Mitomycin C and its analog trigger cytotoxicity in MCF-7 and K562 cancer cells through the regulation of RAS and MAPK/ERK pathways.

Mitomycin C (MC) is an anti-cancer drug which functions by forming interstrand crosslinks (ICLs) between opposing DNA strands. MC analog, 10-decarbamoyl mitomycin C (DMC), unlike MC, has stronger cytotoxic effects on cancer cells with TP53 mutation. We previously demonstrated that MC/DMC could activate p21 in MCF-7 (TP53-proficient) and K562 (TP53 deficient) cells in a TP53-independent mode.

PTPN13 Participates in the Regulation of Epithelial-Mesenchymal Transition and Platinum Sensitivity in High-Grade Serous Ovarian Carcinoma Cells.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological cancers in Western countries. High-Grade Serous Ovarian Carcinoma (HGSOC) accounts for 60-70% of EOC and is the most aggressive subtype. Reduced PTPN13 expression levels have been previously correlated with worse prognosis in HGSOC.

Protein Phosphorylation in Cancer: Unraveling the Signaling Pathways.

The discovery of protein kinase playing key roles in cancer formation and progression has triggered great interest and stimulated intense research on signaling pathways to develop targeted treatments, as well as to identify prognostic and predictive biomarkers [...

[Resistance to BRAF inhibitors: A lesson from clinical observations].

The MAPK/ERK pathway is an essential intracellular signaling pathway. Its deregulation is involved in tumor transformation and progression. The discovery of activating mutations of BRAF in various cancers has opened new therapeutic avenues with BRAF protein kinase inhibitors.

Comparison of SYK Signaling Networks Reveals the Potential Molecular Determinants of Its Tumor-Promoting and Suppressing Functions.

Spleen tyrosine kinase (SYK) can behave as an oncogene or a tumor suppressor, depending on the cell and tissue type. As pharmacological SYK inhibitors are currently evaluated in clinical trials, it is important to gain more information on the molecular mechanisms underpinning these opposite roles. To this aim, we reconstructed and compared its signaling networks using phosphoproteomic data from breast cancer and Burkitt lymphoma cell lines where SYK behaves as a tumor suppressor and promoter.

Dual Role of the PTPN13 Tyrosine Phosphatase in Cancer.

In this review article, we present the current knowledge on PTPN13, a class I non-receptor protein tyrosine phosphatase identified in 1994. We focus particularly on its role in cancer, where PTPN13 acts as an oncogenic protein and also a tumor suppressor. To try to understand these apparent contradictory functions, we discuss PTPN13 implication in the FAS and oncogenic tyrosine kinase signaling pathways and in the associated biological activities, as well as its post-transcriptional and epigenetic regulation.

PTPN13 induces cell junction stabilization and inhibits mammary tumor invasiveness.

Clinical data suggest that the protein tyrosine phosphatase PTPN13 exerts an anti-oncogenic effect. Its exact role in tumorigenesis remains, however, unclear due to its negative impact on FAS receptor-induced apoptosis. We crossed transgenic mice deleted for PTPN13 phosphatase activity with mice that overexpress human HER2 to assess the exact role of PTPN13 in tumor development and aggressiveness.

The therapeutic effectiveness of Lu-lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2/M cell cycle arrest.

Some patients with B-cell non-Hodkin lymphoma Lymphoma (NHL) become refractory to rituximab (anti-CD20 antibody) therapy associated with chemotherapy. Here, the effect of the anti-CD37 antibody-radionuclide conjugate lutetium-177 (Lu)-lilotomab (Betalutin) was investigated in preclinical models of NHL. In SCID mice bearing DOHH2 (transformed follicular lymphoma, FL) cell xenografts, Lu-lilotomab significantly delayed tumor growth, even at low activity (100 MBq/kg).

The Syk Kinase Promotes Mammary Epithelial Integrity and Inhibits Breast Cancer Invasion by Stabilizing the E-Cadherin/Catenin Complex.

