Biology subjects

Storey, K.

Publications and source records attributed to Storey, K..

4 recordsLinked to original sources

bioRxiv2026

Discrete Transcriptional States Define Biphasic Immune Response and Dynamic CMS Transitions in Colorectal Cancer

BackgroundSequential alterations in APC, KRAS, TP53, and SMAD4 have been proposed as a framework for colorectal cancer progression. Human colorectal cancer datasets have not revealed the biological transitions associated with these mutations. When examining a cohort of TCGA-colorectal tumors grouped as AK (APC/KRAS), AKP (APC/KRAS/TP53), and AKPS (APC/KRAS/TP53/SMAD4), we observed no significant differences in immune-cell composition, four previously defined Consensus Molecular Subtypes (CMS1/2/3/4), or transcriptomic clustering between these genomic groups. Therefore, these canonical alterations do not sufficiently characterize the known properties of metastatic progression in human colorectal cancer. MethodsTo overcome these limitations, we developed a genetically defined, organoid-based, orthotopic mouse model whereby mouse colon organoids modeling sequential APC, KRAS, TP53, and SMAD4 alterations were orthotopically injected into the colon. This was followed by RNA-sequence processing, normalization with DESeq2, differential expression, pathway enrichment, and immune/stromal inference. Gene co-expression modules were identified from variance-stabilized mouse expression data, mapped to 1:1 human orthologs, and summarized as eigengenes. A multinomial logistic regression model trained on mouse eigengenes was applied to TCGA-COAD human tumors to assign them to mouse-informed transcriptomic states (AK-like, AKP-like, AKPS-like), which were then used for downstream visualization and comparative analyses. ResultsWhole-transcriptome analysis revealed discrete transcriptional states and immune-cell differences between the organoid AK/AKP/AKPS groups. Early TP53 loss led to strong activation of immune pathways, accompanied by increased infiltration of NK and T cells. As tumors progressed with SMAD4 loss and metastasis, this immune activity collapsed, giving rise to broad immune suppression. CMS classifications also shifted, with AK tumors resembling epithelial CMS2, AKP tumors displaying immune-rich CMS1 features, and AKPS and metastatic lesions adopting mesenchymal CMS4 characteristics. We then applied a progression-based transcriptomic classifier to 460 human colorectal tumors. This reclassification revealed conserved immune remodeling, CMS transitions, pathway-level differences, and significant differences in patient survival. ConclusionWe show that organoid-derived progression profiles reveal hidden evolutionary structure in human colorectal cancer and provide a transcriptional framework for interpreting metastatic potential and clinical outcomes.

cancer biology↗

bioRxiv2019

Crumbs 2 mediates ventricular layer remodelling to form the adult spinal cord central canal

In the spinal cord, the adult central canal forms through a poorly-understood process termed dorsal collapse that involves attrition and remodelling of the pseudostratified dorsal ventricular layer. Here we show, in mouse, that dorsal ventricular layer cells adjacent to midline Nestin(+) radial glia downregulate the apical polarity proteins Crumbs2 (CRB2) and aPKC and delaminate in a step-wise manner; concomitantly, Nestin(+) radial glial end-feet ratchet down, to repeat this process. Nestin(+) radial glia secrete a factor that promotes cell delamination. This activity is mimicked by a secreted variant of CRB2 (CRB2S), which is specifically expressed by dorsal midline Nestin(+) radial glia. In cultured cells, CRB2S associated with apical membranes and decreased cell cohesion. Analysis of Crb2F/F/Nestin-Cre+/- mice further confirmed an essential role for CRB2 in dorsal collapse. We propose a model in which CRB2S promotes the progressive attrition of the ventricular layer without loss of overall integrity. This novel mechanism may operate more widely to promote orderly progenitor delamination.

developmental biology↗

bioRxiv2018

Glioblastoma recurrence and the role of MGMT promoter methylation

Tumor recurrence in glioblastoma multiforme (GBM) is often attributed to acquired resistance to the standard chemotherapeutic agent temozolomide (TMZ). Promoter methylation of the DNA repair gene MGMT has been associated with sensitivity to TMZ, while increased expression of MGMT has been associated with TMZ resistance. Clinical studies have observed a downward shift in MGMT methylation percentage from primary to recurrent stage tumors. However, the evolutionary processes driving this shift, and more generally the emergence and growth of TMZ-resistant tumor subpopulations, are still poorly understood. Here we develop a mathematical model, parameterized using clinical and experimental data, to investigate the role of MGMT methylation in TMZ resistance during the standard treatment regimen for GBM (surgery, chemotherapy and radiation). We first find that the observed downward shift in MGMT promoter methylation status between detection and recurrence cannot be explained solely by evolutionary selection. Next, our model suggests that TMZ has an inhibitory effect on maintenance methylation of MGMT after cell division. Finally, incorporating this inhibitory effect, we study the optimal number of TMZ doses per adjuvant cycle for GBM patients with high and low levels of MGMT methylation at diagnosis.

cancer biology↗

bioRxiv2017

INSULIN-LIKE PEPTIDES REGULATE FEEDING PREFERENCE AND METABOLISM IN DROSOPHILA

Fruit flies have eight identified Drosophila insulin-like peptides (DILPs) involved in regulation of carbohydrate concentrations in hemolymph as well as accumulation of storage metabolites. In the present study, we investigated diet-dependent roles of DILPs encoded by genes dilp1-5, and dilp7 in regulation of insect appetite, food choice, accumulation of triglycerides, glycogen, glucose, and trehalose in fruit fly body and carbohydrates in hemolymph. We found that dilp2 gene predominantly influences body glycogen level, dilp3 - trehalose level in hemolymph, while dilp5 and dilp7 affect triglyceride level. Fruit fly appetite was found to be regulated by dilp3 and dilp7 genes. Our data contribute to the understanding of Drosophila as a model for further studies of metabolic diseases and may serve as a guide for uncovering the evolution of metabolic regulatory pathways.\n\nHIGHLIGHTSDifferent Drosophila insulin-like peptides play distinctive roles in metabolism, physiology and appetite regulation.\n\nLack of Dilp2 and Dilp5 abrogates glycogen accumulation on high carbohydrate diets\n\nLack of Dilp3 leads to build-up of trehalose in haemolymph on high-carbohydrate-low-protein diets\n\nLack of Dilp3 and Dilp7 leads to increased consumption of protein on low-carbohydrate-high-protein diets\n\nGRAPHICAL ABSTRACT O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

physiology↗