Biology subjects

Dixon, M. S.

Publications and source records attributed to Dixon, M. S..

3 recordsLinked to original sources

bioRxiv2025

TMPO promotes cellular dissemination and metastasis in circulating tumor cells

Metastasis--the process by which cancer cells spread beyond the primary tumor to distant organs--accounts for the vast majority of cancer-related deaths. To elucidate mechanisms underlying dissemination and metastasis in prostate cancer, we have investigated circulating tumor cells (CTCs) obtained from genetically engineered mouse models (GEMMs). The phenotypic and molecular properties of the CTCs, and organoids derived from these CTCs, closely model the tumor and metastatic phenotypes of their parental GEMMs. Moreover, organoids derived from individual CTCs exhibit molecular and morphological heterogeneity that is associated with distinct metabolic states as well as differences in human prostate cancer outcome. Using computational systems analyses, we have identified TMPO, encoding the nuclear membrane protein lamina-associated polypeptide 2 (Lap2), as a key driver of this heterogeneity. TMPO activity is upregulated in advanced human prostate tumors, metastases, and CTCs, and is associated with adverse clinical outcome. Our findings indicate that TMPO promotes dissemination and metastasis in vivo by enhancing survival in conditions of metabolic stress, and reveal a novel mechanistic link between CTC heterogeneity, stress adaptation, and metastatic potential.

cell biology↗

bioRxiv2025

From in silico prediction to experimental validation: Identification of drugs and novel synergistic combinations that inhibit growth of inflammatory breast cancer cells

Drug repurposing offers a promising approach for identifying novel treatments, especially for rare cancers like inflammatory breast cancer (IBC), an aggressive type with limited therapeutic options. Here, we present a comprehensive validation and verification study of compounds identified through two computational approaches: Literature Wide Association Studies (LWAS) and Gene Reversal Rate (GRR), using orthogonal cell viability assays in 2D models across IBC and non-IBC cell lines. In the SUM149 IBC cell line, repurposed compounds predicted from LWAS achieved a 70% success rate, with several showing nanomolar potency, while those predicted from GRR showed a 38% success rate. Through systematic combination screening in both 2D and 3D-spheroid models, we identified novel synergistic compound pairs targeting crosstalk between IGF1-R, EGFR and PI3K/Akt/mTOR pathways, with high synergy scores across multiple reference models. Using these combinations, western blotting analysis revealed significant suppression in the phosphorylation of key signaling proteins and downstream effectors, while wound healing assays demonstrated reduced cell migration for some combinations, suggesting effective pathway inhibition. To further validate these findings at the transcriptional level, RNA-Seq analysis in SUM149 cells confirmed that the GRR drug combinations significantly reversed the IBC gene expression signature (IBC-GES). These findings not only validated our computational predictions but also identified promising combination strategies that could potentially overcome drug resistance in IBC. Our integrated computational-experimental approach establishes a framework for systematic drug repurposing and highlights novel therapeutic combinations warranting further investigation.

cancer biology↗

bioRxiv2025

An Iron-regulated Signalling Pathway Controls Adipose Browning and Cancer Cachexia

The browning and atrophy of white adipose tissue (WAT) are early events in cachexia, a lethal metabolic disorder affecting nearly half of cancer patients, including those with pancreatic ductal adenocarcinoma (PDA). Using patient-derived specimens and PDA mouse models, we identified perturbations in iron metabolism and proteinaceous methionine oxidation as key initiating events of adipose browning. In particular, the iron influxes that accompany WAT browning induce the activity of methionine sulfoxide reductase A (MSRA), an enzyme that reverses the oxidation of proteinaceous methionine residues. Mechanistically, iron coordination by the conserved iron-binding motifs (E203-xx-H206) of two MSRA polypeptides serves to multimerize, stabilize, and enzymatically activate MSRA. This in turns facilitates adipose browning by maintaining the reduced state of two methionines near the ATP-binding site of Protein Kinase A (PKA). Remarkably, in mouse models of PDA, MsrA deletion impairs WAT browning, significantly mitigates cachexia, and improves the overall survival of tumor-bearing animals. By establishing the iron-MSRA-PKA axis as a key nexus of cancer-associated cachexia, our study offers new perspectives for the treatment of this condition.

cancer biology↗