<i>STAT3</i>-dependent systems-level analysis reveals<i>PDK4</i>as an independent predictor of biochemical recurrence in prostate cancer

Oberhuber, Monika; Pecoraro, Matteo; Rusz, Mate; Oberhuber, Georg; Wieselberg, Maritta; Haslinger, Peter; Gurnhofer, Elisabeth; Pěnčík, Jan; Wiebringhaus, Robert; Schlederer, Michaela; Weiss, Theresa R.; Schmeidl, Margit; Haitel, Andrea; Brehme, Marc; Wadsak, Wolfgang; Griss, Johannes; Mohr, Thomas; Hofer, Alexandra; Jäger, Anton; Egger, Gerda; Pollheimer, Jürgen; Koellensperger, Gunda; Mann, Matthias; Hantusch, Brigitte; Kenner, Lukas

doi:10.1101/770701

Cited by 15 publications

(19 citation statements)

References 96 publications

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“…49 Interestingly though, an inverse relationship has been reported between STAT3 expression and commitment to oxidative metabolism/tricarboxylic acid (TCA) cycle in other cancers (i.e., prostate cancer). 50 Also, given the known involvement of STAT3 signaling in glycolytic metabolism, 51 a reduced engagement of this cascade could also reflect a favoring of oxidative metabolism in the obese TME. Indeed, metabolic pathways that consume the available oxygen and enforce hypoxia in the TME were recently found to be an obstacle for the mounting of effective immune cell activity, 52 and altered lipid transport and metabolism that can alter the availability of free fatty acids may also modify immune function in the TME.…”

Section: Obesity Exacerbates Lung Cancer Progression In Mice While Altering Tme Gene Expressionmentioning

confidence: 99%

Visceral Obesity Promotes Lung Cancer Progression—Toward Resolution of the Obesity Paradox in Lung Cancer

Barbi

Patnaik

Pabla³

et al. 2021

Journal of Thoracic Oncology

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Introduction: Although obesity is associated with adverse cancer outcomes in general, most retrospective clinical studies suggest a beneficial effect of obesity in NSCLC.Methods: Hypothesizing that this "obesity paradox" arises partly from the limitations of using body mass index (BMI) to measure obesity, we quantified adiposity using preoperative computed tomography images. This allowed the specific determination of central obesity as abdominal visceral fat area normalized to total fat area (visceral fat index [VFI]). In addition, owing to the previously reported salutary effect of metformin on high-BMI patients with lung cancer, metformin users were excluded. We then explored associations between visceral obesity and outcomes after surgical resection of stage I and II NSCLC. We also explored potential immunologic underpinnings of such association using complimentary analyses of tumor gene expression data from NSCLC tumors and the tumor transcriptome and immune microenvironment in an immunocompetent model of lung cancer with diet-induced obesity.Results: We found that in 513 patients with stage I and II NSCLC undergoing lobectomy, a high VFI is associated with decreased recurrence-free and overall survival. VFI was also inversely related to an inflammatory transcriptomic signature in NSCLC tumors, consistent with observations made in immunocompetent murine models wherein diet-induced obesity promoted cancer progression while exacerbating elements of immune suppression in the tumor niche.Conclusions: In all, this study uses multiple lines of evidence to reveal the adverse effects of visceral obesity in patients with NSCLC, which align with those found in animal models. Thus, the obesity paradox may, at least in part, be secondary to the use of BMI as a measure of obesity and the confounding effects of metformin use.

