To determine the impact of basal-like and classical subtypes in advanced pancreatic ductal adenocarcinoma (PDAC) and to explore GATA6 expression as a surrogate biomarker.
Within the COMPASS trial, ...patients proceeding to chemotherapy for advanced PDAC undergo tumor biopsy for RNA-sequencing (RNA-seq). Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of
with the subtypes using gene expression profiling,
hybridization (ISH) was explored.
Between December 2015 and May 2019, 195 patients (95%) had enough tissue for RNA-seq; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% versus 33%, respectively (
= 0.02). In patients with basal-like tumors treated with modified FOLFIRINOX (
= 22), the progression rate was 60% compared with 15% in classical PDAC (
= 0.0002). Median OS in the intention-to-treat population (
= 195) was 9.3 months for classical versus 5.9 months for basal-like PDAC (HR, 0.47; 95% confidence interval, 0.32-0.69;
= 0.0001).
expression by RNA-seq highly correlated with the classifier (
< 0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariate analysis, GATA6 expression was prognostic (
= 0.02). In exploratory analyses, basal-like tumors, could be identified by keratin 5, were more hypoxic and enriched for a T-cell-inflamed gene expression signature.
The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression.
.
DNA sequencing has identified recurrent mutations that drive the aggressiveness of prostate cancers. Surprisingly, the influence of genomic, epigenomic, and transcriptomic dysregulation on the tumor ...proteome remains poorly understood. We profiled the genomes, epigenomes, transcriptomes, and proteomes of 76 localized, intermediate-risk prostate cancers. We discovered that the genomic subtypes of prostate cancer converge on five proteomic subtypes, with distinct clinical trajectories. ETS fusions, the most common alteration in prostate tumors, affect different genes and pathways in the proteome and transcriptome. Globally, mRNA abundance changes explain only ∼10% of protein abundance variability. As a result, prognostic biomarkers combining genomic or epigenomic features with proteomic ones significantly outperform biomarkers comprised of a single data type.
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•A comprehensive proteomic analyses of localized prostate cancers•Integration of all levels of the central dogma (DNA → RNA → protein)•ETS fusions have divergent effects on transcriptome and proteome•Combining genomics and proteomics improves biomarker performance
Sinha et al. determine the proteogenomic landscape of localized, intermediate-risk prostate cancers and show that the presence of ETS gene fusions has one of the strongest effects on the proteome. Prognostic biomarkers that integrate multi-omics significantly outperform those comprised of a single data type.
The statin family of cholesterol-lowering drugs has been shown to induce tumor-specific apoptosis by inhibiting the rate-limiting enzyme of the mevalonate (MVA) pathway, HMG-CoA reductase (HMGCR). ...Accumulating evidence suggests that statin use may delay prostate cancer (PCa) progression in a subset of patients; however, the determinants of statin drug sensitivity in PCa remain unclear. Our goal was to identify molecular features of statin-sensitive PCa and opportunities to potentiate statin-induced PCa cell death.
Deregulation of HMGCR expression in PCa was evaluated by immunohistochemistry. The response of PCa cell lines to fluvastatin-mediated HMGCR inhibition was assessed using cell viability and apoptosis assays. Activation of the sterol-regulated feedback loop of the MVA pathway, which was hypothesized to modulate statin sensitivity in PCa, was also evaluated. Inhibition of this statin-induced feedback loop was performed using RNA interference or small molecule inhibitors. The achievable levels of fluvastatin in mouse prostate tissue were measured using liquid chromatography–mass spectrometry.
High HMGCR expression in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR and other lipid metabolism genes. Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells.
Our study implicates statin-induced SREBP2 activation as a PCa vulnerability that can be exploited for therapeutic purposes using clinically-approved agents.
•High HMGCR protein expression in prostate cancer is associated with poor prognosis.•Statin-mediated HMGCR inhibition induces apoptosis in a subset of prostate cancer cells.•Statin-induced SREBP2 activation modulates statin sensitivity in prostate cancer.•Inhibiting SREBP2 sensitizes prostate cancer cells to statin-induced apoptosis.•Combined statin and dipyridamole therapy significantly delays prostate tumor growth.
The molecular drivers of antitumor immunity in pancreatic ductal adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for ...immune-checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T-cell infiltration in PDAC.
Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases. Validation cohorts comprised 182 PDAC from The Cancer Genome Atlas and 92 PDACs from the Australian International Cancer Genome Consortium. We explored associations between immune cell counts by immunohistochemistry, chemokine expression, and transcriptional hallmarks of antitumor immunity by RNA sequencing (RNA-seq), and mutational burden by whole-genome sequencing.
