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Book ; Conference proceedings: Cell adhesion and migration in inflammation and caner

Pals, Steven T.

[the Second Amsterdam Zoo Meeting on Cell Adhesion and Migration in Inflammation and Cancer was held in Amsterdam, The Netherlands, October 22 - 25, 1997]

(Cell adhesion & communication ; 6,2/3 : Proceedings issue)

1998

Event/congress	Meeting on Cell Adhesion and Migration in Inflammation and Cancer (2, 1997, Amsterdam)
Author's details	guest eds.: Steven T. Pals
Series title	Cell adhesion & communication ; 6,2/3 : Proceedings issue
Collection
Language	English
Size	S. 83 - 276 : Ill., graph. Darst.
Publisher	Harwood
Publishing place	Yverdon
Publishing country	Switzerland
Document type	Book ; Conference proceedings
HBZ-ID	HT011096560
Database	Catalogue ZB MED Medicine, Health

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Article ; Online: Towards genomic-based prognostication and precision therapy for diffuse large B-cell lymphoma.

Minderman, Marthe / Pals, Steven T

Haematologica

2020 Volume 105, Issue 9, Page(s) 2194–2196

MeSH term(s)	Genomics ; Humans ; Lymphoma, Large B-Cell, Diffuse/diagnosis ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Lymphoma, Large B-Cell, Diffuse/genetics ; Mutation ; Prognosis
Language	English
Publishing date	2020-09-01
Publishing country	Italy
Document type	Editorial ; Comment
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2020.255448
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Article ; Online: Syndecan-1 and stromal heparan sulfate proteoglycans: key moderators of plasma cell biology and myeloma pathogenesis.

Ren, Zemin / Spaargaren, Marcel / Pals, Steven T

Blood

2021 Volume 137, Issue 13, Page(s) 1713–1718

Abstract: Plasma cells no longer express a B-cell antigen receptor and are hence deprived of signals crucial for survival throughout B-cell development. Instead, normal plasma cells, as well as their malignant myeloma counterparts, heavily rely on communication ... ...

Abstract	Plasma cells no longer express a B-cell antigen receptor and are hence deprived of signals crucial for survival throughout B-cell development. Instead, normal plasma cells, as well as their malignant myeloma counterparts, heavily rely on communication with the bone marrow (BM) microenvironment for survival. The plasma cell heparan sulfate proteoglycan (HSPG) syndecan-1 (CD138) and HSPGs in the BM microenvironment act as master regulators of this communication by co-opting specific growth and survival factors from the BM niche. This designates syndecan-1/HSPGs and their synthesis machinery as potential treatment targets in multiple myeloma.
MeSH term(s)	Animals ; Bone Marrow/metabolism ; Bone Marrow/pathology ; Heparitin Sulfate/metabolism ; Humans ; Multiple Myeloma/metabolism ; Multiple Myeloma/pathology ; Plasma Cells/metabolism ; Plasma Cells/pathology ; Proteoglycans/metabolism ; Syndecan-1/metabolism ; Tumor Microenvironment
Chemical Substances	Proteoglycans ; SDC1 protein, human ; Syndecan-1 ; Heparitin Sulfate (9050-30-0)
Language	English
Publishing date	2021-01-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2020008188
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Article ; Online: The dual HCK/BTK inhibitor KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma.

Lantermans, Hildo C / Ma, Fangxue / Kuil, Annemieke / van Kesteren, Sanne / Yasinoglu, Sevtap / Yang, Guang / Buhrlage, Sara J / Wang, Jinhua / Gray, Nathanael S / Kersten, Marie José / Treon, Steven P / Pals, Steven T / Spaargaren, Marcel

Leukemia

2024

Abstract: Although Bruton's tyrosine kinase (BTK) inhibitors (BTKi) have significantly improved patient prognosis, mantle cell lymphoma (MCL) is still considered incurable due to primary and acquired resistance. We have recently shown that aberrant expression of ... ...

