Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia

Park, Chun Shik; Yoshihara, Hiroki; Gao, Qingsong; Qu, Chunxu; Iacobucci, Ilaria; Ghate, Pankaj S.; Connelly, Jon P.; Pruett-Miller, Shondra M.; Wagner, Ben; Robinson, Camenzind G.; Mishra, Ashutosh; Peng, Junmin; Yang, Lei; Rankovic, Zoran; Finkelstein, David; Luger, Selina M.; Litzow, Mark R.; Paietta, Elisabeth; Hebbar, Nikhil; Velasquez, Mireya Paulina; Mullighan, Charles G.

doi:10.1016/j.celrep.2023.112804

Cited by 13 publications

(5 citation statements)

References 84 publications

(92 reference statements)

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“…Notably, N-cadherin (N-Cad, encoded by the CDH2 gene), an EMT marker recognized as being critical for the diagnosis and prognosis of breast cancer [ 61 ], was upregulated in this study. Many studies have shown that cells undergoing EMT frequently exhibit amplified EMT traits during drug resistance [ 62 ], which was also reflected in our experimental results. In the PDX-resistant mouse model being constructed by our research group, proteins in the tumor tissues were extracted during the process of gradual induction, and EMT changes in the 5FU treatment group were also detected (relevant results not shown), suggesting that the mobility of tumor cells was stimulated during the development of acquired drug resistance.…”

Section: Discussionsupporting

confidence: 83%

WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical β-catenin pathway

Zhang,

Sun,

Gan

et al. 2024

BMC Cancer

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Background 5-Fluorouracil (5FU) is a primary chemotherapeutic agent used to treat oral squamous cell carcinoma (OSCC). However, the development of drug resistance has significantly limited its clinical application. Therefore, there is an urgent need to determine the mechanisms underlying drug resistance and identify effective targets. In recent years, the Wingless and Int-1 (WNT) signaling pathway has been increasingly studied in cancer drug resistance; however, the role of WNT3, a ligand of the canonical WNT signaling pathway, in OSCC 5FU-resistance is not clear. This study delved into this potential connection. Methods 5FU-resistant cell lines were established by gradually elevating the drug concentration in the culture medium. Differential gene expressions between parental and resistant cells underwent RNA sequencing analysis, which was then substantiated via Real-time quantitative PCR (RT-qPCR) and western blot tests. The influence of the WNT signaling on OSCC chemoresistance was ascertained through WNT3 knockdown or overexpression. The WNT inhibitor methyl 3-benzoate (MSAB) was probed for its capacity to boost 5FU efficacy. Results In this study, the WNT/β-catenin signaling pathway was notably activated in 5FU-resistant OSCC cell lines, which was confirmed through transcriptome sequencing analysis, RT-qPCR, and western blot verification. Additionally, the key ligand responsible for pathway activation, WNT3, was identified. By knocking down WNT3 in resistant cells or overexpressing WNT3 in parental cells, we found that WNT3 promoted 5FU-resistance in OSCC. In addition, the WNT inhibitor MSAB reversed 5FU-resistance in OSCC cells. Conclusions These data underscored the activation of the WNT/β-catenin signaling pathway in resistant cells and identified the promoting effect of WNT3 upregulation on 5FU-resistance in oral squamous carcinoma. This may provide a new therapeutic strategy for reversing 5FU-resistance in OSCC cells.

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Section: Discussionsupporting

confidence: 83%

WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical β-catenin pathway

Zhang,

Sun,

Gan

et al. 2024

BMC Cancer

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“…In addition, a process similar to EMT has been observed and described in cell types other than epithelial cells, suggesting that the frontiers of EMT might be looser than previously thought and that EMT might not be restricted only to epithelia cells [38]. This EMT-like process has been widely described in non-epithelial cancers such as melanoma, sarcoma, and leukemia [39][40][41] and in noncancerous conditions where it aroused in non-epithelial cells such as endothelium [42], mesothelium, [43] or fibroblast-like synoviocytes (FLSs) [44]. Several authors have proposed other terminologies to avoid confusion with EMT arising in epithelial cells and called these processes either endothelial-mesenchymal transition (endoMT) [42] for endothelial cells, mesothelial-mesenchymal transition (MMT) [43] for mesothelial cells, or EMT-like for other cell types than epithelial cells [45].…”

