Kinase Activities in Pancreatic Ductal Adenocarcinoma with Prognostic and Therapeutic Avenues DOI

Andrea Vallés Martí,

Richard Haas,

Alex A. Henneman

et al.

Published: Jan. 1, 2023

Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with limited number of known driver mutations but considerable cancer cell heterogeneity. Phosphoproteomics provides direct read-out aberrant signalling and the resultant clinically relevant phenotype. Methods: Mass spectrometry (MS)-based proteomics phosphoproteomics were applied to 42 PDAC tumors. To this end, protein lysates subjected tryptic digestion sequential phosphopeptide capture using pY antibodies IMAC beads followed by nanoLC-MS/MS database searching. Functional data mining was performed Integrative iNferred Kinase Activity (INKA) scoring, ssGSEA PTM-SEA. subtypes investigated consensus clustering. The collected correlated genomic patient survival outcomes. Findings: Data encompassed over 19936 pS/T (in 5412 phosphoproteins) 1208 sites 501 total 3756 proteins. Proteome identified three distinct tumor intrinsic stromal features. Subsequently, phospho-subtypes apparent: two tumour-intrinsic (Phos1/2) one (Phos3), resembling molecular subtypes. Phos displayed differential phosphorylation signals kinase activity, such as FGR GSK3 activation in Phos1, SRC family EPHA2 Phos2, EGFR, INSR, MET, ABL1, HIPK1, JAK PRKCD Phos3. activity analysis an external cohort supported our findings underscored importance PI3K/AKT ERK pathways, among other. Interestingly, unfavorable prognosis higher RTK, MAPK CDK high proliferation, whereas long associated MYLK, ILK, PTK6 previously unknown. Interpretation: Subtype-associated profiles can guide therapeutic combination approaches tumour stroma enriched tissues, emphasize critical role parallel pathways. In addition, profiling identifies potential markers prognostic significance.Funding: This project Dutch Cancer Society (KWF Kankerbestrijding, grant KWF2016-1 / 10212 C.R.J., M.F.B. E.G.). Center Amsterdam Netherlands Organisation for Scientific Research (NWO-Middelgroot 91116017) are acknowledged support mass infrastructure Surfsara computing (reference e-infra180166).Declaration Interest: has received research funding from Celgene, Frame Therapeutics, Lead Pharma. He acted consultant Servier. Ethical Approval: Tumor tissue specimens, snap-frozen liquid nitrogen stored at -80°C, retrospectively archive Department Pathology (approved Committee Review Biobanks, CTB.2015-081) purpose phosphoproteomic research. Retrospective collection conducted accordance ethical guidelines UMC Code, based on 'Code conduct Health Research' (Dutch Regulation Research).

Language: Английский

Cytotoxic T‐lymphocytes in acute myeloid leukemia: Monitoring prognosis and guiding treatment choice DOI

Mengjiao Lü,

Xialei Yu,

Jingyan Hu

et al.

The Journal of Gene Medicine, Journal Year: 2023, Volume and Issue: 26(1)

Published: Sept. 11, 2023

Abstract Background Cytotoxic T‐lymphocyte (CTL)‐mediated therapy has become the central theme of cancer immunotherapy. The present study emphasized role CTLs in acute myeloid leukemia (AML) and aimed to understand cytogenetic markers monitoring AML prognostic outcomes clinical treatment responses. Methods Seurat was employed analyze single‐cell RNA sequencing data GSE116256. CellChat used detect cell–cell interactions determine CTLs. marker genes were extracted randomForestSRC construct a random forest model. prognosis, immune checkpoint expression, cell infiltration, immunotherapy response drug sensitivity patients evaluated according Results Seven types cellular components identified GSE116256, radiated most with other types. Random analysis screened out six for construction risk score calculated model positively correlated score, expression multiple checkpoints effect pathway. rate significantly higher more sensitive 14 drugs high‐risk samples than low‐risk samples, whereas showed drugs. Conclusions communication established regression based on its markers, which helps stratify prognosis AML, promotes understanding phenotype may also guide choice patients, contributed stratification promoted selection AML.

Language: Английский

Citations

1
Kinase activities in pancreatic ductal adenocarcinoma with prognostic and therapeutic avenues DOI Creative Commons
Andrea Vallés‐Martí,

Richard R. de Goeij‐de Haas,

Alex A. Henneman

et al.

Molecular Oncology, Journal Year: 2024, Volume and Issue: 18(8), P. 2020 - 2041

Published: April 22, 2024

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with limited number of known driver mutations but considerable cancer cell heterogeneity. Phosphoproteomics provides direct read-out aberrant signaling and the resultant clinically relevant phenotype. Mass spectrometry (MS)-based proteomics phosphoproteomics were applied to 42 PDAC tumors. Data encompassed over 19 936 phosphoserine or phosphothreonine (pS/T; in 5412 phosphoproteins) 1208 phosphotyrosine (pY; 501 sites total 3756 proteins. Proteome data identified three distinct subtypes tumor intrinsic stromal features. Subsequently, phospho-subtypes apparent: two (Phos1/2) one (Phos3), resembling molecular subtypes. Kinase activity was analyzed by Integrative iNferred Activity (INKA) scoring. Phospho-subtypes displayed differential phosphorylation signals kinase activity, such as FGR GSK3 activation Phos1, SRC family EPHA2 Phos2, EGFR, INSR, MET, ABL1, HIPK1, JAK, PRKCD Phos3. analysis an external cohort supported our findings underscored importance PI3K/AKT ERK pathways, among others. Interestingly, unfavorable patient prognosis correlated higher RTK, PAK2, STK10, CDK7 high proliferation, whereas long survival associated MYLK PTK6 which previously unknown. Subtype-associated profiles can guide therapeutic combination approaches stroma-enriched tissues, emphasize critical role parallel pathways. In addition, profiling identifies potential markers prognostic significance.

