SOAP: Signaling in Oncogenesis, Angiogenesis, and Permeability
On the ground of our interests for molecular piracy exerted by tumor cells to survive, adapt and remodel their environment, we explore the signaling mechanisms involved in non-oncogene addiction and loss of vascular homeostasis.
Research Highlights
The kinase CK1α coordinates the initiation and termination of the cGAS-STING pathway
Jardine et al., Cell Death Diff 2026
The cGAS-STING pathway is an evolutionarily conserved DNA-sensing mechanism that triggers innate immune responses. cGAS and STING play dual roles in tumorigenesis, promoting antitumor immunity and cell death while fueling tumor growth and metastasis. However, the mechanisms fine-tuning this pathway remain elusive. Using complementary proteomic approaches, we report that Casein Kinase 1 alpha (CK1α) operates as a bimodal regulator of the cGAS-STING pathway. CK1α supports optimal DNA sensing by counteracting proteasome-dependent degradation of cGAS, which involves the Cullin-RING ubiquitin ligase 3 (CRL3). Conversely, CK1α restrains signal propagation in response to STING agonists, tempering IRF3 activation. Exploiting these counterposing functions, we show that selective degradation of CK1α using molecular-glue degraders suppressed aberrant cGAS-STING-driven inflammation signaling in a chromosomally unstable triple-negative breast cancer cell line, while cooperating with a STING agonist to promote apoptosis in acute myeloid leukemia cells. Thus, CK1α’s dual regulatory role in the cGAS-STING pathway presents a promising target for therapeutic development.
Rosinska S, et al. Cell Rep 2025
While locating in different microenvironments, glioblastoma stem-like cells (GSCs) receive maintenance signals and information to exploit neurovascular tracts. Although the cell adhesion mechanisms to blood vessels have been explored, the mediators guiding GSC interaction with the endothelial cells and their matrix remain incompletely resolved. Here, we identify junctional adhesion molecule C (JAMC) as a key regulator of heterophilic and homophilic interactions of GSC to endothelial surfaces. Using decellularized matrices, co-cultures, and organotypic brain slices, we demonstrate that JAMC restrains GSC spreading. JAMC−/− GSCs exhibit extended spreading on endothelial-borne supports, with exacerbated invasive, migratory, and mesenchymal-like behaviors, further eroding mice survival. Spatial transcriptomics of human samples confirmed the association between invasion and JAMC expression pattern. Quantitative proteomics unveiled that JAMC deletion elicits integrin upregulation, concurrent with a downregulation of the integrin negative regulator, SHARPIN. The landscape of adhesion molecules anchoring GSCs to vascular surfaces may coordinate cell migration in glioblastoma territories.
Fundings
