A reversible metabolic stress-sensitive regulation of CRMP2A orchestrates EMT/stemness and increases metastatic potential in cancer

Boukouris, Aristeidis E.; Zhang, Yongneng; Saleme, Bruno; Kinnaird, Adam; Zhao, Yuan; Liu, Yongsheng; Zervopoulos, Sotirios; Das, Sajal Kumar; Mittal, Rohan; Haromy, Alois; Carrillo, Maria Areli Lorenzana; Krysler, Amanda; Cromwell, Christopher R; Hubbard, Basil P.; Sutendra, Gopinath; Michelakis, Evangelos D.

doi:10.1016/j.celrep.2022.110511

Cited by 8 publications

(5 citation statements)

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“…Regarding other functional overlaps, our gene set enrichment analysis revealed that knockout of DPYSL2 - B resulted in upregulation of genes related to the epithelial-mesenchymal transition, an oncogenic process that enables metastasis. This process was found to be suppressed by CRMP2 118 , and later more specifically by CRMP2-A 41 . Our GSEA result suggests the epithelial-mesenchymal transition may also be regulated by CRMP2-B, highlighting a potentially novel functional overlap between these two isoforms.…”

Section: Discussionmentioning

confidence: 91%

“…Additionally, recent studies have implicated CRMP2-A as a molecular brake on carcinogenesis. Downregulation of CRMP2-A has been observed in prostate cancer biopsies, and deletion of CRMP2-A in human lung adenocarcinoma cells results in cytoskeletal reorganization and progression of the epithelial-mesenchymal transition 41 , a process in which epithelial cells acquire mesenchymal properties that enhance metastasis 42 . CRMP2-A has also been shown to regulate the differentiation of hematopoietic stem cells to monocytes, and stimulation of the KLF4-CRMP2-A pathway as a candidate therapeutic for acute myeloid leukemia has been suggested 43; 44 .…”

Section: Introductionmentioning

confidence: 99%

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DPYSL2/CRMP2isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders

Feuer

Peng

Yovo

et al. 2022

Preprint

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DPYSL2/CRMP2 is a microtubule-stabilizing protein crucial for neurogenesis and associated with numerous psychiatric and neurodegenerative disorders. DPYSL2 has multiple RNA and protein isoforms, but few studies have differentiated between them or explored their individual functions. We previously demonstrated in HEK293 cells that a schizophrenia-associated variant in the DPYSL2 B isoform (DPYSL2-B) reduced the length of cellular projections, created a transcriptomic disturbance that captured schizophrenia etiology, and was acted upon by the mTOR pathway. In the present study, we follow up on these results by creating, to our knowledge, the first models of endogenous DPYSL2-B knockout in human induced pluripotent stem cells and excitatory glutamatergic neurons. We use CRISPR/Cas9 to specifically knock out DPYSL2-B and observe corresponding reduction of its RNA and protein. The average length of dendrites in knockout neurons was reduced up to 58% compared to controls. Transcriptome analysis reveals disruptions in pathways highly relevant to psychiatric disease including mTOR signaling, cytoskeletal dynamics, immune function, calcium signaling, and cholesterol biosynthesis. We also observed a significant enrichment of our differentially expressed genes in schizophrenia GWAS-associated loci. Our findings clarify the functions of the human DPYSL2-B isoform and confirm its involvement in molecular pathologies shared between many psychiatric diseases.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

DPYSL2/CRMP2isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders

Feuer

Peng

Yovo

et al. 2022

Preprint

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“…This indicates that hypoxia has varying effects on the EMT process at different stages of the cancer progression. 42 Our study demonstrated that hypoxia inhibited the expression of E‐cadherin and promoted the expression of N‐cadherin in H520 cells, while the opposite pattern was observed in A549 cells, indicating cell‐type‐specificity in hypoxia‐induced EMT process. This may be related to the initial stem cell‐like characteristics of different tissue sources.…”

Section: Discussionmentioning

confidence: 57%

“…However, once the tumor develops mature blood vessels, the expression of CRMP2A decreases, leading to EMT/stemness recovery. This indicates that hypoxia has varying effects on the EMT process at different stages of the cancer progression 42 . Our study demonstrated that hypoxia inhibited the expression of E‐cadherin and promoted the expression of N‐cadherin in H520 cells, while the opposite pattern was observed in A549 cells, indicating cell‐type‐specificity in hypoxia‐induced EMT process.…”

