Trop-2 inhibits prostate cancer cell adhesion to fibronectin through the β1 integrin-RACK1 axis.

Trop-2 is a transmembrane glycoprotein upregulated in several human carcinomas, including prostate cancer (PrCa). Trop-2 has been suggested to regulate cell-cell adhesion, given its high homology with the other member of the Trop family, Trop-1/EpCAM, and its ability to bind the tight junction proteins claudin-1 and claudin-7. However, a role for Trop-2 in cell adhesion to the extracellular matrix has never been postulated. Here, we show for the first time that Trop-2 expression in PrCa cells correlates with their aggressiveness. Using either shRNA-mediated silencing of Trop-2 in cells that endogenously express it, or ectopic expression of Trop-2 in cells that do not express it, we show that Trop-2 inhibits PrCa cell adhesion to fibronectin (FN). In contrast, expression of another transmembrane receptor, α(v) β(5) integrin, does not affect cell adhesion to this ligand. We find that Trop-2 does not modulate either protein or activation levels of the prominent FN receptors, β(1) integrins, but acts through increasing β(1) association with the adaptor molecule RACK1 and redistribution of RACK1 to the cell membrane. As a result of Trop-2 expression, we also observe activation of Src and FAK, known to occur upon β(1) -RACK1 interaction. These enhanced Src and FAK activities are not mediated by changes in either the activity of IGF-IR, which is known to bind RACK1, or IGF-IR\u27s ability to associate with β(1) integrins. In summary, our data demonstrate that the transmembrane receptor Trop-2 is a regulator of PrCa cell adhesion to FN through activation of the β(1) integrin-RACK1-FAK-Src signaling axis

Potential novel therapy targets in neuroendocrine carcinomas of the breast

Neuroendocrine carcinoma (NEC) of the breast is a rare, special type of breast cancer, reportedly constituting 2% to 5% of all breast cancers. Although breast NEC does not have a specific targeted therapy, several new targeted therapies based on specific biomarkers were recently investigated in the NEC of lung and in other types of breast carcinoma, which may provide guidance to their feasibility in breast NEC. Twenty breast NECs were profiled for biomarkers of therapy including antibody-drug conjugates (DLL3, TROP-2, and FOLR1), histone deacetylase (H3K36Me3) inhibitors, tropomyosin receptor kinases (NTRK1/2/3 gene fusions) targeted inhibitors, alkylating agents (MGMT), and immune checkpoint inhibitors (PD-L1, TMB, and MSI) using immunohistochemistry and DNA/RNA next-generation sequencing assays. Predictive expression of TROP-2, FOLR1, and H3K36Me3 were detected in different subsets of tumors and may pave the way for development of novel targeted therapies in some patients with breast NECs. There was no evidence of DLL3 expression, NTRK gene fusions, or MGMT hypermethylation. No biomarkers predictive of immune checkpoint inhibitor efficacy (programmed death-ligand 1 expression, tumor mutational burden, microsatellite instability) were identified. FGFR and CCND1 gene amplifications were detected in isolated cases. This study identified several potential targets for novel therapies in breast NEC, including farletuzumab and mirvetuximab soravtansine (FOLR1), sacituzumab govitecan (TROP-2), and HDAC inhibitors (H3K36Me3). In some cases, CCND1 gene amplification may indicate the usefulness of investigational therapies. The reported results should serve as an early indication of potential clinical relevance in selected patients with breast NEC

Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications.

Trop2 is a transmembrane glycoprotein encoded by the Tacstd2 gene. It is an intracellular calcium signal transducer that is differentially expressed in many cancers. It signals cells for self-renewal, proliferation, invasion, and survival. It has stem cell-like qualities. Trop2 is expressed in many normal tissues, though in contrast, it is overexpressed in many cancers and the overexpression of Trop2 is of prognostic significance. Several ligands have been proposed that interact with Trop2. Trop2 signals the cells via different pathways and it is transcriptionally regulated by a complex network of several transcription factors. Trop2 expression in cancer cells has been correlated with drug resistance. Several strategies target Trop2 on cancer cells that include antibodies, antibody fusion proteins, chemical inhibitors, nanoparticles, etc. The in vitro studies and pre-clinical studies, using these various therapeutic treatments, have resulted in significant inhibition of tumor cell growth both in vitro and in vivo in mice. A clinical study is underway using IMMU-132 (hrS7 linked to SN38) in patients with epithelial cancers. This review describes briefly the various characteristics of cancer cells overexpressing Trop2 and the potential application of Trop2 as both a prognostic biomarker and as a therapeutic target to reverse resistance

Tropical totally positive matrices

We investigate the tropical analogues of totally positive and totally nonnegative matrices. These arise when considering the images by the nonarchimedean valuation of the corresponding classes of matrices over a real nonarchimedean valued field, like the field of real Puiseux series. We show that the nonarchimedean valuation sends the totally positive matrices precisely to the Monge matrices. This leads to explicit polyhedral representations of the tropical analogues of totally positive and totally nonnegative matrices. We also show that tropical totally nonnegative matrices with a finite permanent can be factorized in terms of elementary matrices. We finally determine the eigenvalues of tropical totally nonnegative matrices, and relate them with the eigenvalues of totally nonnegative matrices over nonarchimedean fields.Comment: The first author has been partially supported by the PGMO Program of FMJH and EDF, and by the MALTHY Project of the ANR Program. The second author is sported by the French Chateaubriand grant and INRIA postdoctoral fellowshi

Human prostate sphere-forming cells represent a subset of basal epithelial cells capable of glandular regeneration in vivo.