Among all known human chemokines, a coregulated set of four (
, and
) was strongly associated with CD8
T-cell infiltration (
< 0.001). Expression of this "4-chemokine signature" positively correlated with transcriptional metrics of T-cell activation (
, and
), cytolytic activity (
and
), and immunosuppression (
, and
). Furthermore, the 4-chemokine signature marked tumors with increased T-cell activation scores (MHC I presentation, T-cell/APC costimulation) and elevated expression of innate immune sensing pathways involved in T-cell priming (STING and NLRP3 inflammasome pathways, BATF3-driven dendritic cells). Importantly, expression of this 4-chemokine signature was consistently indicative of a T-cell-inflamed phenotype across primary PDAC and PDAC liver metastases.
A conserved 4-chemokine signature marks resectable and metastatic PDAC tumors with an active antitumor phenotype. This could have implications for the appropriate selection of PDAC patients in immunotherapy trials.
Aims
Intraductal and cribriform carcinoma of the prostate are increasingly recognised as independent prognosticators of poor outcome, both in prostate biopsies and surgical specimens. We studied the ...concordance of biopsy and prostatectomy diagnosis for these two subpathologies in relationship with pathological stage.
Methods and results
Mandatory synoptic reporting of intraductal and cribriform carcinoma in prostate biopsies and prostatectomy specimens was adopted by two academic institutions in November 2015. Synoptic reports of 245 biopsy and corresponding prostatectomy specimens were interrogated to determine the prevalence of intraductal and cribriform carcinoma. Sensitivity and specificity were determined, with prostatectomy diagnosis as the gold standard. Associations with pathological stage as primary outcome parameter were determined using univariable and multivariable logistic regression analysis. Prevalence of the combination of intraductal and cribriform carcinoma was 26.9% in biopsies and 51.8% in prostatectomy specimens. Sensitivity and specificity at biopsy were 47.2% and 94.9%, respectively. Intraductal and cribriform carcinoma at biopsy were associated with advanced pathological stage independent of grade (P = 0.013). Among patients with grade group 2 prostate cancer at biopsy, the more advanced pathological stage distribution was similar for those with a false negative and a true positive biopsy diagnosis of intraductal and cribriform carcinoma (P = 0.29).
Conclusion
In spite of low sensitivity, intraductal and cribriform carcinoma at biopsy was associated strongly with advanced stage at radical prostatectomy. As a false negative biopsy diagnosis was equally associated with advanced pathological stage, efforts should be undertaken to improve the sensitivity of biopsy diagnosis for intraductal and cribriform carcinoma.
Aims
Papillary renal cell carcinoma (PRCC) histologic subtyping is no longer recommended in the 2022 WHO classification. Currently, WHO/ISUP nucleolar grade is the only accepted prognostic histologic ...parameter for PRCC. ABCC2, a renal drug transporter, has been shown to significantly predict outcomes in PRCC. In this study we evaluated the prognostic significance of ABCC2 IHC staining patterns in a large, multi‐institutional PRCC cohort and assessed the association of these patterns with ABCC2 mRNA expression.
Methods and results
We assessed 254 PRCCs for ABCC2 IHC reactivity patterns that were stratified into negative, cytoplasmic, brush‐border <50%, and brush‐border ≥50%. RNA
in situ
hybridization (ISH) was used to determine the transcript level of each group. Survival analysis was performed with SPSS and GraphPad software. RNA‐ISH showed that the ABCC2 group with any brush‐border staining was associated with a significant increase in the transcript level, when compared to the negative/cytoplasmic group (
P
= 0.034). Both ABCC2 groups with brush‐border <50% (
P
= 0.024) and brush‐border ≥50% (
P
< 0.001) were also associated with worse disease‐free survival (DFS) in univariate analysis. Multivariate analysis showed that only ABCC2 IHC brush‐border (<50% and ≥50%) reactivity groups (
P
= 0.037 and
P
= 0.003, respectively), and high‐stage disease (
P
< 0.001) had a DFS of prognostic significance. In addition, ABCC2 brush‐border showed significantly worse DFS in pT1a (
P
= 0.014), pT1 (
P
= 0.013), ≤4 cm tumour (
P
= 0.041) and high stage (
P
= 0.014) groups, while a similar analysis with high WHO/ISUP grade in these groups was not significant.
Conclusion
ABCC2 IHC brush‐border expression in PRCC correlates with significantly higher gene expression and also independently predicts survival outcomes.
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