Abstract	Although Bruton's tyrosine kinase (BTK) inhibitors (BTKi) have significantly improved patient prognosis, mantle cell lymphoma (MCL) is still considered incurable due to primary and acquired resistance. We have recently shown that aberrant expression of the Src-family tyrosine kinase hematopoietic cell kinase (HCK) in MCL correlates with poor prognosis, and that genetic HCK perturbation impairs growth and integrin-mediated adhesion of MCL cells. Here, we show that KIN-8194, a dual inhibitor of BTK and HCK with in vivo activity against Myd88-L265P-driven diffuse large B-cell lymphoma and Waldenström Macroglobulinemia, has a potent growth inhibitory effect in MCL cell lines and primary MCL cells, irrespective of their sensitivity to BTKi (ibrutinib and acalabrutinib). In BTKi-resistant cells this is mediated by inhibition of HCK, which results in repression of AKT-S6 signaling. In addition, KIN-8194 inhibits integrin-mediated adhesion of BTKi-sensitive and insensitive MCL cells to fibronectin and stromal cells in an HCK-dependent manner. Finally, we show that MCL cells with acquired BTKi resistance retain their sensitivity to KIN-8194. Taken together, our data demonstrate that KIN-8194 inhibits growth and integrin-mediated adhesion of BTKi-sensitive MCL cells, as well as MCL cells with primary or acquired BTKi resistance. This renders KIN-8194 a promising novel treatment for MCL patients.
Language	English
Publishing date	2024-03-07
Publishing country	England
Document type	Journal Article
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-024-02207-9
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Article ; Online: Hepatocyte growth factor/MET and CD44 in colorectal cancer: partners in tumorigenesis and therapy resistance.

Joosten, Sander P J / Spaargaren, Marcel / Clevers, Hans / Pals, Steven T

Biochimica et biophysica acta. Reviews on cancer

2020 Volume 1874, Issue 2, Page(s) 188437

Abstract: Intestinal epithelial self-renewal is a tightly controlled process, which is critically dependent on WNT signalling. Aberrant activation of the WNT pathway in intestinal stem cells (ISCs) results in constitutive transcription of target genes, which ... ...

Abstract	Intestinal epithelial self-renewal is a tightly controlled process, which is critically dependent on WNT signalling. Aberrant activation of the WNT pathway in intestinal stem cells (ISCs) results in constitutive transcription of target genes, which collectively drive malignant transformation in colorectal cancer (CRC). However, the contribution of individual genes to intestinal homeostasis and tumorigenesis often is incompletely defined. Here, we discuss converging evidence indicating that the receptor tyrosine kinase (RTK) MET and its ligand hepatocyte growth factor (HGF) play a major role in the intestinal damage response, as well as in intestinal tumorigenesis, by controlling the proliferation, survival, motility, and stemness of normal and neoplastic intestinal epithelial cells. These activities of MET are promoted by specific CD44 isoforms expressed by ISCs. The accrued data indicate that MET and the EGFR have overlapping roles in the biology of intestinal epithelium and that metastatic CRCs can exploit this redundancy to escape from EGFR-targeted treatments, co-opting HGF/MET/CD44v signalling. Hence, targeting both pathways may be required for effective treatment of (a subset of) CRCs. The RTK identity of MET, the distinctive 'plasminogen-like' structure and activation mode of its ligand HGF, and the specific collaboration of MET with CD44, provide several unique targeting options, which merit further exploration.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/metabolism ; Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic/drug effects ; Hepatocyte Growth Factor/metabolism ; Humans ; Hyaluronan Receptors/metabolism ; Intestinal Mucosa/metabolism ; Neoplasm Invasiveness ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Proto-Oncogene Proteins c-met/metabolism ; Wnt Signaling Pathway/drug effects
Chemical Substances	Antineoplastic Agents ; CD44 protein, human ; HGF protein, human ; Hyaluronan Receptors ; Hepatocyte Growth Factor (67256-21-7) ; MET protein, human (EC 2.7.10.1) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1)
Language	English
Publishing date	2020-09-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2918802-7
ISSN	1879-2561 ; 0304-419X
ISSN (online)	1879-2561
ISSN	0304-419X
DOI	10.1016/j.bbcan.2020.188437
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Article ; Online: A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways.

de Rooij, Martin F M / Thus, Yvonne J / Swier, Nathalie / Beijersbergen, Roderick L / Pals, Steven T / Spaargaren, Marcel

Nature communications

2022 Volume 13, Issue 1, Page(s) 2136

Abstract: The clinical introduction of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which targets B-cell antigen-receptor (BCR)-controlled integrin-mediated retention of malignant B cells in their growth-supportive lymphoid organ microenvironment, ... ...

