Differences between Well-Differentiated Neuroendocrine Tumors and Ductal Adenocarcinomas of the Pancreas Assessed by Multi-Omics Profiling

Starzyńska, Teresa; Karczmarski, Jakub; Paziewska, Agnieszka; Kulecka, Maria; Kuśnierz, Katarzyna; Żeber‐Lubecka, Natalia; Ambrożkiewicz, Filip; Mikula, Michał; Kos–Kudła, Beata; Ostrowski, Jerzy

doi:10.3390/ijms21124470

Cited by 14 publications

(15 citation statements)

References 91 publications

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“…S5B ). Dimension 1, containing the highest variability (20.2%), showed segregation of human PDACs from all three PanNET samples, supporting previous work demonstrating that PDACs and PanNETs have significantly distinct molecular profiles [ 50 ]. In dimension 2, containing the second highest variability (6.1%), the two human PanNET datasets separate from one another indicating minor differences may arise during processing of independent sample sets.…”

Section: Resultssupporting

confidence: 83%

Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors

et al. 2021

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Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in β-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.

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Section: Resultssupporting

confidence: 83%

Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors

et al. 2021

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“…For example, when analyzing miRNA expression profiles obtained by small RNA sequencing approach of 378 samples, only nine microRNAs were expressed in samples of at least five types: miRNA-375, -21, -143, -let-7a, -26a, -7, -let-7F, -125B and -141 [22]. Interestingly, when comparing genes with deleterious variants in pancreatic NENs and intestinal NENs, only 4% of genes were common for these types of NEN [61].…”

Section: Mirna Expression In Nens Of Different Localizations: Specificity and Commonalitymentioning

confidence: 99%

MiRNA Expression in Neuroendocrine Neoplasms of Frequent Localizations

Korotaeva

Mansorunov

Apanovich

et al. 2021

ncRNA

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Neuroendocrine neoplasms (NEN) are infrequent malignant tumors of a neuroendocrine nature that arise in various organs. They occur most frequently in the lungs, intestines, stomach and pancreas. Molecular diagnostics and prognosis of NEN development are highly relevant. The role of clinical biomarkers can be played by microRNAs (miRNAs). This work is devoted to the analysis of data on miRNA expression in NENs. For the first time, a search for specificity or a community of their functional characteristics in different types of NEN was carried out. Their properties as biomarkers were also analyzed. To date, more than 100 miRNAs have been characterized as differentially expressed and significant for the development of NEN tumors. Only about 10% of the studied miRNAs are expressed in several types of NEN; differential expression of the remaining 90% was found only in tumors of specific localizations. A significant number of miRNAs have been identified as potential biomarkers. However, only a few miRNAs have values that characterized their quality as markers. The analysis demonstrates the predominant specific expression of miRNA in each studied type of NEN. This indicates that miRNA’s functional features are predominantly influenced by the tissue in which they are formed.

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“…This gene correlates with an aggressive course and frequent relapses in pancreatic neuroendocrine tumors 56 , 57 . Our present survival analysis suggests that high ARX expression is favorable for PAAD patients, which might suggest a subtype-specific behavior that is worth investigation since pancreatic tumors arising from endocrine or epithelial portion have different properties 58 – 60 . The prognostic outcome of COL4A3 could also vary depending on cancer type.…”

Section: Discussionmentioning

confidence: 76%

Prognostic significance of AP-2α/γ targets as cancer therapeutics

Kołat

Kałuzińska

Płuciennik

2022

Sci Rep

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Identifying genes with prognostic importance could improve cancer treatment. An increasing number of reports suggest the existence of successful strategies based on seemingly “untargetable” transcription factors. In addition to embryogenesis, AP-2 transcription factors are known to play crucial roles in cancer development. Members of this family can be used as prognostic factors in oncological patients, and AP-2α/γ transcription factors were previously investigated in our pan-cancer comparative study using their target genes. The present study investigates tumors that were previously found similar with an emphasis on the possible role of AP-2 factors in specific cancer types. The RData workspace was loaded back to R environment and 3D trajectories were built via Monocle3. The genes that met the requirement of specificity were listed using top_markers(), separately for mutual and unique targets. Furthermore, the candidate genes had to meet the following requirements: correlation with AP-2 factor (through Correlation AnalyzeR) and validated prognostic importance (using GEPIA2 and subsequently KM-plotter or LOGpc). Eventually, the ROC analysis was applied to confirm their predictive value; co-dependence of expression was visualized via BoxPlotR. Some similar tumors were differentiated by AP-2α/γ targets with prognostic value. Requirements were met by only fifteen genes (EMX2, COL7A1, GRIA1, KRT1, KRT14, SLC12A5, SEZ6L, PTPRN, SCG5, DPP6, NTSR1, ARX, COL4A3, PPEF1 and TMEM59L); of these, the last four were excluded based on ROC curves. All the above genes were confronted with the literature, with an emphasis on the possible role played by AP-2 factors in specific cancers. Following ROC analysis, the genes were verified using immunohistochemistry data and progression-related signatures. Staining differences were observed, as well as co-dependence on the expression of e.g. CTNNB1, ERBB2, KRAS, SMAD4, EGFR or MKI67. In conclusion, prognostic value of targets suggested AP-2α/γ as candidates for novel cancer treatment. It was also revealed that AP-2 targets are related to tumor progression and that some mutual target genes could be inversely regulated.

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Differences between Well-Differentiated Neuroendocrine Tumors and Ductal Adenocarcinomas of the Pancreas Assessed by Multi-Omics Profiling

Cited by 14 publications

References 91 publications

Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors

Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors

MiRNA Expression in Neuroendocrine Neoplasms of Frequent Localizations

Prognostic significance of AP-2α/γ targets as cancer therapeutics

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