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Section: Obesity Exacerbates Lung Cancer Progression In Mice While Altering Tme Gene Expressionmentioning

confidence: 99%

Visceral Obesity Promotes Lung Cancer Progression—Toward Resolution of the Obesity Paradox in Lung Cancer

Barbi

Patnaik

Pabla³

et al. 2021

Journal of Thoracic Oncology

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“…The single-cell RNA-seq data generated in this study for LuCaP PDX models and LNCaP cells have been deposited in the EMBL-EBI database under accession code E-MTAB-9903 . The publicly available RNA-seq data used in this study are available in GEO (Gene Expression Omnibus), SRA (Short Read Archive), and EMBL-EBI databases under accession codes GSE120795 23 , GSE120741 19 , GSE118435 22 , GSE126078 21 , PRJNA477449 89 , PRJEB21092 90 , and E-MTAB-9656 .…”

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confidence: 99%

Dynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression

et al. 2021

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Comprehensive genomic studies have delineated key driver mutations linked to disease progression for most cancers. However, corresponding transcriptional changes remain largely elusive because of the bias associated with cross-study analysis. Here, we overcome these hurdles and generate a comprehensive prostate cancer transcriptome atlas that describes the roadmap to tumor progression in a qualitative and quantitative manner. Most cancers follow a uniform trajectory characterized by upregulation of polycomb-repressive-complex-2, G2-M checkpoints, and M2 macrophage polarization. Using patient-derived xenograft models, we functionally validate our observations and add single-cell resolution. Thereby, we show that tumor progression occurs through transcriptional adaption rather than a selection of pre-existing cancer cell clusters. Moreover, we determine at the single-cell level how inhibition of EZH2 - the top upregulated gene along the trajectory – reverts tumor progression and macrophage polarization. Finally, a user-friendly web-resource is provided enabling the investigation of dynamic transcriptional perturbations linked to disease progression.

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“…S3 A). Nevertheless, PDK4 and STAT3, two classical genes whose low expression was associated with worse survival of PRAD [ 13 , 14 ], were significantly less expressed in PIS2 and PIS3 (Fig. S3 B and C).…”

Section: Resultsmentioning

confidence: 99%

Tumor-antigens and immune landscapes identification for prostate adenocarcinoma mRNA vaccine

Zheng

et al. 2021

Mol Cancer

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Prostate adenocarcinoma (PRAD) is a leading cause of death among men. Messenger ribonucleic acid (mRNA) vaccine presents an attractive approach to achieve satisfactory outcomes; however, tumor antigen screening and vaccination candidates show a bottleneck in this field. We aimed to investigate the tumor antigens for mRNA vaccine development and immune subtypes for choosing appropriate patients for vaccination. We identified eight overexpressed and mutated tumor antigens with poor prognostic value of PRAD, including KLHL17, CPT1B, IQGAP3, LIME1, YJEFN3, KIAA1529, MSH5 and CELSR3. The correlation of those genes with antigen-presenting immune cells were assessed. We further identified three immune subtypes of PRAD (PRAD immune subtype [PIS] 1–3) with distinct clinical, molecular, and cellular characteristics. PIS1 showed better survival and immune cell infiltration, nevertheless, PIS2 and PIS3 showed cold tumor features with poorer prognosis and higher tumor genomic instability. Moreover, these immune subtypes presented distinguished association with immune checkpoints, immunogenic cell death modulators, and prognostic factors of PRAD. Furthermore, immune landscape characterization unraveled the immune heterogeneity among patients with PRAD. To summarize, our study suggests KLHL17, CPT1B, IQGAP3, LIME1, YJEFN3, KIAA1529, MSH5 and CELSR3 are potential antigens for PRAD mRNA vaccine development, and patients in the PIS2 and PIS3 groups are more suitable for vaccination.

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STAT3-dependent systems-level analysis revealsPDK4as an independent predictor of biochemical recurrence in prostate cancer

Cited by 15 publications

References 96 publications

Visceral Obesity Promotes Lung Cancer Progression—Toward Resolution of the Obesity Paradox in Lung Cancer

Visceral Obesity Promotes Lung Cancer Progression—Toward Resolution of the Obesity Paradox in Lung Cancer

Dynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression

Tumor-antigens and immune landscapes identification for prostate adenocarcinoma mRNA vaccine

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