Abstract	The clinical introduction of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which targets B-cell antigen-receptor (BCR)-controlled integrin-mediated retention of malignant B cells in their growth-supportive lymphoid organ microenvironment, provided a major breakthrough in lymphoma and leukemia treatment. Unfortunately, a significant subset of patients is intrinsically resistant or acquires resistance against ibrutinib. Here, to discover novel therapeutic targets, we present an unbiased loss-of-adhesion CRISPR-Cas9 knockout screening method to identify proteins involved in BCR-controlled integrin-mediated adhesion. Illustrating the validity of our approach, several kinases with an established role in BCR-controlled adhesion, including BTK and PI3K, both targets for clinically applied inhibitors, are among the top hits of our screen. We anticipate that pharmacological inhibitors of the identified targets, e.g. PAK2 and PTK2B/PYK2, may have great clinical potential as therapy for lymphoma and leukemia patients. Furthermore, this screening platform is highly flexible and can be easily adapted to identify cell adhesion-regulatory proteins and signaling pathways for other stimuli, adhesion molecules, and cell types.
MeSH term(s)	Agammaglobulinaemia Tyrosine Kinase/genetics ; Agammaglobulinaemia Tyrosine Kinase/metabolism ; CRISPR-Cas Systems ; Cell Adhesion/genetics ; Humans ; Integrins/metabolism ; Leukemia/drug therapy ; Protein Kinase Inhibitors/therapeutic use ; Signal Transduction ; Tumor Microenvironment
Chemical Substances	Integrins ; Protein Kinase Inhibitors ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2)
Language	English
Publishing date	2022-04-19
Publishing country	England
Document type	Journal Article ; 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/s41467-022-29835-y
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Article ; Online: Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options.

van Andel, Harmen / Kocemba, Kinga A / Spaargaren, Marcel / Pals, Steven T

Leukemia

2019 Volume 33, Issue 5, Page(s) 1063–1075

Abstract: Aberrant activation of Wnt/β-catenin signaling plays a central role in the pathogenesis of a wide variety of malignancies and is typically caused by mutations in core Wnt pathway components driving constitutive, ligand-independent signaling. In multiple ... ...

Abstract	Aberrant activation of Wnt/β-catenin signaling plays a central role in the pathogenesis of a wide variety of malignancies and is typically caused by mutations in core Wnt pathway components driving constitutive, ligand-independent signaling. In multiple myelomas (MMs), however, these pathway intrinsic mutations are rare despite the fact that most tumors display aberrant Wnt pathway activity. Recent studies indicate that this activation is caused by genetic and epigenetic lesions of Wnt regulatory components, sensitizing MM cells to autocrine Wnt ligands and paracrine Wnts emanating from the bone marrow niche. These include deletion of the tumor suppressor CYLD, promotor methylation of the Wnt antagonists WIF1, DKK1, DKK3, and sFRP1, sFRP2, sFRP4, sFRP5, as well as overexpression of the co-transcriptional activator BCL9 and the R-spondin receptor LGR4. Furthermore, Wnt activity in MM is strongly promoted by interaction of both Wnts and R-spondins with syndecan-1 (CD138) on the MM cell-surface. Functionally, aberrant canonical Wnt signaling plays a dual role in the pathogenesis of MM: (I) it mediates proliferation, migration, and drug resistance of MM cells; (II) MM cells secrete Wnt antagonists that contribute to the development of osteolytic lesions by impairing osteoblast differentiation. As discussed in this review, these insights into the causes and consequences of aberrant Wnt signaling in MM will help to guide the development of targeting strategies. Importantly, since Wnt signaling in MM cells is largely ligand dependent, it can be targeted by drugs/antibodies that act upstream in the pathway, interfering with Wnt secretion, sequestering Wnts, or blocking Wnt (co)receptors.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Autocrine Communication ; Biomarkers ; Bone Diseases/etiology ; Bone Diseases/metabolism ; Epigenesis, Genetic ; Gene Deletion ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Silencing ; Humans ; Ligands ; Molecular Targeted Therapy ; Multiple Myeloma/drug therapy ; Multiple Myeloma/etiology ; Multiple Myeloma/metabolism ; Multiple Myeloma/pathology ; Paracrine Communication ; Protein Binding ; Protein Processing, Post-Translational ; Wnt Signaling Pathway/drug effects
Chemical Substances	Antineoplastic Agents ; Biomarkers ; Ligands
Language	English
Publishing date	2019-02-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-019-0404-1
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Article ; Online: Sinonasal DLBCL: molecular profiling identifies subtypes with distinctive prognosis and targetable genetic features.

