Biology subjects

Olow, A.

Publications and source records attributed to Olow, A..

2 recordsLinked to original sources

bioRxiv2025

Multicellular Calcium Waves in Cancer-Associated Fibroblasts Regulate Neuronal Mimicry and Anisotropy Leading to Immune Exclusion

Stromal barriers exclude CD8+ T cells from accessing cancer cells and hamper immune-mediated tumour control. Through multi-pronged analysis of tumours that transition from immune inflamed to immune excluded, we reveal that the formation of stromal barriers is associated with the acquisition of neuronal gene expression programmes in cancer-associated fibroblasts (CAFs), including TUBB3 expression. This leads to neuronal mimicry, with stromal barrier formation underpinned by coordinated transient bursts of intracellular calcium release, similar to those observed in neuronal tissue. Blockade of calcium release through either pharmacological or molecular interventions, such as STC2 depletion, prevents CAF alignment and the build-up of CD8+ T cells at stromal boundaries. Nintedanib treatment prevents neuronal mimicry and restores immune-mediated tumour control. Thus, we uncover unexpected mimicry of neuronal behaviour in CAFs, document the mechanism by which it leads to immune exclusion, and identify ways to prevent the induction of neuronal mimicry and restore immune-mediated tumour control. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/684281v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@938ee5org.highwire.dtl.DTLVardef@18a9c48org.highwire.dtl.DTLVardef@11a5982org.highwire.dtl.DTLVardef@ea6a79_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

YAP/TEAD4-reagulated placental alkaline phosphatases ALPP and ALPPL2 are immunosuppressive ectonucleotidases modulated by MAPK inhibitors

Placental alkaline phosphatases ALPP and ALPPL2 (ALPP/L2) are promising clinical targets for therapies such as antibody-drug conjugates (ADCs). However, their regulation and biological functions remain unclear. Here, we identify the YAP/TEAD4 signaling axis as the primary regulator of ALPP/L2 expression in tumor cells. Importantly, we demonstrate that inhibitors targeting KRAS, MEK, and ERK upregulate ALPP/L2 expression in vitro and in vivo, thereby enhancing the efficacy of antibody-drug conjugates (ADCs) when used in combination. Moreover, our work reveals a novel immunomodulatory function of ALPP/L2 as cell surface ectonucleotidases that hydrolyze extracellular ATP, ADP, and AMP to adenosine, promoting regulatory T cell infiltration into the tumor microenvironment. Together, these findings reveal a biological function of ALPP/L2 and identify druggable regulators to enhance ALPP/L2-targeted therapies. SIGNIFICANCEThis study uncovers the YAP/TEAD pathway as a positive regulator of the clinically relevant tumor-associated antigens ALPP and ALPPL2. Kras, MEK, or ERK inhibitors enhance ALPP/L2 expression in tumor cells, thereby increasing the efficacy of ALPP/L2-targeted antibody-drug conjugates. These findings offer a promising combination strategy to overcome resistance to ALPP/L2-based therapies caused by low target expression.

cancer biology↗