD/PhD, professor and WELBIO investigator at the IRIBHM, Université libre de Bruxelles, Belgium, report the mechanisms regulating the different functions of Twist1 controlling skin tumour initiation, cancer stem cell function and tumor progression.

Benjamin Beck and colleagues used state-of-the-art genetic mouse models to determine the functional role and molecular mechanisms by which Twist1 controls tumor initiation, cancer stem cell function and tumor progression. Collaborating researchers demonstrated that while Twist1 is not expressed in the normal skin, Twist1 deletion prevents formation, demonstrating the essential role of Twist1 during tumorigenesis. “It was really surprising to observe the essential role of Twist1 at the earliest step of , as Twist1 was thought to stimulate tumor progression and metastasis,” says Benjamin Beck, the first author of this study.

The authors demonstrate that different levels of Twist1 are necessary for tumor initiation and progression. Low levels of Twist1 are required for the initiation of benign tumors, while higher levels of Twist1 are necessary for tumor progression. They also demonstrate that Twist1 is essential for tumor maintenance and the regulation of cancer stem cell function. The researchers also reported that the different functions of Twist1 are regulated by different molecular mechanisms, and identified a p53 independent role of Twist1 in regulating cancer stem cell functions.

In conclusion, this work shows that Twist1, a well-known regulator of , is necessary for , regulation of cancer stem cell function and malignant progression. “It was really interesting to see that different levels of Twist1 are required to carry out these different tumor functions and that these different Twist1 functions are regulated by different molecular pathways. Given the diversity of cancers expressing Twist1, the identification of the different mechanisms controlled by Twist1 is likely to be relevant for other cancers,” says Cédric Blanpain, the last and corresponding author of this study.

 

More information: Benjamin Beck, Gaëlle Lapouge, Sandrine Rorive, Benjamin Drogat, Kylie Desaedelaere, Stephanie Delafaille, Christine Dubois, Isabelle Salmon, Karen Willekens, Jean-Christophe Marine, and Cédric Blanpain. “Different Levels of Twist1 Regulate Skin Tumor Initiation, Stemness and Progression.” Cell Stem Cell 2015,dx.doi.org/10.1016/j.stem.2014.12.002.

 

TWIST 1….

SO WHAT IS  TWIST1 ?    It functions as an anti-inflammatory agent.

“…Twist1 expression in different fat depots and cellular components of AT and to discuss the potential mechanisms suggesting a role for Twist1 in AT metabolism, inflammation and remodeling…”

“…We identify the transcription factor Twist1 as a component of a STAT3-induced feedback loop that controls IL-6 signals by directly repressing Il6ra…”

 

1.
Eur J Immunol. 2014 Dec 8. doi: 10.1002/eji.201444633. [Epub ahead of print]

miR-148a is upregulated by Twist1 and T-bet and promotes Th1-cell survival by regulating the proapoptotic gene Bim.

Abstract

Repeatedly activated T helper 1 (Th1) cells present during chronic inflammation can efficiently adapt to the inflammatory milieu, e.g. by expressing the transcription factor Twist1, which limits the immunopathology caused by Th1 cells. Here, we show that in repeatedly reactivated murine Th1 cells, Twist1 and T-bet induce expression of microRNA-148a (miR-148a). miR-148a regulates expression of the proapoptotic gene Bim, resulting in a decreased Bim/Bcl2 ratio. Inhibition of miR-148a by antagomirs in repeatedly reactivated Th1 cells increases the expression of Bim, leading to enhanced apoptosis. Knockdown of Bim expression by siRNA in miR-148a antagomir-treated cells restores viability of the Th1 cells, demonstrating that miR-148a controls survival by regulating Bim expression. Thus, Twist1 and T-bet not only control the differentiation and function of Th1 cells, but also their persistence in chronic inflammation.

Related citations

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2.
Oncotarget. 2014 Sep 15;5(17):7260-71.

TWIST and ovarian cancer stem cells: implications for chemoresistance and metastasis.

Nuti SV1, Mor G1, Li P2, Yin G2.

Abstract

The transcription factor TWIST1 is a highly evolutionally conserved basic Helix-Loop-Helix (bHLH) transcription factor that functions as a master regulator of gastrulation and mesodermal development. Although TWIST1 was initially associated with embryo development, an increasing number of studies have shown TWIST1 role in the regulation of tissue homeostasis, primarily as a regulator of inflammation. More recently, TWIST1 has been found to be involved in the process of tumor metastasis through the regulation of Epithelial Mesenchymal Transition (EMT). The objective of this review is to examine the normal functions of TWIST1 and its role in tumor development, with a particular focus on ovarian cancer. We discuss the potential role of TWIST1 in the context of ovarian cancer stem cells and its influence in the process of tumor formation.

3.
Cancer Cell. 2014 Feb 10;25(2):210-25. doi: 10.1016/j.ccr.2014.01.028.

Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer.

Shi J1, Wang Y2, Zeng L3, Wu Y4, Deng J5, Zhang Q3, Lin Y1, Li J1, Kang T6, Tao M7, Rusinova E3, Zhang G3, Wang C8, Zhu H9, Yao J10, Zeng YX6, Evers BM11, Zhou MM12, Zhou BP13.

