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Article ; Online: Macrothrombocytopenia associated with a rare GFI1B missense variant confounding the presentation of immune thrombocytopenia.

Cheng, Aaron N / Bao, Erik L / Fiorini, Claudia / Sankaran, Vijay G

2019 Volume 66, Issue 9, Page(s) e27874

Abstract: Growth factor-independent 1B (GFI1B) variants are a rare cause of thrombocytopenia. We report on a male child who was initially diagnosed with immune thrombocytopenia. However, subtle clinical signs led to suspicion of a genetic cause of thrombocytopenia. ...

Abstract	Growth factor-independent 1B (GFI1B) variants are a rare cause of thrombocytopenia. We report on a male child who was initially diagnosed with immune thrombocytopenia. However, subtle clinical signs led to suspicion of a genetic cause of thrombocytopenia. Gene panel sequencing revealed a rare variant in GFI1B (C168F), which has recently been reported in several families with thrombocytopenia. We demonstrate that this variant significantly alters platelet parameters in population studies. This case highlights how diagnoses of exclusion, such as immune thrombocytopenia, can be confounded by genetic variation. Our understanding of blood disorders will undoubtedly evolve from an increased knowledge of human genetic variation.
MeSH term(s)	Blood Platelets/metabolism ; Child, Preschool ; Genetic Diseases, Inborn/blood ; Genetic Diseases, Inborn/diagnosis ; Genetic Diseases, Inborn/genetics ; Humans ; Male ; Mutation, Missense ; Proto-Oncogene Proteins/genetics ; Purpura, Thrombocytopenic, Idiopathic/blood ; Purpura, Thrombocytopenic, Idiopathic/diagnosis ; Purpura, Thrombocytopenic, Idiopathic/genetics ; Repressor Proteins/genetics
Chemical Substances	GFI1B protein, human ; Proto-Oncogene Proteins ; Repressor Proteins
Language	English
Publishing date	2019-06-17
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2131448-2
ISSN	1545-5017 ; 1545-5009
ISSN (online)	1545-5017
ISSN	1545-5009
DOI	10.1002/pbc.27874
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Article: RNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation.

Martell, Danya J / Merens, Hope E / Fiorini, Claudia / Caulier, Alexis / Ulirsch, Jacob C / Ietswaart, Robert / Choquet, Karine / Graziadei, Giovanna / Brancaleoni, Valentina / Cappellini, Maria Domenica / Scott, Caroline / Roberts, Nigel / Proven, Melanie / Roy, Noémi Ba / Babbs, Christian / Higgs, Douglas R / Sankaran, Vijay G / Churchman, L Stirling

medRxiv : the preprint server for health sciences

2023

Abstract: The controlled release of promoter-proximal paused RNA polymerase II (Pol II) into productive elongation is a major step in gene regulation. However, functional analysis of Pol II pausing is difficult because factors that regulate pause release are ... ...

Abstract	The controlled release of promoter-proximal paused RNA polymerase II (Pol II) into productive elongation is a major step in gene regulation. However, functional analysis of Pol II pausing is difficult because factors that regulate pause release are almost all essential. In this study, we identified heterozygous loss-of-function mutations in
Language	English
Publishing date	2023-03-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.03.23286760
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Article ; Online: RNA polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation.

Martell, Danya J / Merens, Hope E / Caulier, Alexis / Fiorini, Claudia / Ulirsch, Jacob C / Ietswaart, Robert / Choquet, Karine / Graziadei, Giovanna / Brancaleoni, Valentina / Cappellini, Maria Domenica / Scott, Caroline / Roberts, Nigel / Proven, Melanie / Roy, Noémi B A / Babbs, Christian / Higgs, Douglas R / Sankaran, Vijay G / Churchman, L Stirling

Developmental cell

2023 Volume 58, Issue 20, Page(s) 2112–2127.e4

Abstract: Controlled release of promoter-proximal paused RNA polymerase II (RNA Pol II) is crucial for gene regulation. However, studying RNA Pol II pausing is challenging, as pause-release factors are almost all essential. In this study, we identified ... ...

