BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer

The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in protecting CSCs from cell death, where its inhibition with high doses of BH3 mimetics can induce apoptosis. Here, we screen a compound library for synergy with low-dose BCL-XL inhibitor A-1155463 to identify pathways that regulate sensitivity to BCL-XL inhibition and reveal that fibroblast growth factor receptor (FGFR)4 inhibition effectively sensitizes to A-1155463 both in vitro and in vivo. Mechanistically, we identify a rescue response that is activated upon BCL-XL inhibition and leads to rapid FGF2 secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1. FGFR4 inhibition prevents MCL-1 upregulation and thereby sensitizes CSCs to BCL-XL inhibition. Altogether, our findings suggest a cell transferable induction of a FGF2/FGFR4 rescue response in CRC that is induced upon BCL-XL inhibition and leads to MCL-1 upregulation

CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin

Limited therapeutic options are available for advanced colorectal cancer (CRC). Herein, we report that exposure to a neo-synthetic bis(indolyl)thiazole alkaloid analog, nortopsentin 234 (NORA234), leads to an initial reduction of proliferative and clonogenic potential of CRC sphere cells (CR-CSphCs), followed by an adaptive response selecting the CR-CSphC-resistant compartment. Cells spared by the treatment with NORA234 express high levels of CD44v6, associated with a constitutive activation of Wnt pathway. In CR-CSphC-based organoids, NORA234 causes a genotoxic stress paralleled by G2-M cell cycle arrest and activation of CHK1, driving the DNA damage repair of CR-CSphCs, regardless of the mutational background, microsatellite stability, and consensus molecular subtype. Synergistic combination of NORA234 and CHK1 (rabusertib) targeting is synthetic lethal inducing death of both CD44v6-negative and CD44v6-positive CRC stem cell fractions, aside from Wnt pathway activity. These data could provide a rational basis to develop an effective strategy for the treatment of patients with CRC

Analysis of cCx39 expression pattern during chick development

The present study reports the expression pattern of connexin39 (cCx39) in chick embryos at different stages of central nervous system development. We examined the expression between HH17 and HH40 developmental stages of chicken embryos by in situ hybridization (ISH) technique. Connexin39 was first expressed at HH17. It stained neuroepithelial cells in the optic (OV) and telencephalic (TEL) vesicles, plus in the superficial mesenchyme of the two rostral branchial arches (maxilar and mandibular). These cells probably originated from the neural crest. This expression pattern changed drastically between stages HH17 and HH23, while it showed relatively little modifications from HH23 to HH29. At these times, connexin39 was expressed in three regions: the telencephalic vesicle, the diencephalon and the isthmus. At later stages, HH35 and HH40, connexin39 was mainly expressed in the ventricular epithelium and three cell layers of the stratum griseum and fibrosum superficialis (SGFS) in the optic tectum, as well as in granular and nuclear cells in the cerebellum. In conclusion, the expression pattern of connexin39 in embryonic nervous system is dynamic. This pattern is different from, and in some aspects complementary to, those showed by other connexins during brain development.Peer reviewe

Bv8/Prokineticins and their Receptors A New Pronociceptive System.

Bv8 is a small protein secreted by frog skin. Mammalian homologues of Bv8, the prokineticins PK1 and PK2, and their G-protein coupled receptors prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) have been identified and linked to several biological effects as gut motility, neurogenesis, angiogenesis, circadian rhythms, hematopoiesis, and nociception. Emerging evidences indicated that prokineticins are also associated with pathologies of the reproductive and nervous system, myocardial infarction, and tumorigenesis. Bv8 elicits a dose-dependent reduction in nociceptive threshold to thermal, mechanical, and chemical stimuli. The prokineticin receptors are present in a fraction of G and A delta-fiber neurons also expressing the vanilloid receptors, TRPV1 and TRPA1. Mice lacking PKR genes exhibit impaired Bv8-induced hyperalgesia, develop deficient responses to noxious heat, capsaicin, and protons and show reduced thermal and mechanical hypersensitivity to paw inflammation, indicating a requirement for PKR signaling in activation and sensitization of primary afferent fibers. Bv8/PK2 is highly expressed by neutrophils and other inflammatory cells and must be considered as new pronociceptive mediators in inflamed tissues. Bv8-like hyperalgesic activity was demonstrated in extracts of rat inflammatory granulocytes. Bv8 stimulates macrophage and T lymphocyte to differentiate towards an inflammatory and Th1 profile indicating that Bv8/PK2 plays a role in immunoinflammatory responses. Blockade of PKRs may represent a novel therapeutic strategy in acute and inflammatory pain conditions

The three objects used in study 1 and 2.

<p>A: Furry fake dog; B: Plastic fake dog; C: Puppet.</p

(Study 2): Mean percentage± SD of time spent for each behavior across the experimental phases.

<p>(Study 2): Mean percentage± SD of time spent for each behavior across the experimental phases.</p

Ethogram used in study 1 and 2 and interobserver agreement.

<p>Ethogram used in study 1 and 2 and interobserver agreement.</p

Mean percentage ± SE of time spent by dogs interacting with the object in Study 1.

<p>Legend: black line, the owner is manipulating the objects; grey line: the stranger is manipulating the objects. Post-hoc values: Fake dog -Owner vs. Book-Owner, p<0.001; Puppet-Owner vs. Book-Owner, p = 0.035; Fake dog-Stranger vs. Book-Stranger, p = 0.014; Puppet-Stranger vs. Book-Stranger, p = 0.066.</p

(Study 2): statistical values of the GLM ANOVA for main and interaction effects.

<p>(Study 2): statistical values of the GLM ANOVA for main and interaction effects.</p