RET isoforms contribute differentially to invasive processes in pancreatic ductal adenocarcinoma

Lian, Eric; Hyndman, Brandy D.; Moodley, Serisha; Maritan, Sarah M.; Mulligan, Lois M.

doi:10.1038/s41388-020-01448-z

Cited by 13 publications

(17 citation statements)

References 81 publications

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“…Structural studies have documented that RET has two isoforms, namely RET9 and RET51, which are completely different in terms of protein interactions and oncogenic potentials [ 30 ]. RET51 plays a leading role in the GDNF‐RET‐mediated PDAC invasion process [ 31 ]. After RET was activated, it not only induced the polarization and invadopodia of cancer cells but also facilitated matrix degradation by producing more matrix metallopeptidase 2 (MMP2), MMP9, and MMP14 [ 31 ], thereby accelerating cell invasion.…”

Section: Molecular Mediators Of Pnimentioning

confidence: 99%

“…RET51 plays a leading role in the GDNF‐RET‐mediated PDAC invasion process [ 31 ]. After RET was activated, it not only induced the polarization and invadopodia of cancer cells but also facilitated matrix degradation by producing more matrix metallopeptidase 2 (MMP2), MMP9, and MMP14 [ 31 ], thereby accelerating cell invasion. Similarly, the knockdown of GDNF family receptor alpha 1 (GFRA1), the co‐receptor of RET, limited the migration of MiaPACA2 cells.…”

Section: Molecular Mediators Of Pnimentioning

confidence: 99%

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Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

Kang

Tang

2021

Cancer Communications

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells. Recent works have revealed that the dynamic interaction between cancer cells and neuronal cells leads to perineural invasion (PNI), a clinical pathological feature of PDAC. The formation and function of PNI are dually regulated by molecular (e.g., involving neurotrophins, cytokines, chemokines, and neurotransmitters), metabolic (e.g., serine metabolism), and cellular mechanisms (e.g., involving Schwann cells, stromal cells, T cells, and macrophages). Such integrated mechanisms of PNI not only support tumor development, growth, invasion, and metastasis but also mediate the formation of pain, all of which are closely related to poor disease prognosis in PDAC. This review details the modulation, signaling pathways, detection, and clinical relevance of PNI and highlights the opportunities for further exploration that may benefit PDAC patients.

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Section: Molecular Mediators Of Pnimentioning

confidence: 99%

Section: Molecular Mediators Of Pnimentioning

confidence: 99%

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

Kang

Tang

2021

Cancer Communications

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“…2; refs. 29,[31][32][33][34][35][36]. Roles for RET in the more recently proposed 'emerging hallmarks' and 'enabling characteristics' remain to be more directly examined, but at least early reports suggests RET-driven cancers (both MTC and NSCLC) have a low tumor-mutational burden and characterized by lower PD-L1 expression (37,38).…”

Section: Ret and The Hallmarks Of Cancermentioning

confidence: 99%

Hallmarks of RET and Co-occuring Genomic Alterations inRET-aberrant Cancers

Adashek

Desai

Andreev-Drakhlin³

et al. 2021

Molecular Cancer Therapeutics

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Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers.Herein, we review the registrational data from the selective RETinhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRAS G12C inhibition.

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“…The risk score (RS) of each patient was calculated by multiplying the expression level of each IRG with its corresponding regression coefficients. The following computational algorithm was used for this analysis (25)(26)(27): RS=βgene(1) x exprgene(1) + βgene (2) x exprgene(2) + … + βgene(n) x exprgene(n). 'β' is the regression coefficient generated from univariate Cox analysis of IRGs, and 'exprgene' refers to the expression of IRGs in the sample.…”

Section: Acquisition Of Gene Expression Profiles Gene Expression Profilesmentioning

confidence: 99%

“…In 2010, it has been reported that pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy with a 5-year survival rate <5% in the United States, giving patients with pancreatic cancer the poorest prognosis among patients with malignant cancer types (1). PDAC is characterized by rapid progression and metastasis (2), and poses a great threat to human health. At present, TNM staging (3) is regarded as a convincing cancer staging system to guide clinical treatment and offer a method for predicting the prognosis of patients with cancer (4).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of prognostic immune‑related genes associated with the tumor microenvironment of pancreatic ductal adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with a specific tumor immune microenvironment (TIME). Therefore, investigating prognostic immune-related genes (IRGs) that are closely associated with TIME to predict PDAC clinical outcomes is necessary. In the present study, 459 samples of PDAC from the Genotype-Tissue Expression database, The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) were included and a survival-associated module was identified using weighted gene co-expression network analysis. Based on the Cox regression analysis and least absolute shrinkage and selection operator analysis, four IRGs (2′-5′-oligoadenylate synthetase 1, MET proto-oncogene, receptor tyrosine kinase, interleukin 1 receptor type 2 and interleukin 20 receptor subunit β) were included in the prognostic model to calculate the risk score (RS), and patients with PDAC were divided into high- and low-RS groups. Kaplan-Meier survival and receiver operating characteristic curve analyses demonstrated that the low-RS group had significantly improved survival conditions compared with the high-RS group in TCGA training set. The prognostic function of the model was also validated using ICGC and GEO cohorts. To investigate the mechanism of different overall survival between the high- and low-RS groups, the present study included Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data and Cell Type Identification by Estimating Relative Subset of Known RNA Transcripts algorithms to investigate the state of the tumor microenvironment and immune infiltration inpatients in the cohort from TCGA. In summary, four genes associated with the TIME of PDAC were identified, which may provide a reference for clinical treatment.

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RET isoforms contribute differentially to invasive processes in pancreatic ductal adenocarcinoma

Cited by 13 publications

References 81 publications

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

Hallmarks of RET and Co-occuring Genomic Alterations inRET-aberrant Cancers

Comprehensive analysis of prognostic immune‑related genes associated with the tumor microenvironment of pancreatic ductal adenocarcinoma

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