Abstract	Controlled release of promoter-proximal paused RNA polymerase II (RNA Pol II) is crucial for gene regulation. However, studying RNA Pol II pausing is challenging, as pause-release factors are almost all essential. In this study, we identified heterozygous loss-of-function mutations in SUPT5H, which encodes SPT5, in individuals with β-thalassemia. During erythropoiesis in healthy human cells, cell cycle genes were highly paused as cells transition from progenitors to precursors. When the pathogenic mutations were recapitulated by SUPT5H editing, RNA Pol II pause release was globally disrupted, and as cells began transitioning from progenitors to precursors, differentiation was delayed, accompanied by a transient lag in erythroid-specific gene expression and cell cycle kinetics. Despite this delay, cells terminally differentiate, and cell cycle phase distributions normalize. Therefore, hindering pause release perturbs proliferation and differentiation dynamics at a key transition during erythropoiesis, identifying a role for RNA Pol II pausing in temporally coordinating the cell cycle and erythroid differentiation.
MeSH term(s)	Humans ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; Gene Expression Regulation ; Cell Differentiation ; Cell Cycle ; Transcription, Genetic ; Nuclear Proteins/metabolism ; Transcriptional Elongation Factors/genetics
Chemical Substances	RNA Polymerase II (EC 2.7.7.-) ; SUPT5H protein, human ; Nuclear Proteins ; Transcriptional Elongation Factors
Language	English
Publishing date	2023-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2054967-2
ISSN	1878-1551 ; 1534-5807
ISSN (online)	1878-1551
ISSN	1534-5807
DOI	10.1016/j.devcel.2023.07.018
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Zs.A 5742: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia.

Voit, Richard A / Tao, Liming / Yu, Fulong / Cato, Liam D / Cohen, Blake / Fleming, Travis J / Antoszewski, Mateusz / Liao, Xiaotian / Fiorini, Claudia / Nandakumar, Satish K / Wahlster, Lara / Teichert, Kristian / Regev, Aviv / Sankaran, Vijay G

Nature immunology

2022 Volume 24, Issue 1, Page(s) 69–83

Abstract: The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare ... ...

Abstract	The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate. We show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.
MeSH term(s)	Humans ; Hematopoietic Stem Cells ; Leukemia/genetics ; Neoplasms ; Transcription Factors/genetics ; Cell Differentiation/genetics
Chemical Substances	Transcription Factors
Language	English
Publishing date	2022-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-022-01370-4
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Regulation of miR-23b expression and its dual role on ROS production and tumour development.

Donadelli, Massimo / Dando, Ilaria / Fiorini, Claudia / Palmieri, Marta

Cancer letters

2014 Volume 349, Issue 2, Page(s) 107–113

Abstract: Among the wide family of microRNAs, microRNA 23b (miR-23b) intriguingly assumes opposite roles on regulation of reactive oxygen species (ROS) and on the development of human cancers. In this review we describe novel findings concerning the molecular ... ...

Abstract	Among the wide family of microRNAs, microRNA 23b (miR-23b) intriguingly assumes opposite roles on regulation of reactive oxygen species (ROS) and on the development of human cancers. In this review we describe novel findings concerning the molecular events involved in miR-23b gene activation or repression and in both ROS regulation and tumour development. In particular, we define the molecular targets of miR-23b that determine its function as either a tumour suppressor or oncomir in different cell types. Finally, we analyze the involvement of miR-23b in cancer cell metabolism, including autophagy, and in biomarker signatures of microRNAs allowing a prognostic and therapeutic evaluation in various human cancers.
MeSH term(s)	Animals ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; MicroRNAs/biosynthesis ; MicroRNAs/genetics ; Neoplasms/genetics ; Neoplasms/metabolism ; Reactive Oxygen Species/metabolism
Chemical Substances	MIRN23a microRNA, human ; MicroRNAs ; Reactive Oxygen Species
Language	English
Publishing date	2014-04-19
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2014.04.012
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Article ; Online: A unified model of human hemoglobin switching through single-cell genome editing.

Shen, Yong / Verboon, Jeffrey M / Zhang, Yuannyu / Liu, Nan / Kim, Yoon Jung / Marglous, Samantha / Nandakumar, Satish K / Voit, Richard A / Fiorini, Claudia / Ejaz, Ayesha / Basak, Anindita / Orkin, Stuart H / Xu, Jian / Sankaran, Vijay G

Nature communications

2021 Volume 12, Issue 1, Page(s) 4991

Abstract: Key mechanisms of fetal hemoglobin (HbF) regulation and switching have been elucidated through studies of human genetic variation, including mutations in the HBG1/2 promoters, deletions in the β-globin locus, and variation impacting BCL11A. While this ... ...