Abstract

Twist is a key transcription activator of epithelial-mesenchymal transition (EMT). It remains unclear how Twist induces gene expression. Here we report a mechanism by which Twist recruits BRD4 to direct WNT5A expression in basal-like breast cancer (BLBC). Twist contains a “histone H4-mimic” GK-X-GK motif that is diacetylated by Tip60. The diacetylated Twist binds the second bromodomain of BRD4, whose first bromodomain interacts with acetylated H4, thereby constructing an activated Twist/BRD4/P-TEFb/RNA-Pol II complex at the WNT5A promoter and enhancer. Pharmacologic inhibition of the Twist-BRD4 association reduced WNT5A expression and suppressed invasion, cancer stem cell (CSC)-like properties, and tumorigenicity of BLBC cells. Our study indicates that the interaction with BRD4 is critical for the oncogenic function of Twist in BLBC.Related citations

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4.
J Biol Chem. 2013 Sep 20;288(38):27423-33. doi: 10.1074/jbc.M113.497248. Epub 2013 Aug 9.

The transcription factor Twist1 limits T helper 17 and T follicular helper cell development by repressing the gene encoding the interleukin-6 receptor α chain.

Abstract

Cytokine responsiveness is a critical component of the ability of cells to respond to the extracellular milieu. Transcription factor-mediated regulation of cytokine receptor expression is a common mode of altering responses to the external environment. We identify the transcription factor Twist1 as a component of a STAT3-induced feedback loop that controls IL-6 signals by directly repressing Il6ra. Human and mouse T cells lackingTwist1 have an increased ability to differentiate into Th17 cells. Mice with a T cell-specific deletion of Twist1demonstrate increased Th17 and T follicular helper cell development, early onset experimental autoimmune encephalomyelitis, and increased antigen-specific antibody responses. Thus, Twist1 has a critical role in limiting both cell-mediated and humoral immunity.

5.
Front Endocrinol (Lausanne). 2012 Aug 30;3:108. doi: 10.3389/fendo.2012.00108. eCollection 2012.

A tale with a Twist: a developmental gene with potential relevance for metabolic dysfunction and inflammation in adipose tissue.

Abstract

The Twist proteins (Twist-1 and -2) are highly conserved developmental proteins with key roles for the transcriptional regulation in mesenchymal cell lineages. They belong to the super-family of bHLH proteins and exhibit bi-functional roles as both activators and repressors of gene transcription. The Twist proteins are expressed at low levels in adult tissues but may become abundantly re-expressed in cells undergoing malignant transformation. This observation prompted extensive research on the roles of Twist proteins in cancer progression and metastasis. Very recent studies indicate a novel role for Twist-1 as a potential regulator of adipose tissue (AT) remodeling and inflammation. Several studies suggested that developmental genes are important determinants of obesity, fat distribution and remodeling capacity of different adipose depots. Twist-1 is abundantly and selectively expressed in the adult AT and its constitutive expression is significantly higher in subcutaneous (SAT) vs. visceral (VAT) fat in both mice and humans. Moreover, Twist1 expression is strongly correlated with BMI and insulin resistance in humans. However, the functional roles and transcriptional downstream targets of Twist1 in AT are largely unexplored. The purpose of this review is to highlight the major findings related to Twist1 expression in different fat depots and cellular components of AT and to discuss the potential mechanisms suggesting a role for Twist1 in AT metabolism, inflammation and remodeling.

6.
J Immunol. 2012 Jul 15;189(2):832-40. doi: 10.4049/jimmunol.1200854. Epub 2012 Jun 8.

Twist1 regulates Ifng expression in Th1 cells by interfering with Runx3 function.

Abstract

A transcription factor network that includes STAT4, T-bet, and Runx3 promotes the differentiation of Th1 cells and inflammatory immune responses. How additional transcription factors regulate the function of Th1 cells has not been defined. In this study we show that the negative regulatory factor Twist1 decreases expression of T-bet, Runx3, and IL-12Rβ2 as it inhibits IFN-γ production. Ectopic expression of Runx3, but not T-bet or IL-12Rβ2, compensates for the effects of Twist1 on IFN-γ production, and Twist1 regulation of Ifng depends on complex formation with Runx3. Twist1 decreases Runx3 and T-bet binding at the Ifng locus, and it decreases chromatin looping within the Ifng locus. These data define an IL-12/STAT4-induced negative regulatory loop that impacts multiple components of the Th1 transcriptional network and provide further insight into regulation of Th1 differentiation.

7.
Cancer Cell. 2010 Nov 16;18(5):448-58. doi: 10.1016/j.ccr.2010.10.020.

Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells.

Abstract

Mutational activation of KRas is the first and most frequently detected genetic lesion in pancreatic ductal adenocarcinoma (PDAC). However, the precise role of oncogenic KRas in the pathogenesis of PDAC is not fully understood. Here, we report that the endogenous expression of oncogenic KRas suppresses premature senescence in primary pancreatic duct epithelial cells (PDEC). Oncogenic KRas-mediated senescence bypass is conferred by the upregulation of the basic helix-loop-helix transcription factor Twist that in turn abrogates p16(INK4A) induction. Moreover, the KRas-Twist-p16(INK4A) senescence bypass pathway is employed in vivo to prevent inflammation-associated senescence of pancreatic ductal epithelium. Our findings indicate that oncogenic KRas could contribute to PDAC initiation by protecting cells from entering a state of permanent growth arrest.

 

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Dr. Weeks’ Comment: Skin cancer – like all cancer – spreads via inflammatory mechanisms which is why anyone with skin cancer needs to take safe and effective anti-inflammatory agents.  Topical SOUL – a drink made from WHOLE seeds with anti-inflammatory properties is appreciated many people suffering with cancer. “…Twist1, a well-known regulator of tumor progression, is necessary for tumor…
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