While first discovered in immunoreceptor signaling, the Syk protein kinase behaves as a tumor and metastasis suppressor in epithelial cells. Its reduced expression in breast and other carcinomas is correlated with decreased survival and increased metastasis risk, but its action mechanism remains largely unknown. Using phosphoproteomics we found that Syk phosphorylated E-cadherin and α-, β-, and p120-catenins on multiple tyrosine residues that concentrate at intercellular junctions.

FKBP4 connects mTORC2 and PI3K to activate the PDK1/Akt-dependent cell proliferation signaling in breast cancer.

Among the FKBP family members, FKBP4 has been described to have a potential role in tumorigenesis, and as a putative tissue marker. We previously showed that FKBP4, an HSP90-associated co-chaperone, can elicit immune response as a tumor-specific antigen, and are overexpressed in breast cancer. In this study, we examined how loss of FKBP4 affect breast cancer progression and exploited protein interactomics to gain mechanistic insight into this process.

Network Reconstruction and Significant Pathway Extraction Using Phosphoproteomic Data from Cancer Cells.

Protein phosphorylation acts as an efficient switch controlling deregulated key signaling pathway in cancer. Computational biology aims to address the complexity of reconstructed networks but overrepresents well-known proteins and lacks information on less-studied proteins. A bioinformatic tool to reconstruct and select relatively small networks that connect signaling proteins to their targets in specific contexts is developed.

SYK Inhibition Potentiates the Effect of Chemotherapeutic Drugs on Neuroblastoma Cells in Vitro.

Neuroblastoma is a malignancy arising from the developing sympathetic nervous system and the most common and deadly cancer of infancy. New therapies are needed to improve the prognosis for high-risk patients and to reduce toxicity and late effects. Spleen tyrosine kinase (SYK) has previously been identified as a promising drug target in various inflammatory diseases and cancers but has so far not been extensively studied as a potential therapeutic target in neuroblastoma.

Phosphorylated Tyr142 β-catenin localizes to centrosomes and is regulated by Syk.

β-catenin is a central component of adherent junctions and a key effector of canonical Wnt signaling, in which dephosphorylated Ser/Thr β-catenin regulates gene transcription. β-catenin phosphorylation at Tyr142 (PTyr142 β-catenin), which is induced by receptor and Src family Tyr kinases, represents a previously described β-catenin switch from adhesive to migratory roles. In addition to classical β-catenin roles, phosphorylated Ser/Thr β-catenin and total β-catenin were involved in centrosomal functions, including mitotic spindle formation and centrosome separation.

High PTPN13 expression in high grade serous ovarian carcinoma is associated with a better patient outcome.

Background: Chromosome 4q loss of heterozygosity (LOH) is frequently observed in high-grade serous ovarian carcinoma (HGSOC). However, this LOH has not been clearly associated with the inactivation of any tumor suppressor gene(s). As the tumor suppressor gene is located on chromosome 4q21, we investigated its expression in HGSOC.

Detection of known and novel ALK fusion transcripts in lung cancer patients using next-generation sequencing approaches.

Rearrangements of the anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) represent a novel molecular target in a small subset of tumors. Although ALK rearrangements are usually assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), molecular approaches have recently emerged as relevant alternatives in routine laboratories. Here, we evaluated the use of two different amplicon-based next-generation sequencing (NGS) methods (AmpliSeq and ArcherFusionPlex) to detect ALK rearrangements, and compared these with IHC and FISH.

Reconstruction and signal propagation analysis of the Syk signaling network in breast cancer cells.

The ability to build in-depth cell signaling networks from vast experimental data is a key objective of computational biology. The spleen tyrosine kinase (Syk) protein, a well-characterized key player in immune cell signaling, was surprisingly first shown by our group to exhibit an onco-suppressive function in mammary epithelial cells and corroborated by many other studies, but the molecular mechanisms of this function remain largely unsolved. Based on existing proteomic data, we report here the generation of an interaction-based network of signaling pathways controlled by Syk in breast cancer cells.

Circulating Cell Free Tumor DNA Detection as a Routine Tool forLung Cancer Patient Management.