Abstract	Key mechanisms of fetal hemoglobin (HbF) regulation and switching have been elucidated through studies of human genetic variation, including mutations in the HBG1/2 promoters, deletions in the β-globin locus, and variation impacting BCL11A. While this has led to substantial insights, there has not been a unified understanding of how these distinct genetically-nominated elements, as well as other key transcription factors such as ZBTB7A, collectively interact to regulate HbF. A key limitation has been the inability to model specific genetic changes in primary isogenic human hematopoietic cells to uncover how each of these act individually and in aggregate. Here, we describe a single-cell genome editing functional assay that enables specific mutations to be recapitulated individually and in combination, providing insights into how multiple mutation-harboring functional elements collectively contribute to HbF expression. In conjunction with quantitative modeling and chromatin capture analyses, we illustrate how these genetic findings enable a comprehensive understanding of how distinct regulatory mechanisms can synergistically modulate HbF expression.
MeSH term(s)	CRISPR-Cas Systems ; Chromatin ; Chromosomes ; DNA-Binding Proteins/metabolism ; Fetal Hemoglobin/genetics ; Fetal Hemoglobin/metabolism ; Gene Editing ; Gene Expression ; Globins ; Hemoglobins/genetics ; Hemoglobins/metabolism ; Humans ; Mutation ; Repressor Proteins ; Transcription Factors/metabolism ; beta-Globins/genetics
Chemical Substances	BCL11A protein, human ; Chromatin ; DNA-Binding Proteins ; Hemoglobins ; Repressor Proteins ; Transcription Factors ; ZBTB7A protein, human ; beta-Globins ; Globins (9004-22-2) ; Fetal Hemoglobin (9034-63-3)
Language	English
Publishing date	2021-08-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-25298-9
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Article ; Online: UCP2, a mitochondrial protein regulated at multiple levels.

Donadelli, Massimo / Dando, Ilaria / Fiorini, Claudia / Palmieri, Marta

Cellular and molecular life sciences : CMLS

2013 Volume 71, Issue 7, Page(s) 1171–1190

Abstract: An ever-increasing number of studies highlight the role of uncoupling protein 2 (UCP2) in a broad range of physiological and pathological processes. The knowledge of the molecular mechanisms of UCP2 regulation is becoming fundamental in both the ... ...

Abstract	An ever-increasing number of studies highlight the role of uncoupling protein 2 (UCP2) in a broad range of physiological and pathological processes. The knowledge of the molecular mechanisms of UCP2 regulation is becoming fundamental in both the comprehension of UCP2-related physiological events and the identification of novel therapeutic strategies based on UCP2 modulation. The study of UCP2 regulation is a fast-moving field. Recently, several research groups have made a great effort to thoroughly understand the various molecular mechanisms at the basis of UCP2 regulation. In this review, we describe novel findings concerning events that can occur in a concerted manner at various levels: Ucp2 gene mutation (single nucleotide polymorphisms), UCP2 mRNA and protein expression (transcriptional, translational, and protein turn-over regulation), UCP2 proton conductance (ligands and post-transcriptional modifications), and nutritional and pharmacological regulation of UCP2.
MeSH term(s)	Antibiotics, Antineoplastic/pharmacology ; Doxorubicin/pharmacology ; Gene Expression Regulation/drug effects ; Hypoglycemic Agents/pharmacology ; Ion Channels/chemistry ; Ion Channels/genetics ; Ion Channels/metabolism ; Metformin/pharmacology ; Mitochondrial Proteins/chemistry ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Models, Genetic ; Polymorphism, Single Nucleotide ; Protein Processing, Post-Translational ; RNA, Messenger/metabolism ; Uncoupling Protein 2
Chemical Substances	Antibiotics, Antineoplastic ; Hypoglycemic Agents ; Ion Channels ; Mitochondrial Proteins ; RNA, Messenger ; Uncoupling Protein 2 ; Doxorubicin (80168379AG) ; Metformin (9100L32L2N)
Language	English
Publishing date	2013-06-27
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-013-1407-0
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Article: Onconase induces autophagy sensitizing pancreatic cancer cells to gemcitabine and activates Akt/mTOR pathway in a ROS-dependent manner.

