DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway

Lin, Chao-Chieh; Yang, Wen‐Hsuan; Lin, Yi-Tzu; Tang, Xiaohu; Chen, Po‐Han; Ding, Chien‐Kuang Cornelia; Qu, Dan; Alvarez, James V.; Chi, Jen-Tsan

doi:10.1038/s41388-021-01676-x

Cited by 62 publications

(51 citation statements)

References 70 publications

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“…Cell viability and cytotoxicity assays were performed as previously described [ 40 , 41 ]. Cell viability of RCC4 cells was determined by CellTiter-Glo luminescent cell viability assay (Promega) following the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

The regulation of ferroptosis by MESH1 through the activation of the integrative stress response

et al. 2021

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All organisms exposed to metabolic and environmental stresses have developed various stress adaptive strategies to maintain homeostasis. The main bacterial stress survival mechanism is the stringent response triggered by the accumulation “alarmone” (p)ppGpp, whose level is regulated by RelA and SpoT. While metazoan genomes encode MESH1 (Metazoan SpoT Homolog 1) with ppGpp hydrolase activity, neither ppGpp nor the stringent response is found in metazoa. The deletion of Mesh1 in Drosophila triggers a transcriptional response reminiscent of the bacterial stringent response. However, the function of MESH1 remains unknown until our recent discovery of MESH1 as the first cytosolic NADPH phosphatase that regulates ferroptosis. To further understand whether MESH1 knockdown triggers a similar transcriptional response in mammalian cells, here, we employed RNA-Seq to analyze the transcriptome response to MESH1 knockdown in human cancer cells. We find that MESH1 knockdown induced different genes involving endoplasmic reticulum (ER) stress, especially ATF3, one of the ATF4-regulated genes in the integrative stress responses (ISR). Furthermore, MESH1 knockdown increased ATF4 protein, eIF2a phosphorylation, and induction of ATF3, XBPs, and CHOP mRNA. ATF4 induction contributes to ~30% of the transcriptome induced by MESH1 knockdown. Concurrent ATF4 knockdown re-sensitizes MESH1-depleted RCC4 cells to ferroptosis, suggesting its role in the ferroptosis protection mediated by MESH1 knockdown. ATF3 induction is abolished by the concurrent knockdown of NADK, implicating a role of NADPH accumulation in the integrative stress response. Collectively, these results suggest that MESH1 depletion triggers ER stress and ISR as a part of its overall transcriptome changes to enable stress survival of cancer cells. Therefore, the phenotypic similarity of stress tolerance caused by MESH1 removal and NADPH accumulation is in part achieved by ISR to regulate ferroptosis.

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Section: Methodsmentioning

confidence: 99%

The regulation of ferroptosis by MESH1 through the activation of the integrative stress response

et al. 2021

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“…DDR2 is concordantly upregulated in metastatic cancer and maintains a fibroblastic phenotype. Interestingly, we report in Lin et al ( 2021 ) that DDR2 is essential for ferroptosis susceptibility. Given the ability of YAP/TAZ and DDR2 to promote both ferroptosis and metastasis, triggering ferroptosis is an incredibly promising approach to target cancer cells at their initial stage of metastasis.…”

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confidence: 72%

Editorial: Novel Insights Into Ferroptosis

Setayeshpour

Chi

2021

Front. Cell Dev. Biol.

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“…At which step does ferroptosis sensitivity occur and is this sensitivity dependent on the activation of a specific transcription factor? While Lin and coworkers could induce erastin sensitivity by overexpression of TWIST or SNAI1 in primary mouse breast tumour cells, overexpression of SNAI1 in MCF7 breast or of TWIST in a lung cancer cell line did not change susceptibility to GPX4 inhibition [ 133 , 136 ]. These discrepancies might be due to the different ferroptotic stimuli the authors used, or they might be due to gene mutations changing intracellular signalling and additional factors regulating EMT, such as miRNAs [ 150 ].…”

Section: Discussionmentioning

confidence: 99%

“…These observations raise the interesting question of whether a mesenchymal phenotype of carcinoma cells does also increase ferroptosis sensitivity and, if so, what would be the underlying mechanism. Indeed, recurrent breast cancer cells having acquired a mesenchymal phenotype show upregulation of the receptor for collagen I discoidin domain receptor tyrosine kinase 2 (DDR2), which causes activation of YAP/TAZ and increases ferroptosis susceptibility [ 133 ]. The authors also provide evidence that induction of EMT in epithelial breast cancer cells by overexpressing TWIST or SNAI1 leads to similar results [ 133 ].…”

Section: Regulation Of Ferroptosis By Cell–cell Contactsmentioning

confidence: 99%

“…Indeed, recurrent breast cancer cells having acquired a mesenchymal phenotype show upregulation of the receptor for collagen I discoidin domain receptor tyrosine kinase 2 (DDR2), which causes activation of YAP/TAZ and increases ferroptosis susceptibility [ 133 ]. The authors also provide evidence that induction of EMT in epithelial breast cancer cells by overexpressing TWIST or SNAI1 leads to similar results [ 133 ]. In accordance, a reciprocal association between differentiation and sensitivity to ferroptosis has been shown in a panel of head and neck cancer cells with either epithelial or mesenchymal phenotype [ 134 ].…”

Section: Regulation Of Ferroptosis By Cell–cell Contactsmentioning

confidence: 99%

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Ferroptosis Meets Cell–Cell Contacts

Dietrich

Hofmann

2021

Cells

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Ferroptosis is a regulated form of cell death characterized by iron dependency and increased lipid peroxidation. Initially assumed to be selectively induced in tumour cells, there is increasing evidence that ferroptosis plays an important role in pathophysiology and numerous cell types and tissues. Deregulated ferroptosis has been linked to human diseases, such as neurodegenerative diseases, cardiovascular disorders, and cancer. Along these lines, ferroptosis is a promising pathway to overcoming therapy resistance of cancer cells. It is therefore of utmost importance to understand the cellular signalling pathways and the molecular mechanisms underlying ferroptosis regulation, including context-specific effects mediated by the neighbouring cells through cell–cell contacts. Here, we give an overview on the molecular events and machinery linked to ferroptosis induction and commitment. We further summarize and discuss current knowledge about the role of cell–cell contacts, which differ in ferroptosis regulation between normal somatic cells and cancer cells. We present emerging concepts on the underlying mechanisms, address open questions, and discuss the possible impact of cell–cell contacts on exploiting ferroptosis in cancer therapy.

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DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway

Cited by 62 publications

References 70 publications

The regulation of ferroptosis by MESH1 through the activation of the integrative stress response

The regulation of ferroptosis by MESH1 through the activation of the integrative stress response

Editorial: Novel Insights Into Ferroptosis

Ferroptosis Meets Cell–Cell Contacts

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