Section: Biological Mechanisms Underlying Emtmentioning

confidence: 82%

Involvement of Epithelial-Mesenchymal Transition (EMT) in Autoimmune Diseases

Sarrand,

Soyfoo

2023

IJMS

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Epithelial-mesenchymal transition (EMT) is a complex reversible biological process characterized by the loss of epithelial features and the acquisition of mesenchymal features. EMT was initially described in developmental processes and was further associated with pathological conditions including metastatic cascade arising in neoplastic progression and organ fibrosis. Fibrosis is delineated by an excessive number of myofibroblasts, resulting in exuberant production of extracellular matrix (ECM) proteins, thereby compromising organ function and ultimately leading to its failure. It is now well acknowledged that a significant number of myofibroblasts result from the conversion of epithelial cells via EMT. Over the past two decades, evidence has accrued linking fibrosis to many chronic autoimmune and inflammatory diseases, including systemic sclerosis (SSc), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), and inflammatory bowel diseases (IBD). In addition, chronic inflammatory states observed in most autoimmune and inflammatory diseases can act as a potent trigger of EMT, leading to the development of a pathological fibrotic state. In the present review, we aim to describe the current state of knowledge regarding the contribution of EMT to the pathophysiological processes of various rheumatic conditions.

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“…We next delved deeper into the single cell transcriptomic data to investigate specific pathways active in this dormant cell population. Performing GSEA revealed a strong enrichment in cell adhesion (NES 2.33, FDR <0.05), as well as NF-κB (NES 2.31, FDR < 0.05) and TGF-β signaling (NES 2.19, FDR <0.05) which are known to enforce drug resistance 16,17 (Figure 2f). Additionally, unlike the cell population with a transcriptional profile of rapidly proliferating cells, the cells with a dormancy phenotype showed a marked downregulation of metabolic processes (−2.86, FDR <0.05, FDR), a common characteristic of stem-like cells 13 .…”

Section: Resultsmentioning

confidence: 99%

Role of Stem-Like Cells in Chemotherapy Resistance and Relapse in pediatric T Cell Acute Lymphoblastic Leukemia

Costea,

Rauwolf,

Zafferani

et al. 2024

Preprint

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T cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia predominantly affecting adolescents and young adults. T-ALL relapses are characterized by chemotherapy resistance, cellular heterogeneity and dismal outcome. To gain a deeper understanding of the cellular heterogeneity and mechanisms driving relapse, we conducted single-cell full-length RNA sequencing of 13 matched pediatric T-ALL patient-derived xenografts (PDX) samples obtained at initial diagnosis and relapse, generating the to date most comprehensive longitudinal single cell study in paired T-ALL samples, along with 5 non-relapsing PDX samples collected at initial diagnosis. This dataset identifies considerable transcriptomic diversity among individual T-ALL cell populations. Notably however, 11 of the 18 patients exhibit a small T-ALL cell subpopulation with a shared set of gene regulatory networks characterized by a common set of active regulons, expression patterns and splice isoforms. This profile involves the upregulation of a stem-like cell signature with enrichment of cell adhesion, and inhibition of the cell cycle and metabolic activity. Comprehensive investigations of these networks identify transcripts enforcing drug resistance through NF-κB expression and TGF-β signaling and of anti-apoptotic T cell signaling. Longitudinal monitoring of these stem-like cells demonstrates this subpopulation to account for only a small proportion of leukemia cells initially with a substantial expansion at relapse suggesting resistance to first line therapy. Chemotherapy resistance is functionally corroborated throughin vitroandin vivodrug testing. We thus report the discovery of inherently treatment-resistant stem-like T-ALL cell populations underscoring the potential for devising future therapeutic strategies aimed at targeting stemness pathways in pediatric T-ALL.Key PointsSingle-cell full-length RNA sequencing reveals dormant, treatment-resistant cells expanding upon T cell acute lymphoblastic leukemia relapse.Stem-like T-ALL cells exhibit a shared gene regulatory network conferring chemotherapy resistance and relapse.

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Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia

Cited by 13 publications

References 84 publications

WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical β-catenin pathway

WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical β-catenin pathway

Involvement of Epithelial-Mesenchymal Transition (EMT) in Autoimmune Diseases

Role of Stem-Like Cells in Chemotherapy Resistance and Relapse in pediatric T Cell Acute Lymphoblastic Leukemia

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