Fiorini, Claudia / Cordani, Marco / Gotte, Giovanni / Picone, Delia / Donadelli, Massimo

Biochimica et biophysica acta

2015 Volume 1853, Issue 3, Page(s) 549–560

Abstract: Onconase® (ONC) is a member of the RNase super-family that is secreted in oocytes and early embryos of Rana pipiens. Over the last years, research interest about this small and basic frog RNase, also called ranpirnase, constantly increased because of its ...

Abstract	Onconase® (ONC) is a member of the RNase super-family that is secreted in oocytes and early embryos of Rana pipiens. Over the last years, research interest about this small and basic frog RNase, also called ranpirnase, constantly increased because of its high cytotoxicity and anticancer properties. Onconase is currently used in clinical trials for cancer therapy; however, the precise mechanisms determining cytotoxicity in cancer cells have not yet been fully investigated. In the present manuscript, we evaluate the antitumoral property of onconase in pancreatic adenocarcinoma cells and in non-tumorigenic cells as a control. We demonstrate that ONC stimulates a strong antiproliferative and proapoptotic effect in cancer cells by reporting for the first time that ONC triggers Beclin1-mediated autophagic cancer cell death. In addition, ONC inhibits the expression of mitochondrial uncoupling protein 2 (UCP2) and of manganese-dependent superoxide dismutase (MnSOD) triggering mitochondrial superoxide ion production. ONC-induced reactive oxygen species (ROS) are responsible for Akt/mTOR pathway stimulation determining the sensitivity of cancer cells to mTOR inhibitors and lessening autophagic stimulation. This indicates ROS/Akt/mTOR axis as a strategy adopted by cancer cells to reduce ONC-mediated cytotoxic autophagy stimulation. In addition, we demonstrate that ONC can sensitize pancreatic cancer cells to the standard chemotherapeutic agent gemcitabine allowing a reduction of drug concentration when used in combination settings, thus suggesting a lowering of chemotherapy-related side effects. Altogether, our results shed more light on the mechanisms lying at the basis of ONC antiproliferative effect in cancer cells and support its potential use to develop new anticancer strategies.
MeSH term(s)	Adenocarcinoma/metabolism ; Adenocarcinoma/pathology ; Antineoplastic Agents/pharmacology ; Autophagy/drug effects ; Cells, Cultured ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Drug Resistance, Neoplasm/drug effects ; Drug Synergism ; Humans ; Oncogene Protein v-akt/metabolism ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Reactive Oxygen Species/metabolism ; Reactive Oxygen Species/pharmacology ; Ribonucleases/pharmacology ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; Up-Regulation/drug effects
Chemical Substances	Antineoplastic Agents ; Reactive Oxygen Species ; Deoxycytidine (0W860991D6) ; gemcitabine (B76N6SBZ8R) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Oncogene Protein v-akt (EC 2.7.11.1) ; Ribonucleases (EC 3.1.-) ; ranpirnase (ZE15FIT23E)
Language	English
Publishing date	2015-03
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2014.12.016
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Article: Bovine seminal ribonuclease triggers Beclin1-mediated autophagic cell death in pancreatic cancer cells.

Fiorini, Claudia / Gotte, Giovanni / Donnarumma, Federica / Picone, Delia / Donadelli, Massimo

Biochimica et biophysica acta

2014 Volume 1843, Issue 5, Page(s) 976–984

Abstract: Among the large number of variants belonging to the pancreatic-type secretory ribonuclease (RNase) superfamily, bovine pancreatic ribonuclease (RNase A) is the proto-type and bovine seminal RNase (BS-RNase) represents the unique natively dimeric member. ... ...