Eriksen, Patrick R G / de Groot, Fleur / Clasen-Linde, Erik / de Nully Brown, Peter / de Groen, Ruben / Melchior, Linea C / Maier, Andrea D / Minderman, Marthe / Vermaat, Joost S P / von Buchwald, Christian / Pals, Steven T / Heegaard, Steffen

Blood advances

2024 Volume 8, Issue 8, Page(s) 1946–1957

Abstract: Abstract: Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare lymphoma with a variable prognosis and a unique relapse/dissemination pattern involving the central nervous system and skin. The underlying molecular mechanisms leading to ... ...

Abstract	Abstract: Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare lymphoma with a variable prognosis and a unique relapse/dissemination pattern involving the central nervous system and skin. The underlying molecular mechanisms leading to this heterogeneity and progression pattern remain uncharted, hampering patient-tailored treatment. To investigate associated mechanisms, we analyzed clinical data and used immunohistochemistry, gene-expression profiling, cytogenetics, and next-generation sequencing in a cohort of 117 patients with PSDLBCL. The distribution in cell-of-origin (COO) was 68 (58%) activated B-cell (ABC), 44 (38%) germinal center B-cell (GCB), and 5 (4%) unclassifiable. COO was significantly associated with progression-free survival (PFS) and lymphoma-specific mortality (LSM) in both the overall cohort (5-year PFS: ABC, 43% vs GCB, 73%; LSM: ABC, 45% vs GCB, 14%) and in the subgroup of patients receiving immunochemotherapy (5-year PFS: ABC, 55% vs GCB, 85%; LSM: ABC, 28% vs GCB, 0%). ABC lymphomas were mainly MCD class, showing a high prevalence of MYD88 (74%) and CD79B (35%) mutations compared with GCB lymphomas (MYD88 23%; CD79B 10%) (P < .01). The ABC subtype frequently displayed cMYC/BCL2 coexpression (76% vs 18% GCB; P < .001) and HLA-II loss (48% vs 10% GCB; P < .001). PD-L1 expression and copy-number alterations were rare. All lymphomas were Epstein-Barr virus-negative. Our data suggest molecular profiling as a potent tool for detecting prognostic subgroups in PSDLBCL, exposing links to known relapse/dissemination sites. The ABC subgroup's MCD genetic features, shared with lymphomas at other nonprofessional lymphoid sites, make them potential candidates for targeted B-cell and toll-like receptor signaling therapy.
MeSH term(s)	Humans ; Epstein-Barr Virus Infections ; Myeloid Differentiation Factor 88/metabolism ; Herpesvirus 4, Human/metabolism ; Neoplasm Recurrence, Local ; Prognosis ; Lymphoma, Large B-Cell, Diffuse/diagnosis ; Lymphoma, Large B-Cell, Diffuse/genetics ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Recurrence
Chemical Substances	Myeloid Differentiation Factor 88
Language	English
Publishing date	2024-02-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023011517
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Article ; Online: MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas.

Minderman, Marthe / Lantermans, Hildo C / Grüneberg, Leonie J / Cillessen, Saskia A G M / Bende, Richard J / van Noesel, Carel J M / Kersten, Marie José / Pals, Steven T / Spaargaren, Marcel

Blood cancer journal

2023 Volume 13, Issue 1, Page(s) 37

Abstract: The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is a protease and scaffold protein essential in propagating B-cell receptor (BCR) signaling to NF-κB. The deubiquitinating enzyme cylindromatosis (CYLD) is a recently discovered MALT1 target ... ...

