Identification of TP53RK-Binding Protein (TPRKB) Dependency in <i>TP53</i>-Deficient Cancers

Goswami, Moloy T.; VanDenBerg, Kelly R.; Han, Sumin; Wang, Lei Lucy; Singh, Bhavneet; Weiss, Travis; Barlow, Myles; Kamberov, Steven; Wilder-Romans, Kari; Rhodes, Daniel R.; Feng, Felix Y.; Tomlins, Scott A.

doi:10.1158/1541-7786.mcr-19-0144

Cited by 12 publications

(9 citation statements)

References 34 publications

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“…Moreover, a previous study verified that TP53-deficient cells were dependent on TPRKB through knockdown of TPRKB in TP53-deffficient and TP53 wild-type cell lines. They found that after knockdown of TPRKB , the growth of TP53 -deficient cells was significantly inhibited but knockdown of TPRKB in TP53 wild-type cells had minimal influences [ 42 ]. Here, through integrated analysis of CNVs, mitochondrial mutations, and gene expression patterns, we showed that EKC/KEOPS complex might play important role for metastasis of TP53-deficient tumor cells in CRC patients in vivo (Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell genomic and transcriptomic landscapes of primary and metastatic colorectal cancer tumors

Wang

Zhou

et al. 2022

Genome Med

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Background Colorectal cancer (CRC) ranks as the second-leading cause of cancer-related death worldwide with metastases being the main cause of cancer-related death. Here, we investigated the genomic and transcriptomic alterations in matching adjacent normal tissues, primary tumors, and metastatic tumors of CRC patients. Methods We performed whole genome sequencing (WGS), multi-region whole exome sequencing (WES), simultaneous single-cell RNA-Seq, and single-cell targeted cDNA Sanger sequencing on matching adjacent normal tissues, primary tumors, and metastatic tumors from 12 metastatic colorectal cancer patients (n=84 for genomes, n=81 for exomes, n=9120 for single cells). Patient-derived tumor organoids were used to estimate the anti-tumor effects of a PPAR inhibitor, and self-renewal and differentiation ability of stem cell-like tumor cells. Results We found that the PPAR signaling pathway was prevalently and aberrantly activated in CRC tumors. Blocking of PPAR pathway both suppressed the growth and promoted the apoptosis of CRC organoids in vitro, indicating that aberrant activation of the PPAR signaling pathway plays a critical role in CRC tumorigenesis. Using matched samples from the same patient, distinct origins of the metastasized tumors between lymph node and liver were revealed, which was further verified by both copy number variation and mitochondrial mutation profiles at single-cell resolution. By combining single-cell RNA-Seq and single-cell point mutation identification by targeted cDNA Sanger sequencing, we revealed important phenotypic differences between cancer cells with and without critical point mutations (KRAS and TP53) in the same patient in vivo at single-cell resolution. Conclusions Our data provides deep insights into how driver mutations interfere with the transcriptomic state of cancer cells in vivo at a single-cell resolution. Our findings offer novel knowledge on metastatic mechanisms as well as potential markers and therapeutic targets for CRC diagnosis and therapy. The high-precision single-cell RNA-seq dataset of matched adjacent normal tissues, primary tumors, and metastases from CRCs may serve as a rich resource for further studies.

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Section: Resultsmentioning

confidence: 99%

Single-cell genomic and transcriptomic landscapes of primary and metastatic colorectal cancer tumors

Wang

Zhou

et al. 2022

Genome Med

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“…In our previous research, we found that LAGE3 was a prognostic biomarker associated with levels of immune infiltration in colorectal cancer (CRC), clear cell renal cell cancer (ccRCC), and malignant pleural mesothelioma microenvironment (18)(19)(20). Goswami MT et al had found that knockdown of LAGE3 significantly reduced cell proliferation in NSCLC cell lines (21). To our best knowledge, the clinical significance of LAGE3 and its distinct functions are yet to be fully elucidated in BC.…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of L Antigen Family Member 3 Associates With Aggressive Progression of Breast Cancer

Dong

et al. 2021

Front. Oncol.

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The role of L Antigen Family Member 3 (LAGE3) in breast cancer (BC) has not been sufficiently studied. In this study, we explored the clinical value and biological functions of LAGE3 in BC. Comprehensive analysis of LAGE3 was carried out on The Cancer Genome Atlas, Molecular Taxonomy of Breast Cancer International Consortium and Gene Expression Omnibus datasets. Results showed that LAGE3 expression was higher in BC tissues than in normal breast tissues of public datasets and our local cohort. Moreover, its expression was higher in BC patients with larger tumor size, significant lymph node metastasis, higher tumor grade, and more advanced disease stage. High expression of LAGE3 was correlated with poor prognosis, and LAGE3 could independently predict survival of BC patients. Functional enrichment analysis revealed a correlation between LAGE3 expression and biochemical metabolism and immune-related terms and cancer-related pathways. Analysis of tumor microenvironment indicated that LAGE3 expression was associated with the immune cell infiltration and anti-cancer immunity cycle. LAGE3 expression was higher in triple-negative breast cancer (TNBC) compared to hormone receptor-positive BC, but not HER2-positive subtype. Suppression of LAGE3 expression inhibited the proliferation and induced apoptosis of TNBC cell lines. Besides, the down-regulation of LAGE3 attenuated the migration and invasion but reduced the expression level of epithelial-mesenchymal-transition related proteins in TNBC cell lines. In conclusion, this study demonstrated for the first time that LAGE3 promotes the progression of BC. Therefore, it may be a potential diagnostic and prognostic biomarker, as well as a treatment target for BC.

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“…Previous studies showed that LAGE3 was one of the most frequently upregulated RNA modification-related proteins in multiple cancer types [ 14 ]. The knockdown of LAGE3 significantly reduces cell proliferation in non-small-cell lung carcinoma cell lines [ 39 ]. Here, we aimed to explore the clinical value, potential biological function, and immune-related effects of the LAGE3 protein in CM.…”

Section: Discussionmentioning

confidence: 99%

L Antigen Family Member 3 Serves as a Prognostic Biomarker for the Clinical Outcome and Immune Infiltration in Skin Cutaneous Melanoma

Song

Jin

Chen

et al. 2021

BioMed Research International

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L Antigen Family Member 3 (LAGE3) is an important RNA modification-related protein. Whereas few studies have interrogated the LAGE3 protein, there is limited data on its role in tumors. Here, we analyzed and profiled the LAGE3 protein in skin cutaneous melanoma (CM) using TCGA, GTEx, or GEO databases. Our data showed an upregulation of LAGE3 in melanoma cell lines compared to normal skin cell lines. Besides, the Kaplan–Meier curves and Cox proportional hazard model revealed that LAGE3 was an independent survival indicator for CM, especially in metastatic CM. Moreover, LAGE3 was negatively associated with multiple immune cell infiltration levels in CM, especially CD8+ T cells in metastatic CM. Taken together, our study suggests that LAGE3 could be a potential prognostic biomarker and might be a potential target for the development of novel CM treatment strategies.

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Identification of TP53RK-Binding Protein (TPRKB) Dependency in TP53-Deficient Cancers

Cited by 12 publications

References 34 publications

Single-cell genomic and transcriptomic landscapes of primary and metastatic colorectal cancer tumors

Single-cell genomic and transcriptomic landscapes of primary and metastatic colorectal cancer tumors

Up-regulation of L Antigen Family Member 3 Associates With Aggressive Progression of Breast Cancer

L Antigen Family Member 3 Serves as a Prognostic Biomarker for the Clinical Outcome and Immune Infiltration in Skin Cutaneous Melanoma

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