Yeong, J. P. S. | bioRxiv Science

bioRxiv2026

Brain state locks silent memories in a trained fly connectome

Complete connectomes now exist for insect nervous systems, but whether a fixed wiring diagram can learn, and what its memories consist of, is unknown. Here, we trained a spiking model of the whole male Drosophila central nervous system, 167,106 neurons with fixed wiring, to plan moves and to remember a visual cue. Spikes write the cue into neuronal adaptation, which holds it silently until the next input reads it out. Cells that hold the trace are enriched for transcripts of a calcium-activated potassium channel in fly cell atlases. The learned readout recalls the trace only in the brain state of learning: the same trace evokes a different response at another delay, and a disease-like loss of potassium current rewrites the trace and changes how it is read. Learning in the new state is spared. Memory failure can arise from a change of state rather than a loss of storage.

neuroscience↗

bioRxiv2026

Spatial patterns of APOBEC mutagenesis in the tumour microenvironment of Asian breast cancer

A germline deletion of the coding region at the APOBEC3B (A3B) gene that is common in Asian and Oceanic populations has been found to be correlated with increased APOBEC mutagenesis, immune activation, and tumour heterogeneity in breast cancer. The mechanism by which A3B deletion and APOBEC mutagenesis induces immune activation in Asian breast cancers is still unclear, but has been thought to involve increased neoantigen burden. In this study, we investigated the mechanisms by which A3B deletion and APOBEC mutagenesis may lead to immune activation using Stereo-seq spatial transcriptomics of Malaysian triple-negative breast cancer (TNBC) tumours with and without the A3B deletion to examine the spatial expression patterns of APOBEC3A/B as well the spatial patterns of APOBEC-associated mutations and neoantigens. Unexpectedly, we found only limited associations between A3B deletion, APOBEC-associated neoantigens, and immune activation. Instead, we found strong spatial associations between mitochondrial APOBEC-associations mutations, the cGAS-STING pathway, and the NF-{kappa}B pathway. Our study thus supports a new model whereby APOBEC-mediated activation of the immune system does not occur via neoantigen presentation, but instead occurs via mitochondrial hypermutation that drives cGAS-STING activation of the NF-{kappa}B pathway. Our study may provide new insights into the spatial landscape of Asian breast tumours and the effect of germline A3B deletion and APOBEC mutagenesis on the tumour immune microenvironment.

cancer biology↗

bioRxiv2020

Single cell RNA-seq reveals immunosuppressive gastric stem-like cancer cells as a poor prognostic factor

ObjectiveGastric cancer (GC) tumors are highly heterogenous with different subpopulations of epithelial cells. We employed single cell RNA sequencing (scRNA-seq) to dissect the heterogeneity and identified subpopulations of cancer cells with stem-like properties. We further investigated their resistance to oxaliplatin chemotherapy and their contribution to gastric cancer outcome. DesignWe performed scRNA-seq on FACS sorted epithelial and immune cells from paired samples of GC tumors and normal adjacent tissues. We identified two epithelial subpopulations (STMN1+IQGAP3+ and STMN1+IQGAP3-) with stem-like properties. We characterized and compared them to known healthy gastric stem cell populations. We also cultivated GC derived organoids to study the chemoresistance of similarly marked populations. Lastly, we employed immunohistochemistry (IHC) staining to ascertain the predicted immunosuppressive interactions. ResultsThe STMN1+IQGAP3+ subpopulation showed a higher tumor mutation burden, upregulated proliferative pathways and transcriptomically resembled proliferative healthy gastric isthmus stem cells. The STMN1+IQGAP3- subpopulation were comparatively quiescent and transcriptomically resembled enteroendocrine cells. Both transcriptomic signatures were associated with worse mortality than other epithelial subpopulations with the quiescent being associated with the poorest patient survival. GC tissue derived organoids were dominated by STMN1+IQGAP3+ cells but the STMN1+IQGAP3- compartment was more resistant to chemotherapy. We also verified the likely suppression of CD8 T cell cytotoxicity by STMN1+IQGAP3+ cells through the NECTIN2/TIGIT interaction. ConclusionsCancer cells with stem-like characteristics are associated with poor survival through chemoresistance and immunosuppression. Reactivating the immune system through checkpoint blockade is an opportunity to eliminate these cells. What is already known on this topicMultiple gastric stem cell populations have been identified and linked to tumor initiation in rodent-based studies. However, none of them have been conclusively proven in human tumors. Isolating and characterizing tumor cells with stem-like properties will help shed light on their possible origin and possible mitigation strategies. What this study addsHere we identified two sets of stem-like gastric cancer cells that are associated with poorer patient prognosis. One set is highly proliferative and exhibits oxaliplatin susceptibility. It also engages in immunosuppressive interactions such as NECTIN2/TIGIT. The other set is quiescent and highly resistant to oxaliplatin. How this study might affect research, practice or policyThe transcriptome signatures of the identified stem-like cells can aid in patient prognosis and identify patients who can benefit from checkpoint blockade therapy to reactivate their immune response towards gastric cancer cells.

immunology↗