Biology subjects

Azorin, D. D.

Publications and source records attributed to Azorin, D. D..

3 recordsLinked to original sources

bioRxiv2026

Collective cancer cell calcium activity drives brain metastasis

Communication in multicellular networks is a cancer-intrinsic neural feature and crucial for primary brain tumor growth and resistance, but it is unclear whether brain metastases (BrM), the most common and deadliest brain malignancy, are also driven by communicating cancer networks. Using intravital two-photon microscopy in awake mice, clinical specimens, and Ca2+ integrators, we demonstrate that brain-colonizing breast and lung cancer and melanoma cells display gap-junction-dependent, coordinated Ca2+ activity in multicellular, cancer-cell intrinsic networks, which drives their proliferation. Mechanistically, Ca2+ oscillations induce transcription of immediate early genes, adoption of a neuronal expression profile, and cell cycle progression. While many of those features are enriched in BrM, all investigated cancer cell lines showed collective Ca2+ activity. Therapeutically, blocking Ca2+ activity with gap junction inhibitors reduces BrM burden in mouse models. Here we show communicating cancer cell syncytia as drivers of BrM growth, pointing to a targetable pathomechanism, and potentially a new pan-cancer hallmark. Graphical AbstractIn brief Brain metastases form gap-junction-coupled networks exhibiting spontaneous, coordinated Ca2+ activity linked to immediate early gene activation, neuronal gene programs, and cell cycle progression. Disrupting Ca2+ network communication with gap junction inhibitors induces cell cycle arrest and reduces brain metastatic burden in vivo. O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/723715v1_ufig1.gif" ALT="Figure 1"> View larger version (88K): org.highwire.dtl.DTLVardef@1130ea0org.highwire.dtl.DTLVardef@254dcdorg.highwire.dtl.DTLVardef@117021forg.highwire.dtl.DTLVardef@18c4f1e_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBrain metastases display collective Ca2+ activity in gap-junction-coupled networks C_LIO_LICa2+ co-activity is conserved across cancers but enriched in brain metastasis C_LIO_LICa2+ oscillations robustly induce neuronal gene programs and cell cycle progression C_LIO_LIGap junction inhibition reduces brain metastasis burden in mice C_LI

cancer biology↗

bioRxiv2024

Molecular recording of cellular protein kinase activity with chemical labeling

Protein kinases control most cellular processes and aberrant kinase activity is involved in numerous diseases. To investigate the link between specific kinase activities and cellular phenotypes in heterogeneous cell populations and in vivo, we introduce molecular recorders of kinase activities for later analysis. Based on split-HaloTag and a phosphorylation-dependent molecular switch, our recorders become rapidly labeled in the presence of a specific kinase activity and a fluorescent HaloTag substrate. The kinase activity in a given cell controls the degree of fluorescent labeling whereas the recording window is set by the presence of the fluorescent substrate. We have designed specific recorders for four protein kinases, including protein kinase A. We apply our protein kinase A recorder for the sorting of heterogeneous cell populations and subsequent transcriptome analysis, in genome-wide CRISPR screens to discover regulators of PKA activity and for the tracking of neuromodulation in freely moving mice.

biochemistry↗

bioRxiv2021

A connectivity signature for glioblastoma

Tumor cell extensions called tumor microtubes (TMs) in glioma resemble neurites during neurodevelopment and connect glioma cells to a network that has considerable relevance for tumor progression and therapy resistance. The determination of interconnectivity in individual tumors has been challenging and the impact of tumor cell connectivity on patient survival remained unresolved so far. Here, a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells was established and clinically validated. Thirty-four of 40 connectivity genes were related to neurogenesis, neural tube development or glioma progression, including the TM-network-relevant GAP43 gene. Astrocytic-like and mesenchymal-like GB cells had the highest connectivity signature scores in scRNA-Seq data of patient-derived xenografts and patient samples. In 230 human GBs, high connectivity correlated with the mesenchymal expression subtype, TP53 wildtype, and with dismal patient survival. CHI3L1 was identified as a robust molecular marker of connectivity. Thus, the connectivity signature allows novel insights into brain tumor biology, provides a proof-of-principle that tumor cell connectivity is relevant for patients prognosis, and serves as a robust biomarker that can be used for future clinical trials. Statement of significanceIntegration of GB cells into functional networks drives tumor progression and resistance. Here, we established and validated a novel connectivity gene expression signature of single GB cells and whole tumors that can be easily applied to clinical and preclinical samples. It is shown that connectivity is determining prognosis combining molecular, functional and clinical insights into the disease.

cancer biology↗