Abstract	The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is a protease and scaffold protein essential in propagating B-cell receptor (BCR) signaling to NF-κB. The deubiquitinating enzyme cylindromatosis (CYLD) is a recently discovered MALT1 target that can negatively regulate NF-κB activation. Here, we show that low expression of CYLD is associated with inferior prognosis of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) patients, and that chronic BCR signaling propagates MALT1-mediated cleavage and, consequently, inactivation and rapid proteasomal degradation of CYLD. Ectopic overexpression of WT CYLD or a MALT1-cleavage resistant mutant of CYLD reduced phosphorylation of IκBα, repressed transcription of canonical NF-κB target genes and impaired growth of BCR-dependent lymphoma cell lines. Furthermore, silencing of CYLD expression rendered BCR-dependent lymphoma cell lines less sensitive to inhibition of NF-κΒ signaling and cell proliferation by BCR pathway inhibitors, e.g., the BTK inhibitor ibrutinib, indicating that these effects are partially mediated by CYLD. Taken together, our findings identify an important role for MALT1-mediated CYLD cleavage in BCR signaling, NF-κB activation and cell proliferation, which provides novel insights into the underlying molecular mechanisms and clinical potential of inhibitors of MALT1 and ubiquitination enzymes as promising therapeutics for DLBCL, MCL and potentially other B-cell malignancies.
MeSH term(s)	Humans ; Caspases/metabolism ; Deubiquitinating Enzyme CYLD/genetics ; Deubiquitinating Enzyme CYLD/metabolism ; Lymphoma, Large B-Cell, Diffuse/pathology ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/genetics ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/metabolism ; NF-kappa B/metabolism ; Receptors, Antigen, B-Cell ; Signal Transduction/physiology
Chemical Substances	Caspases (EC 3.4.22.-) ; CYLD protein, human (EC 3.4.19.12) ; Deubiquitinating Enzyme CYLD (EC 3.4.19.12) ; MALT1 protein, human (EC 3.4.22.-) ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein (EC 3.4.22.-) ; NF-kappa B ; Receptors, Antigen, B-Cell
Language	English
Publishing date	2023-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2600560-8
ISSN	2044-5385 ; 2044-5385
ISSN (online)	2044-5385
ISSN	2044-5385
DOI	10.1038/s41408-023-00809-7
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Article ; Online: The oncogenic human B-cell lymphoma MYD88 L265P mutation genocopies activation by phosphorylation at the Toll/interleukin-1 receptor (TIR) domain.

Minderman, Marthe / Lantermans, Hildo / van der Zwaan, Carmen / Hoogendijk, Arie J / van den Biggelaar, Maartje / Kersten, Marie José / Spaargaren, Marcel / Pals, Steven T

Blood cancer journal

2023 Volume 13, Issue 1, Page(s) 125

Abstract: MYD88 is the key signaling adaptor-protein for Toll-like and interleukin-1 receptors. A somatic L265P mutation within the Toll/interleukin-1 receptor (TIR) domain of MYD88 is found in 90% of Waldenström macroglobulinemia cases and in a significant subset ...

Abstract	MYD88 is the key signaling adaptor-protein for Toll-like and interleukin-1 receptors. A somatic L265P mutation within the Toll/interleukin-1 receptor (TIR) domain of MYD88 is found in 90% of Waldenström macroglobulinemia cases and in a significant subset of diffuse large B-cell lymphomas. MYD88-L265P strongly promotes NF-κB pathway activation, JAK-STAT signaling and lymphoma cell survival. Previous studies have identified other residues of the TIR-domain crucially involved in NF-κB activation, including serine 257 (S257), indicating a potentially important physiological role in the regulation of MYD88 activation. Here, we demonstrate that MYD88 S257 is phosphorylated in B-cell lymphoma cells and that this phosphorylation is required for optimal TLR-induced NF-κB activation. Furthermore, we demonstrate that a phosphomimetic MYD88-S257D mutant promotes MYD88 aggregation, IRAK1 phosphorylation, NF-κB activation and cell growth to a similar extent as the oncogenic L265P mutant. Lastly, we show that expression of MYD88-S257D can rescue cell growth upon silencing of endogenous MYD88-L265P expression in lymphoma cells addicted to oncogenic MYD88 signaling. Our data suggest that the L265P mutation promotes TIR domain homodimerization and NF-κB activation by copying the effect of MY88 phosphorylation at S257, thus providing novel insights into the molecular mechanism underlying the oncogenic activity of MYD88-L265P in B-cell malignancies.
MeSH term(s)	Humans ; Adaptor Proteins, Signal Transducing ; Lymphoma, Large B-Cell, Diffuse ; Myeloid Differentiation Factor 88/genetics ; NF-kappa B ; Phosphorylation
Chemical Substances	Adaptor Proteins, Signal Transducing ; Myeloid Differentiation Factor 88 ; NF-kappa B ; MYD88 protein, human
Language	English
Publishing date	2023-08-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2600560-8
ISSN	2044-5385 ; 2044-5385
ISSN (online)	2044-5385
ISSN	2044-5385
DOI	10.1038/s41408-023-00896-6
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