Abstract	Among the large number of variants belonging to the pancreatic-type secretory ribonuclease (RNase) superfamily, bovine pancreatic ribonuclease (RNase A) is the proto-type and bovine seminal RNase (BS-RNase) represents the unique natively dimeric member. In the present manuscript, we evaluate the anti-tumoral property of these RNases in pancreatic adenocarcinoma cell lines and in nontumorigenic cells as normal control. We demonstrate that BS-RNase stimulates a strong anti-proliferative and pro-apoptotic effect in cancer cells, while RNase A is largely ineffective. Notably, we reveal for the first time that BS-RNase triggers Beclin1-mediated autophagic cancer cell death, providing evidences that high proliferation rate of cancer cells may render them more susceptible to autophagy by BS-RNase treatment. Notably, to improve the autophagic response of cancer cells to BS-RNase we used two different strategies: the more basic (as compared to WT enzyme) G38K mutant of BS-RNase, known to interact more strongly than wt with the acidic membrane of cancer cells, or BS-RNase oligomerization (tetramerization or formation of larger oligomers). Both mutant BS-RNase and BS-RNase oligomers potentiated autophagic cell death as compared to WT native dimer of BS-RNase, while the various RNase A oligomers remained completely ineffective. Altogether, our results shed more light on the mechanisms lying at the basis of BS-RNase antiproliferative effect in cancer cells, and support its potential use to develop new anti-cancer strategies.
MeSH term(s)	Adenocarcinoma/pathology ; Animals ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/physiology ; Autophagy/drug effects ; Autophagy/physiology ; Beclin-1 ; Cattle ; Cell Line, Tumor ; Male ; Membrane Proteins/physiology ; Pancreatic Neoplasms/pathology ; Ribonuclease, Pancreatic/pharmacology ; Semen/enzymology
Chemical Substances	Apoptosis Regulatory Proteins ; BECN1 protein, human ; Beclin-1 ; Membrane Proteins ; Ribonuclease, Pancreatic (EC 3.1.27.5)
Language	English
Publishing date	2014-05
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2014.01.025
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Article ; Online: Loss of FGFR4 promotes the malignant phenotype of PDAC.

D'Agosto, Sabrina / Pezzini, Francesco / Veghini, Lisa / Delfino, Pietro / Fiorini, Claudia / Temgue Tane, Gael D / Del Curatolo, Anais / Vicentini, Caterina / Ferrari, Giorgia / Pasini, Davide / Andreani, Silvia / Lupo, Francesca / Fiorini, Elena / Lorenzon, Giulia / Lawlor, Rita T / Rusev, Borislav / Malinova, Antonia / Luchini, Claudio / Milella, Michele /

Sereni, Elisabetta / Pea, Antonio / Bassi, Claudio / Bailey, Peter / Scarpa, Aldo / Bria, Emilio / Corbo, Vincenzo

Oncogene

2022 Volume 41, Issue 38, Page(s) 4371–4384

Abstract: Transcriptomic analyses of pancreatic ductal adenocarcinoma (PDAC) have identified two major epithelial subtypes with distinct biology and clinical behaviours. Here, we aimed to clarify the role of FGFR1 and FGFR4 in the definition of aggressive PDAC ... ...

Abstract	Transcriptomic analyses of pancreatic ductal adenocarcinoma (PDAC) have identified two major epithelial subtypes with distinct biology and clinical behaviours. Here, we aimed to clarify the role of FGFR1 and FGFR4 in the definition of aggressive PDAC phenotypes. We found that the expression of FGFR4 is exclusively detected in epithelial cells, significantly elevated in the classical PDAC subtype, and associates with better outcomes. In highly aggressive basal-like/squamous PDAC, reduced FGFR4 expression aligns with hypermethylation of the gene and lower levels of histone marks associated with active transcription in its regulatory regions. Conversely, FGFR1 has more promiscuous expression in both normal and malignant pancreatic tissues and is strongly associated with the EMT phenotype but not with the basal-like cell lineage. Regardless of the genetic background, the increased proliferation of FGFR4-depleted PDAC cells correlates with hyperactivation of the mTORC1 pathway both in vitro and in vivo. Downregulation of FGFR4 in classical cell lines invariably leads to the enrichment of basal-like/squamous gene programs and is associated with either partial or full switch of phenotype. In sum, we show that endogenous levels of FGFR4 limit the malignant phenotype of PDAC cells. Finally, we propose FGFR4 as a valuable marker for the stratification of PDAC patients.
MeSH term(s)	Carcinoma, Pancreatic Ductal/pathology ; Carcinoma, Squamous Cell ; Humans ; Mechanistic Target of Rapamycin Complex 1/genetics ; Pancreatic Neoplasms/pathology ; Phenotype ; Receptor, Fibroblast Growth Factor, Type 4/genetics ; Pancreatic Neoplasms
Chemical Substances	FGFR4 protein, human (EC 2.7.10.1) ; Receptor, Fibroblast Growth Factor, Type 4 (EC 2.7.10.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2022-08-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-022-02432-5
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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