Pancreatic Circulating Tumour Cell Profiling Identifies LIN28B as a Metastasis Driver and Drug Target
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE144561 | GEO | 2020/03/01
REPOSITORIES: GEO
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Project description:Pancreatic Circulating Tumour Cell Profiling Identifies LIN28B as a Metastasis Driver and Drug Target
| PRJNA604022 | ENA
Project description:Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. Characterization of rare, heterogeneous circulating tumor cells (CTCs) can provide insight into metastasis and guide development of novel therapies. Using the CTC-iChip to purify CTCs from PDAC patients for RNA-seq characterization, we identify three major correlated gene sets, with stemness genes LIN28B/KLF4, WNT5A, and LGALS3 enriched in each correlated gene set; only LIN28B CTC expression was prognostic. CRISPR knockout of LIN28B-an oncofetal RNA-binding protein exerting diverse effects via negative regulation of let-7 miRNAs and other RNA targets-in cell and animal models confers a less aggressive/metastatic phenotype. This correlates with de-repression of let-7 miRNAs and is mimicked by silencing of downstream let-7 target HMGA2 or chemical inhibition of LIN28B/let-7 binding. Molecular characterization of CTCs provides a unique opportunity to correlated gene set metastatic profiles, identify drivers of dissemination, and develop therapies targeting the "seeds" of metastasis.
| S-EPMC7335061 | biostudies-literature
Project description:High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we show that LIN28B expression is associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7 independent enrichment of transcripts encoding components of the translational and ribosomal apparatus, particularly those with higher adenine/uridine (AU)-content, and depletion of transcripts of neuronal developmental programs. We further show that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrate that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a post-transcriptional driver of the metastatic phenotype.
2022-09-30 | GSE183336 | GEO
Project description:High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we show that LIN28B expression is associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7 independent enrichment of transcripts encoding components of the translational and ribosomal apparatus, particularly those with higher adenine/uridine (AU)-content, and depletion of transcripts of neuronal developmental programs. We further show that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrate that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a post-transcriptional driver of the metastatic phenotype.
2022-09-30 | GSE183335 | GEO
Project description:High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we show that LIN28B expression is associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7 independent enrichment of transcripts encoding components of the translational and ribosomal apparatus, particularly those with higher Adenine/Uridine (AU)-content, and depletion of GC-rich transcripts of neuronal developmental programs. We further show that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrate that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a post-transcriptional driver of the metastatic phenotype.
2022-09-30 | GSE158320 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE40171: RNA sequencing of circulating tumour cells implicates WNT signaling in pancreatic cancer metastasis (mouse data) GSE40174: RNA sequencing of circulating tumour cells implicates WNT signaling in pancreatic cancer metastasis (human data) Refer to individual Series
2012-08-17 | E-GEOD-40176 | biostudies-arrayexpress
Project description:Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD+-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1 and IGF2BP3. This epigenetic program defines a distinct subset representing 30-40% of human PDAC, characterized by poor prognosis and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor, and uncover the Lin28b pathway as a potential therapeutic target in a molecularlydefined PDAC subset. Small RNA-Seq experiments for PLKO and shLIN28B (three replicates each) in human Panc3.27 PDAC cells to identify miRNAs modulateed by LIN28B knockdown.
2016-04-01 | E-GEOD-79504 | biostudies-arrayexpress
Project description:Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD+-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1 and IGF2BP3. This epigenetic program defines a distinct subset representing 30-40% of human PDAC, characterized by poor prognosis and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor, and uncover the Lin28b pathway as a potential therapeutic target in a molecularlydefined PDAC subset. ChIP-Seq experiments to examine H3K56ac histone modifications in murine PDAC cells that are Sirt6 wild type (WT), Sirt6 knock-out (KO), and Sirt6 KO cells engineered to express Sirt6 WT (Sirt6 KO + Sirt6 WT Restored).
2016-04-01 | E-GEOD-79503 | biostudies-arrayexpress
Project description:Circulating tumour cells (CTCs) shed into blood from primary cancers include putative precursors that initiate distal metastases. While these cells are extraordinarily rare, they may identify cellular pathways contributing to the blood-borne dissemination of cancer. Here, we adapted a microfluidic device for efficient capture of CTCs from an endogenous mouse pancreatic cancer model and subjected CTCs to single-molecule RNA sequencing, identifying Wnt2 as enriched in CTCs. Expression of Wnt2 in pancreatic cancer cells suppresses anoikis, enhances anchorage-independent sphere formation, and increases metastatic propensity in vivo. The effect of Wnt2 is correlated with fibronectin upregulation, and it is mediated in part through non-canonical Wnt signaling and suppressed by inhibition of the Map3k7 (Tak1) kinase, an integrator of Wnt, BMP and TGF-beta signaling. In humans, formation of non-adherent tumour spheres by pancreatic cancer cells is associated with upregulation of multiple Wnt genes, and pancreatic CTCs revealed significant enrichment for non-canonical Wnt signaling in 5 of 11 cases. Thus, molecular analysis of CTCs may identify novel therapeutic targets to prevent the distal spread of cancer. Expression profiling of circulating tumor cells in human pancreatic cancer patients support a hypothesis that WNT signaling plays a role in pancreatic cancer metastasis.
2012-08-17 | E-GEOD-40174 | biostudies-arrayexpress
Project description:The RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unravel a novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using human CRC cells (DLD-1, Caco-2 and LoVo) with either knockdown or overexpression of LIN28B, we identified Claudin 1 (CLDN1) tight junction protein as a direct downstream target and effector of LIN28B. RNA immunoprecipitation revealed that LIN28B directly binds to and post-transcriptionally regulates CLDN1 mRNA. Furthermore, using in vitro assays and a novel murine model of metastatic CRC, we show that LIN28B-mediated CLDN1 expression enhances collective invasion, cell migration, and metastatic liver tumor formation. Bulk RNA-sequencing of the metastatic liver tumors identified NOTCH3 as a downstream effector of the LIN28B-CLDN1 axis. Additionally, genetic and pharmacologic manipulation of NOTCH3 signaling revealed that NOTCH3 was necessary for invasion and metastatic liver tumor formation. In summary, our results suggest that LIN28B promotes invasion and liver metastasis of CRC by post-transcriptionally regulating CLDN1 and activating NOTCH3 signaling. This discovery offers a promising new therapeutic option for metastatic CRC to the liver, an area where therapeutic advancements have been relatively scarce.
2023-09-14 | GSE234513 | GEO