Language: Английский

Citations

0
The Era of Molecular Hematopathology DOI
Paweł Mróz, Mark D. Ewalt,

Susan E Harley

et al.

Journal of Molecular Diagnostics, Journal Year: 2024, Volume and Issue: 26(11), P. 945 - 949

Published: Oct. 24, 2024

Language: Английский

Citations

0
Clinical Peptidomics in Acute Leukemias: Current Advances and Future Perspectives DOI Creative Commons

Danila Félix Coutinho,

Túlio Resende Freitas, Ana Carolina Silva Batista

et al.

Journal of Proteome Research, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

The study of circulating peptides in the blood offers significant opportunities for diagnosing, stratifying, and managing various diseases. With recent technological advances ongoing need to understand complex diseases such as acute leukemias (AL), peptidomic analysis peripheral blood, especially serum plasma, has become increasingly important studying human biology pathophysiology. Here, we provide insights perspectives on developments potential clinical applications using widely used methods. We discuss examples where peptidomics or plasma contributed understanding AL. Specifically, highlight scarcity studies applied AL emphasize importance exploring this area, few published present promising results that can significantly contribute precision medicine.

Language: Английский

Citations

0
Proteogenomic profiling of acute myeloid leukemia to identify therapeutic targets DOI
Heather C. Murray, Jonathan R. Sillar, Melissa G. Chambers

et al.

Expert Review of Proteomics, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 14

Published: Nov. 22, 2024

Acute myeloid leukemia (AML) is an aggressive and poor-prognosis blood cancer. Despite a low mutation burden compared to other cancers, AML heterogenous identifying robust therapeutic targets has been difficult. Genomic profiling greatly advanced our understanding of AML, revealed for therapy. However, only 50% patients have gene mutations that are currently druggable, relapse rates remain high. The addition proteomic emerging address these challenges.

Language: Английский

Citations

0
Kinase Activities in Pancreatic Ductal Adenocarcinoma with Prognostic and Therapeutic Avenues DOI

Andrea Vallés Martí,

Richard Haas,

Alex A. Henneman

et al.

Published: Jan. 1, 2023

Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with limited number of known driver mutations but considerable cancer cell heterogeneity. Phosphoproteomics provides direct read-out aberrant signalling and the resultant clinically relevant phenotype. Methods: Mass spectrometry (MS)-based proteomics phosphoproteomics were applied to 42 PDAC tumors. To this end, protein lysates subjected tryptic digestion sequential phosphopeptide capture using pY antibodies IMAC beads followed by nanoLC-MS/MS database searching. Functional data mining was performed Integrative iNferred Kinase Activity (INKA) scoring, ssGSEA PTM-SEA. subtypes investigated consensus clustering. The collected correlated genomic patient survival outcomes. Findings: Data encompassed over 19936 pS/T (in 5412 phosphoproteins) 1208 sites 501 total 3756 proteins. Proteome identified three distinct tumor intrinsic stromal features. Subsequently, phospho-subtypes apparent: two tumour-intrinsic (Phos1/2) one (Phos3), resembling molecular subtypes. Phos displayed differential phosphorylation signals kinase activity, such as FGR GSK3 activation in Phos1, SRC family EPHA2 Phos2, EGFR, INSR, MET, ABL1, HIPK1, JAK PRKCD Phos3. activity analysis an external cohort supported our findings underscored importance PI3K/AKT ERK pathways, among other. Interestingly, unfavorable prognosis higher RTK, MAPK CDK high proliferation, whereas long associated MYLK, ILK, PTK6 previously unknown. Interpretation: Subtype-associated profiles can guide therapeutic combination approaches tumour stroma enriched tissues, emphasize critical role parallel pathways. In addition, profiling identifies potential markers prognostic significance.Funding: This project Dutch Cancer Society (KWF Kankerbestrijding, grant KWF2016-1 / 10212 C.R.J., M.F.B. E.G.). Center Amsterdam Netherlands Organisation for Scientific Research (NWO-Middelgroot 91116017) are acknowledged support mass infrastructure Surfsara computing (reference e-infra180166).Declaration Interest: has received research funding from Celgene, Frame Therapeutics, Lead Pharma. He acted consultant Servier. Ethical Approval: Tumor tissue specimens, snap-frozen liquid nitrogen stored at -80°C, retrospectively archive Department Pathology (approved Committee Review Biobanks, CTB.2015-081) purpose phosphoproteomic research. Retrospective collection conducted accordance ethical guidelines UMC Code, based on 'Code conduct Health Research' (Dutch Regulation Research).

Language: Английский

Citations

0