Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche

Condello, Salvatore; Sima, Livia Elena; Ivan, Cristina; Cárdenas, Horacio; Schiltz, Gary E.; Mishra, Rama K.; Matei, Daniela

doi:10.1158/0008-5472.can-17-2319

Cited by 60 publications

(91 citation statements)

References 47 publications

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“…Data were normalized using the housekeeping genes included in the array, and relative mRNA amounts were calculated employing the 2 -ΔΔCt method. was Analyses were performed using a Microsoft Excel algorithm provided by the manufacturer and as described previously (15).…”

Section: Lipid Peroxidation Assay: Intracellular Lipid Peroxidation Wmentioning

confidence: 99%

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Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

Wang

Zhao

Condello

et al. 2020

Preprint

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The authors have no conflicts of interest to declare. AbstractDefining traits of platinum tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum tolerant cells and tumors were identified by using in vitro and in vivo ovarian cancer (OC) models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were found to be enriched in ALDH (+) cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared to parental cells. Additionally, platinum-tolerant cells and tumors highly expressed the Wnt receptor, Frizzled 7 (FZD7). FZD7 knock down improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7(+) from FZD7(-) cells included epithelial-to-mesenchymal (EMT), stemness, and oxidative phosphorylation enriched gene sets. Overexpression of FZD7 activated the oncogenic factor Tp63, driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protects cells from chemotherapy-induced oxidative stress. FZD7(+) platinum-tolerant OC cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. FZD7, Tp63 and glutathione metabolism gene sets were strongly correlated in the OC Tumor Cancer Genome Atlas (TCGA) database and in human OC specimens residual after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial stem cell features, characterized by FZD7 expression and dependent on FZD7-b-catenin-Tp63-GPX4 pathway for survival. The findings reveal a novel therapeutic vulnerability of platinum tolerant cancer cells and provide new insight into a potential "persister cancer cell" phenotype.glutathione peroxidase 4 (GPX4) tumor initiation capacity (TIC) (10). Importantly, ovarian CSCs possess a phenotype associated with drug resistance, including enhanced DNA repair, diminished apoptotic responses, increased efflux mechanisms and enhanced antioxidation defense (8,11), which allow them to escape from chemotherapy. The boundaries between stemness and chemotherapy tolerant phenotypes remain blurry and while an overlap exists, it is assumed that distinct pathways drive the two entities.As platinum tolerant cancer cells drive tumor relapse, decreasing survival rate of women with OC, we aimed to identify specific markers, by using in vitro and in vivo models of repeated exposure to the cytotoxic agent. We observed that platinum-tolerant cells and tumors contained an increased ALDH+ cell population, expressing stemness related transcription factors (TFs), and able to form more spheroids compared to chemotherapy naïve cells. We identified the Frizzled 7 receptor (FZD7) as a novel cell surface marker significantly upregulated in the platinum tolerant cell population. FZD7 knock down increased sensitivity to platinum, decreased spheroid formation in vitro, and delayed tumor initiation in vivo. FZD7...

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Section: Lipid Peroxidation Assay: Intracellular Lipid Peroxidation Wmentioning

confidence: 99%

“…Aldehyde dehydrogenase (ALDH) activity was measured using an Aldefluor assay kit (Stemcell Technologies, Cat#01700, Cambridge, MA, USA) following the manufacturer's instructions and as described previously (6) Cell survival assay. Cell Spheroid formation and clonogenic assays were performed as described previously (see SM) (15,16).…”

Section: Introductionmentioning

confidence: 99%

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

Wang

Zhao

Condello

et al. 2020

Preprint

Self Cite

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“…The conventions are as indicated in Figure . A, The ovarian cancer reference are . B, The lung cancer reference are …”

Section: Tg2 In Tumor Typesmentioning

confidence: 99%

Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target

Eckert

2019

Molecular Carcinogenesis

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Transglutaminase 2 (TG2) has emerged as a key cancer cell survival factor that drives epithelial to mesenchymal transition, angiogenesis, metastasis, inflammation, drug resistance, cancer stem cell survival and stemness, and invasion and migration. TG2 can exist in a GTP‐bound signaling‐active conformation or in a transamidase‐active conformation. The GTP bound conformation of TG2 contributes to cell survival and the transamidase conformation can contribute to cell survival or death. We present evidence suggesting that TG2 has a role in human cancer, summarize what is known about the TG2 mechanism of action in a range of cancer types, and discuss TG2 as a cancer therapy target.

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“…TGM2 is a multifunctional protein with transamidating, deamidation, and GTPase activity, as well as enzyme-independent scaffolding functions. 45 It cross-links fibronectin and has scaffolding functions with integrin β1, both of which are associated with radiation resistance and stemness, 46,47 and has recently been proposed to promote neurogensis from neural stem cells in the adult brain. 48 Its inhibition improved survival in a glioma xenograft model 49 and it has been shown to be a prognostic indicator of shorter time to relapse after chemoradiotherapy.…”

Section: Irradiated Astrocytes Secrete Tgm2 In Vitro and In Vivo Aftementioning

confidence: 99%

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

Berg

Marques²,

Pantazopoulou

et al. 2020

Preprint

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The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance; however, little is known about how the microenvironment responds to radiation. Here, we found that astrocytes, when pre-irradiated, increased stemness and survival of co-cultured glioma cells. Tumor-naïve brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. We identified extracellular matrix derived from irradiated astrocytes as a major driver of this phenotype, and astrocyte-derived transglutaminase 2 (TGM2) as a promoter of glioma stemness and radioresistance. TGM2 inhibitors abrogated glioma stemness induced by irradiated astrocytes. TGM2 inhibition reduced survival of glioma cells in in vitro and ex vivo tumor models.These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard of care radiotherapy in glioma.

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Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche

Cited by 60 publications

References 47 publications

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

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