Shitara, K. | Search bioRxiv

bioRxiv2026

Single-cell spatial multiomics identifies POSTN+ CAFs mediating chemoradiotherapy resistance in rectal cancer

Neoadjuvant chemoradiotherapy (CRT) is standard for locally advanced rectal cancer (LARC), yet many patients retain residual disease. To resolve CRT-associated remodeling of the tumor microenvironment, we generated a multimodal spatial atlas from serial sections of paired pretreatment and post-treatment specimens from 24 patients using Xenium single-cell spatial transcriptomics and PhenoCycler multiplex proteomics, profiling 2.8 million cells; matched Visium HD datasets were generated on adjacent serial sections. Resistance was most strongly associated with fibroblast and myeloid programs adjacent to residual tumor. We identify a periostin (POSTN)-expressing CAF subset selectively enriched around residual tumor cells in non-responders, displaying a myofibroblastic phenotype and activating extracellular matrix remodeling, noncanonical WNT signaling, and immunosuppressive pathways. Tumor cells neighboring POSTN+ CAFs show consistent epithelial-mesenchymal transition signatures. Together, this atlas enables interrogation of CRT-induced spatial remodeling and nominates POSTN+ CAFs as key mediators and targets of CRT resistance, with direct relevance to CRT-based combination strategies.

cancer biology↗

bioRxiv2025

Intensity-dependent corticospinal facilitation by repetitive peripheral magnetic stimulation: Evidence for a major contribution of group I afferents

BackgroundRepetitive peripheral magnetic stimulation (PMS) is increasingly used in neurorehabilitation, yet the optimal stimulation intensity for inducing corticospinal facilitation and the underlying afferent mechanisms remain unclear. We investigated the intensity-dependent effects of repetitive PMS on corticospinal excitability and single motor unit responses, and tested group I afferent contribution. MethodsHealthy participants received repetitive PMS (25 Hz; 2-s ON/2-s OFF) over the extensor carpi radialis (ECR) in a crossover design at 0.9x motor threshold (MT), 1.2xMT, and high intensity sufficient to induce maximal wrist dorsiflexion (mean 1.8xMT). Motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation were recorded from the ECR and flexor carpi radialis (FCR) before and during the intervention (total 15 min). The lasting effects were assessed after 9 min of high-intensity PMS for 50 min. To examine group I afferent contribution, the same high-intensity protocol was applied during upper-arm ischemia after reducing the ECR H-reflex to <10% of baseline. Sensory-motor input characteristics across stimulation intensities were compared using post-stimulus time histograms of ECR single motor unit firings during weak voluntary contraction. ResultsHigh-intensity PMS significantly increased ECR MEPs after 9 min of intervention, whereas 1.2xMT of PMS required 15 min to induce a marked effect. PMS at 0.9xMT did not induce significant MEP changes. Across all intensities, the FCR MEPs remained unaltered. ECR MEPs remained markedly elevated for up to 30 min after 9 min of high-intensity PMS. In contrast, PMS delivered during ischemia produced no MEP enhancement. The motor unit analysis revealed that suprathreshold PMS elicited an early peak in firing probability--consistent with monosynaptic Ia excitation--whose amplitude increased with stimulation intensity, whereas PMS at 0.9xMT produced no discernible peak. ConclusionsRepetitive PMS above MT facilitates corticospinal excitability in an intensity-dependent manner. Facilitation was abolished during ischemia. Together with the presence of a short-latency peak in motor unit firing via a monosynaptic pathway, this finding supports a major contribution of large-diameter muscle afferents, with a substantial Ia component, to PMS-induced corticospinal facilitation.

neuroscience↗