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Biology subjects

Kisis, I.

Publications and source records attributed to Kisis, I..

2 recordsLinked to original sources

Raw-count embeddings improve single-cell foundation models

Single-cell transformer foundation models have grown to hundreds of millions of parameters, yet the preprocessing choices that underlie them, including gene ranking and library-size normalisation, have not been systematically benchmarked. Testing seven strategies, we find these elaborations are largely unnecessary: non-normalised, log-transformed counts give the best performance, and gene order barely matters, with even random ordering outperforming sophisticated rank-based schemes. The resulting model, Gene Intelligence, projects log1p-transformed raw counts directly onto each token embedding and jointly predicts masked tokens and counts, using no normalisation, positional encoding, or read-depth tokens. Despite this simplicity, it achieves state-of-the-art performance in the tested gene-level tasks and in doublet detection, and matches large current foundation models on cell-classification tasks while using 10-to 200-fold fewer parameters.

bioinformatics↗

Functional synapses between small cell lung cancer and glutamatergic neurons

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, clinical recurrence and high rate of mortality. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified a strong and consistent signal for neuronal, synaptic, and glutamatergic signaling gene sets in murine and human SCLC. We show that SCLC cells have the ability to develop intimate contacts with neuronal glutamatergic terminals in vitro, in autochthonous primary lung tumors and in brain-engrafted tumors. These contacts can develop into bona fide synapses, allowing SCLC cells to receive glutamatergic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we show that SCLC cells derive a robust proliferation advantage when co-cultured with neurons. Moreover, the repression of glutamate release and the stimulation of the inhibitory glutamate receptor GRM8 displayed therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells appear to hijack glutamatergic signaling to sustain tumor growth, thereby exposing a novel entry route for therapeutic intervention.

cancer biology↗