Biology subjects

Overman, M. J.

Publications and source records attributed to Overman, M. J..

4 recordsLinked to original sources

bioRxiv2026

KRAS inhibition is an effective therapy for appendiceal adenocarcinoma

BackgroundAppendiceal adenocarcinoma (AA) is a rare cancer with limited treatment options. KRAS is the most commonly mutated gene in AA and a promising therapeutic target, but its preclinical and translational relevance in AA remains unclear. MethodsWe evaluated KRASG12D-specific (MRTX1133) and pan-KRAS inhibitor (RMC-6236) in KRASmut organoid and orthotopic PDX models of AA. Tumor-intrinsic and microenvironmental responses were characterized using multi-omics profiling. Clinical outcomes were also assessed in six heavily pre-treated AA patients treated with KRAS inhibitors. ResultsMRTX1133 was highly effective for KRASG12D organoids (IC50=4.1 nM); both KRASG12D and KRASG12V organoids were sensitive to RMC-6236 (IC50=4.4 nM vs 0.5 nM, respectively). In orthotopic PDX models of peritoneal carcinomatosis from AA, MRTX1133 significantly reduced tumor growth in the KRASG12D model TM00351, and RMC-6236 reduced tumor growth in KRASG12V model AAPDX-16. Pathologic evaluation showed dramatically reduced tumor cellularity, proliferation, and pERK expression as well as induction of apoptosis. Gene Sets Enrichment Analysis (GSEA) revealed significant downregulations of E2F targets (NES=-1.9, p-adj=0.06) and the newly developed RAS/ERK (NES=-2.3, p-adj=0.06) gene set, consistent with the observed decrease in cell proliferation. There was marked upregulation of EMT (NES=2.7, FDR<0.001) and TGF-{beta} signaling (NES=2.3, FDR=0.004) in remaining tumor cells, suggesting these pathways could confer resistance. scRNA-seq analysis of TME showed dramatic shifts in cancer-associated fibroblasts (CAFs), with KRAS inhibition driving a shift from normal fibroblasts to inflammatory CAFs, and upregulation of interferon alpha and gamma pathways, suggesting that KRAS inhibition can activate innate immune response in the setting of peritoneal metastases. In a cohort of 6 heavily pre-treated patients with AA treated with KRAS inhibitors (1 G12D, 3 G12C, 2 pan-KRAS), all had biochemical response based on CEA/Ca19-9 or ctDNA and clinical benefit by RECIST criteria (1 CR, 1 PR, 4 SD). ConclusionsWhile effective suppression of RAS/ERK signaling by KRAS inhibitors reduces tumor growth, adaptive activation of EMT and TGF-{beta} pathways may mediate resistance in KRASmut AA. Additionally, KRAS inhibition remodels TME and may enhance innate immune signaling. These findings support continued clinical development of KRAS inhibitors in AA and provide a rationale for combination strategies targeting resistance pathways and stromal remodeling.

cancer biology↗

bioRxiv2026

CROCHET: a versatile pipeline for automated analysis and visual atlas creation from single-cell spatialomic data

Spatial biology technologies offer a unique opportunity to link tissue composition with function. However, analytical methods for quantifying and interpreting highly complex spatial data remain limited. We present CROCHET (ChaRacterization Of Cellular HEterogeneity in Tissues), an end-to-end analysis pipeline for construction of spatially resolved cell atlases from raw data covering millions of cells across large sample cohorts. Its modular architecture supports the integration of diverse data modalities and novel analytical methods for image processing and segmentation, spatialomics quantification and downstream analyses. With comprehensive, open-source, user-friendly, interactive, and visual analysis modules, CROCHET aims to democratize spatial omics for a broad community of users.

bioinformatics↗

bioRxiv2025

A spatially resolved single cell proteomic atlas of Small Bowel Adenocarcinoma

Small bowel adenocarcinoma (SBA) is a rare malignancy marked with a poor prognosis. The cellular and proteomic heterogeneity within the tumor immune microenvironment (TIME) of SBA is a likely driver of prognosis, disease progression and response to therapy. We have addressed a major gap in knowledge of the TIME in SBA using highly multiplexed, protein imaging of the SBA tumor-immune ecosystem generating a comprehensive, single-cell level, spatial, proteomic atlas of TIME in > 600,000 cells from 136 tumor and matched normal samples from clinically and genomically annotated SBA patients (N=37). The SBA TIME Atlas informs on spatial distribution and interactions of tumor-intrinsic processes, diverse immune cell types, immune checkpoints, and vascularization. Enrichment of proliferating epithelial tissue, stem cells, and likely pro-tumor immune signatures in the tumor niche is contrasted by the representation of naive and early-effector T-cells in the epithelial compartments of adjacent normal tissues. Epithelial-stem-immune cell spatial architectures within tumor and matched-normal niches were strongly associated with patient survival, suggesting malignancy is driven by spatial architecture beyond the tumor microenvironment. The blueprints of therapeutically actionable immune checkpoints at the interface between epithelial and microenvironmental T-cells as well as macrophages have established a guideline for precision immunotherapies tailored to the TIME composition in SBA. We expect that this SBA atlas will contribute to a deeper understanding of the immune contexture in this rare disease as well as other gastrointestinal cancers and help guide future precision immune-oncology strategies.

cancer biology↗

bioRxiv2021

Stimulating human prefrontal cortex increases reward learning

Work in computational psychiatry suggests that mood disorders may stem from aberrant reinforcement learning processes. Specifically, it is proposed that depressed individuals believe that negative events are more informative than positive events, resulting in faster learning from negative outcomes (Pulcu & Browning, 2019). In this proof-of-concept study, we investigated whether learning rates for affective outcomes are malleable using transcranial direct current stimulation (tDCS). Healthy adults completed an established reinforcement learning task (Pulcu & Browning, 2017) in which the information content of reward and loss outcomes was manipulated by varying the volatility of stimulus-outcome associations. Learning rates on the tasks were quantified using computational models. Stimulation over dorsolateral prefrontal cortex (DLPFC) but not motor cortex (M1) specifically increased learning rates for reward outcomes. The effects of prefrontal tDCS were cognitive state-dependent: online stimulation increased learning rates for wins; offline stimulation decreased both win and loss learning rates. A replication study confirmed the key finding that online tDCS to DLPFC specifically increased learning rates for rewards relative to losses. Taken together, these findings demonstrate the potential of tDCS for modulating computational parameters of reinforcement learning relevant to mood disorders. Significance statementDisproportionate learning from negative relative to positive outcomes has been implicated in the development and maintenance of depression. The present work demonstrates that transcranial direct current stimulation (tDCS) to dorsolateral prefrontal cortex can specifically increase learning from positive events in healthy adults. Our results provide preliminary evidence that non-invasive brain stimulation can be used to shape reinforcement learning, indicating a potential novel cognitive neurostimulation intervention strategy for affective disorders.

neuroscience↗