Circulating tumoral DNA (ctDNA), commonly named "liquid biopsy", has emerged as a new promising noninvasive tool to detect biomarker in several cancers including lung cancer. Applications involving molecular analysis of ctDNA in lung cancer have increased and encompass diagnosis, response to treatment, acquired resistance and prognosis prediction, while bypassing the problem of tumor heterogeneity. ctDNA may then help perform dynamic genetic surveillance in the era of precision medicine through indirect tumoral genomic information determination.

An integrated cell line-based discovery strategy identified follistatin and kallikrein 6 as serum biomarker candidates of breast carcinoma.

Unlabelled: Secreted proteins constitute a relevant source of putative cancer biomarkers. Here, we compared the secretome of a series of four genetically-related breast cancer cell lines as a model of aggressiveness using quantitative mass spectrometry. 537 proteins (59.

Adherens Junction and E-Cadherin complex regulation by epithelial polarity.

E-Cadherin-based Adherens Junctions (AJs) are a defining feature of all epithelial sheets. Through the homophilic association of E-Cadherin molecules expressed on neighboring cells, they ensure intercellular adhesion amongst epithelial cells, and regulate many key aspects of epithelial biology. While their adhesive role requires these structures to remain stable, AJs are also extremely plastic.

Centrosomal targeting of Syk kinase is controlled by its catalytic activity and depends on microtubules and the dynein motor.

The nonreceptor Syk kinase is detected in epithelial cells, where it acts as a tumor suppressor, in addition to its well-established role in immunoreceptor-based signal transduction in hematopoietic cells. Thus, several carcinomas and melanomas have subnormal concentrations of Syk. Although Syk is mainly localized at the plasma membrane, it is also present in centrosomes, where it is involved in the control of cell division.

Pro-cathepsin D interacts with the extracellular domain of the beta chain of LRP1 and promotes LRP1-dependent fibroblast outgrowth.

Interactions between cancer cells and fibroblasts are crucial in cancer progression. We have previously shown that the aspartic protease cathepsin D (cath-D), a marker of poor prognosis in breast cancer that is overexpressed and highly secreted by breast cancer cells, triggers mouse embryonic fibroblast outgrowth via a paracrine loop. Here, we show the requirement of secreted cath-D for human mammary fibroblast outgrowth using a three-dimensional co-culture assay with breast cancer cells that do or do not secrete pro-cath-D.

Cell membrane extensions, generated by mechanical constraint, are associated with a sustained lipid raft patching and an increased cell signaling.

Platelet activation triggers an imbalance in plasma membrane phospholipids by a specific aminophospholipid outflux, resulting in filopodia formation. Similarly, the addition of a phospholipid excess in the outer leaflet of the plasma membrane induces cellular extensions and actin polymerization. The implication of membrane microdomains in sustaining these mechanical constraints remains, however, unknown and was investigated in human platelets and mouse fibroblasts.

Characterization of centrosomal localization and dynamics of Cdc25C phosphatase in mitosis.

In mammalian cells, three Cdc25 phosphatases A, B, C coordinate cell cycle progression through activating dephosphorylation of Cyclin-dependent kinases. Whereas Cdc25B is believed to trigger entry into mitosis, Cdc25C is thought to act at a later stage of mitosis and in the nucleus. We report that a fraction of Cdc25C localises to centrosomes in a cell cycle-dependent fashion, as of late S phase and throughout G(2) and mitosis.

The Syk tyrosine kinase: a new negative regulator in tumor growth and progression.

The spleen tyrosine kinase Syk was long thought to be a hematopoietic cell-specific signaling molecule. Recent evidence demonstrated that it is also expressed by many non-hematopoietic cell types and that it plays a negative role in cancer. A significant drop in its expression was first observed during breast cancer progression, but an anomalous Syk expression has now also been evidenced in many other tumor types.

The Syk tyrosine kinase localizes to the centrosomes and negatively affects mitotic progression.

We showed previously that the spleen tyrosine kinase Syk is expressed by mammary epithelial cells and that it suppresses malignant growth of breast cancer cells. The exact molecular mechanism of its tumor-suppressive activity remains, however, to be identified. Here, we show that Syk colocalizes and copurifies with the centrosomal component gamma-tubulin and exhibits a catalytic activity within the centrosomes.