Section: Discussionmentioning

confidence: 64%

Hypoxia differently regulates the proportion of ALDH^hi cells in lung squamous carcinoma H520 and adenocarcinoma A549 cells via the Wnt/β‐catenin pathway

Liu,

Zheng,

Zhang

et al. 2024

Thoracic Cancer

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BackgroundCancer stem cells (CSCs) are a specific subpopulation of cancer cells with the ability of self‐renewal, infinite proliferation, multidifferentiation and tumorigenicity, and play critical roles in cancer progression and treatment resistance. CSCs are tightly regulated by the tumor microenvironment, such as hypoxia; however, how hypoxia regulates CSCs in non‐small cell lung cancer (NSCLC) remains unclear.MethodsThe proportion of ALDHhi cells was examined using the Aldefluor assay. Tankyrase inhibitor XAV939 and siRNA were used to inhibit β‐catenin while pcDNA3‐β‐catenin (S33Y) plasmid enhanced the expression of β‐catenin. Western blot was administered for protein detection. The mRNA expression was measured by quantitative real‐time PCR.ResultsWe found that hypoxia led to an increase in the proportion of ALDHhi cells in lung squamous carcinoma (LUSC) H520 cells, while causing a decrease in the ALDHhi cell proportion in lung adenocarcinoma (LUAD) A549 cells. Similarly, β‐catenin expression was upregulated in H520 cells but downregulated in A549 cells upon exposure to hypoxia. Mechanically, the proportion of ALDHhi cells in both cell lines was decreased by β‐catenin inhibitor or siRNA knockdown, whereas increased after β‐catenin overexpression. Furthermore, hypoxia treatment suppressed E‐cadherin expression in H520 cells and enhanced N‐cadherin and β‐catenin expression, while this effect was completely opposite in A549 cells.ConclusionThe hypoxia‐EMT‐β‐catenin axis functions as an important regulator for the proportion of CSCs in NSCLC and could potentially be explored as therapeutic targets in the future.

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“…The downregulation of SNAIL enhanced the sensitivity of prostate cancer cells to anti-cancer drugs [ 83 ]. EMT activated cancer stem cells (CSCs) resistant to chemotherapy and target therapy [ 84 ]. Figure 3 C shows the targets of the miR-200 family and the roles of these targets in anti-cancer drug resistance.…”

Section: Mir-200 Family and Targets Of The Mir-200 Familymentioning

confidence: 99%

Potential of the miR-200 Family as a Target for Developing Anti-Cancer Therapeutics

Shim

Jeoung

2022

IJMS

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MicroRNAs (miRNAs) are small non-coding RNAs (18–24 nucleotides) that play significant roles in cell proliferation, development, invasion, cancer development, cancer progression, and anti-cancer drug resistance. miRNAs target multiple genes and play diverse roles. miRNAs can bind to the 3′UTR of target genes and inhibit translation or promote the degradation of target genes. miR-200 family miRNAs mostly act as tumor suppressors and are commonly decreased in cancer. The miR-200 family has been reported as a valuable diagnostic and prognostic marker. This review discusses the clinical value of the miR-200 family, focusing on the role of the miR-200 family in the development of cancer and anti-cancer drug resistance. This review also provides an overview of the factors that regulate the expression of the miR-200 family, targets of miR-200 family miRNAs, and the mechanism of anti-cancer drug resistance regulated by the miR-200 family.

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A reversible metabolic stress-sensitive regulation of CRMP2A orchestrates EMT/stemness and increases metastatic potential in cancer

Cited by 8 publications

References 50 publications

DPYSL2/CRMP2isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders

DPYSL2/CRMP2isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders

Hypoxia differently regulates the proportion of ALDH^hi cells in lung squamous carcinoma H520 and adenocarcinoma A549 cells via the Wnt/β‐catenin pathway

Potential of the miR-200 Family as a Target for Developing Anti-Cancer Therapeutics

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A reversible metabolic stress-sensitive regulation of CRMP2A orchestrates EMT/stemness and increases metastatic potential in cancer

Cited by 8 publications

References 50 publications

DPYSL2/CRMP2isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders

DPYSL2/CRMP2isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders

Hypoxia differently regulates the proportion of ALDHhi cells in lung squamous carcinoma H520 and adenocarcinoma A549 cells via the Wnt/β‐catenin pathway

Potential of the miR-200 Family as a Target for Developing Anti-Cancer Therapeutics

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Hypoxia differently regulates the proportion of ALDH^hi cells in lung squamous carcinoma H520 and adenocarcinoma A549 cells via the Wnt/β‐catenin pathway