BackgroundProstate stem/progenitor cells function in glandular development and maintenance. They may be targets for tumor initiation, so characterization of these cells may have therapeutic implications. Cells from dissociated tissues that form spheres in vitro often represent stem/progenitor cells. A subset of human prostate cells that form prostaspheres were evaluated for self-renewal and tissue regeneration capability in the present study.MethodsProstaspheres were generated from 59 prostatectomy specimens. Lineage marker expression and TMPRSS-ERG status was determined via immunohistochemistry and fluorescence in situ hybridization (FISH). Subpopulations of prostate epithelial cells were isolated by cell sorting and interrogated for sphere-forming activity. Tissue regeneration potential was assessed by combining sphere-forming cells with rat urogenital sinus mesenchyme (rUGSM) subcutaneously in immunocompromised mice.ResultsProstate tissue specimens were heterogeneous, containing both benign and malignant (Gleason 3-5) glands. TMPRSS-ERG fusion was found in approximately 70% of cancers examined. Prostaspheres developed from single cells at a variable rate (0.5-4%) and could be serially passaged. A basal phenotype (CD44+CD49f+CK5+p63+CK8-AR-PSA-) was observed among sphere-forming cells. Subpopulations of prostate cells expressing tumor-associated calcium signal transducer 2 (Trop2), CD44, and CD49f preferentially formed spheres. In vivo implantation of sphere-forming cells and rUGSM regenerated tubular structures containing discreet basal and luminal layers. The TMPRSS-ERG fusion was absent in prostaspheres derived from fusion-positive tumor tissue, suggesting a survival/growth advantage of benign prostate epithelial cells.ConclusionHuman prostate sphere-forming cells self-renew, have tissue regeneration capability, and represent a subpopulation of basal cells

The family "Thelypteridaceae" in Europe

Thelypteridaceae are mainly tropical ferns, the total number of species is about one thousand. The five European species represent five different groups, each of which has recently been accorded generic status. Thelypteris palustris Schott (including three varieties) extends throughout north temperate regions, with a closely allied species south of the equator; chromosome number n=35. Phaegopteris connectilis (Michx) Watt (triploid with base number 30) and Oreopteris limbosperma (All.) Holub (n=34) are members of small genera confined to north temperate regions. Stegnogramma pozoi (Lag.) K. Iwats. (n=36) represents a genus of 12-15 species, mainly in Africa and Asia, with one in Mexico. Christella dentata (Forsk.) Brownsey & Jermy is a wide-ranging and variable tetraploid species of a pantropic genus (c. 60 spp) the centre of distribution of wich appears to be Burma-Assam (base number 36).The genus Cyclosurus (s. str.) comprises a small pantropic group of species with grow (like Thelypteris) in open permanently swampy ground; I belive Cyclosorus and Thelypteris to be closely related genera. Stegnogramma is related to Sphaerostephanos which (in arrangement of Holttum) is the most diversified genus in the Old World with c. 140 spp. in Malesia . Christella is probably also related to Sphaerostephanos though less nearly than Stegnogramma.Las Thelypteridaceae son helechos principalmente tropicales, comprende aproximadamente mil especies. Las cinco especies europeas representan cinco grupos diferentes cada uno de los cuales ha recibido recientemente un estatus genérico. Thelypteris palustris Schott (incluyendo tres variedades) se extiende por las regiones templadas del norte, con un conjunto de especies próximas al sur del ecuador; el número cromosómico es n=35. Phegopteris connectilis (Michx) Watt (triploide con número básico 30) y Oreopteris limbosperma (All.) Holub (n=34), son miembros de pequeños géneros confinados a las regiones templadas del norte.Stegnogramma pozoi (Lag.) K. Iwats. (n=36) representa un género de 12-15 especies principalmente de Africa y Asia con una en Méjico. Christe lla dentata (Forsk.) Brownsey & Jermy es una variable especie tetraploide de amplia distribución cuyo género pantropical (cerca de 60 especies) parece tener su centro de distribución en Burma-Assam (número básico 36).El género Cyclosorus (s. str.) comprende un pequeño grupo de especies pantropicales que viven en llanuras permanentemente pantanosas. Creemos que Cyclosorus y Thelypteris son géneros muy emparentados. Stegnogramma está relacionado con Sphaerostephanos, el cual (en la ordenación de Holttum) es el género más diversificado en el viejo mundo con cerca de 140 especies en Malasia Christella esta tambien relacionada,probablemente, con Sphaerostephanos aunque su proximidad es menor que la mantenida con Stegnogramma

Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells

The aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs), cancers occurring increasingly in children to young adults, is poorly understood. We present a transplantable tumour line, maintained in immune-compromised mice, and validate it as a bona fide model of hFL-HCCs by multiple methods. RNA-seq analysis confirms the presence of a fusion transcript (DNAJB1-PRKACA) characteristic of hFL-HCC tumours. The hFL-HCC tumour line is highly enriched for cancer stem cells as indicated by limited dilution tumourigenicity assays, spheroid formation and flow cytometry. Immunohistochemistry on the hFL-HCC model, with parallel studies on 27 primary hFL-HCC tumours, provides robust evidence for expression of endodermal stem cell traits. Transcriptomic analyses of the tumour line and of multiple, normal hepatic lineage stages reveal a gene signature for hFL-HCCs closely resembling that of biliary tree stem cells-newly discovered precursors for liver and pancreas. This model offers unprecedented opportunities to investigate mechanisms underlying hFL-HCCs pathogenesis and potential therapies