Biology subjects

Fennell, L.

Publications and source records attributed to Fennell, L..

3 recordsLinked to original sources

bioRxiv2025

A spatial atlas of colorectal cancer reveals the influence of stromal niches on tumour differentiation

Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer-related mortality. Tumour architecture is spatially heterogeneous, ranging from the necrotic core to the invasive front, accompanied by diverse stromal and immune responses that influence tumour progression and treatment outcomes. To explore the spatial organisation of the tumour microenvironment, we profiled 1000 genes in 846,469 cells in 23 normal and late-stage colorectal tumour samples. We identified nine distinct spatial niches based on their cellular composition. We show that lymphoid aggregates enriched for CCR7/SELL+ CD4 T cells displayed heightened interferon signalling, more proliferating B cells and gene expression changes indicative of an adaptive immune response. We defined granulocyte-rich regions are concomitant with inflammation-mediated stromal reprogramming and increased tumour stemness. Finally, we uncovered the impact of the tumour microenvironment by distinguishing gene expression programs that were intrinsic to cancerous epithelial cells from those mediated by niche-specific changes. Key pointsO_LIWe present a spatial atlas of colorectal cancer and normal colon alongside an R/shiny interface to interactively explore this data: https://abud-apps.abud-lab-spatial.cloud.edu.au/shiny/cosmxos/. We analysed nine CosMx slides and provide QC metrics, identify strengths and weaknesses and provide suggestions for analysis of imaging-based spatial data. C_LIO_LIWe identify and characterise nine distinct spatial niches, each with their unique gene expression profile. C_LIO_LIWe observe granulocyte infiltration associated with spatially controlled TNF and IL1 signalling from granulocytes and myeloid cells. This signalling associates with a reduction in pro-differentiation CXCL14 fibroblasts and an increase in MMP tissue-remodelling fibroblasts, ultimately reprogramming tumours toward a more foetal/stem-like (progenitor) state. We suggest IL24 as a potential regulatory factor of this response. C_LIO_LIGranulocyte chemoattractants were consistently expressed at higher levels by both cancerous epithelial cells and the tumour microenvironment (TME) relative to normal colon. C_LIO_LIWe identify colonic LAs associated with T cell infiltration, including a population of CCR7/SELL+ CD4 T cells linked to significant reprogramming of B cells. Furthermore, we show that granulocyte-driven fibroblast and myeloid reprogramming is reversed within LAs. C_LIO_LIWe show that mutated epithelial cells within tumours are uniquely marked by an FXYD5+ PIGRlow expression profile, allowing for tumour vs normal epithelial cell differential gene expression analysis. This distinction clarifies cancerous tumour-intrinsic expression changes versus those promoted by the TME. C_LI

cancer biology↗

bioRxiv2020

APC Mutation marks an aggressive subtype of BRAF mutant colorectal cancers that are associated with early-onset and dismal prognosis

Background & AimsWNT activation is a hallmark of colorectal cancer. BRAF mutation is present in 15% of colorectal cancers, and the role of mutations in WNT signaling regulators in this context is unclear. Here we evaluate the mutational landscape of WNT signaling regulators in BRAF mutant cancers. MethodsWe performed exome-sequencing on 24 BRAF mutant colorectal cancers and analysed these data in combination with 175 publicly available BRAF mutant colorectal cancer exomes. We assessed the somatic mutational landscape of WNT signaling regulators, and performed hotspot and driver mutation analyses to identify potential drivers of WNT signaling. The effects of Apc and Braf mutation were modelled, in vivo, using the Apcmin/+ and BrafV637/Villin-CreERT2/+ mouse, respectively. ResultsRNF43 was the most frequently mutated WNT signaling regulator (41%). Mutations in the beta-catenin destruction complex occurred in 48% of cancers. Hotspot analyses identified potential cancer driver genes in the WNT signaling cascade, including MEN1, GNG12 and WNT16. Truncating APC mutation was identified in 20.8% of cancers. Truncating APC mutation was associated with early age at diagnosis (P< 2x10-5), advanced stage (P<0.01), and poor survival (P=0.026). Apcmin/+/BrafV637 animals had more numerous and larger SI and colonic lesions (P<0.0001 and P<0.05, respectively), and a markedly reduced survival (Median survival: 3.2 months, P=8.8x10-21) compared to animals with Apc or Braf mutation alone. ConclusionsThe WNT signaling axis is frequently mutated in BRAF mutant colorectal cancers. WNT16 and MEN1 may be novel drivers of aberrant WNT signaling in colorectal cancer. Co-mutation of BRAF and APC generates an extremely aggressive neoplastic phenotype that is associated with poor patient outcome. SynopsisWe have comprehensively evaluated the somatic mutation landscape of WNT signaling regulators in serrated colorectal cancers. We identified a mosaic of mutations that may be responsible for elevating WNT signaling in this context. Approximately 20% of serrated colorectal cancers harbor truncating APC mutation, and these cancers confer extremely poor prognoses.

cancer biology↗

bioRxiv2018

Genome Scale Epigenetic Profiling Reveals Five Distinct Subtypes of Colorectal Cancer

BACKGROUNDColorectal cancer is an epigenetically heterogeneous disease, however the extent and spectrum of the CpG Island Methylator Phenotype (CIMP) is not clear.\n\nRESULTSAn unselected cohort of 216 colorectal cancers clustered into five clinically and molecularly distinct subgroups using Illumina 450K DNA methylation arrays. CIMP-High cancers were most frequent in the proximal colons of female patients. These dichotomised into CIMP-Hl and CIMP-H2 based on methylation profile which was supported by over representation of BRAF (74%, P<0.0001) or KRAS (55%, P<0.0001) mutation, respectively. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CI MP-Negative subgroup to 75 years in the CIMP-Hl subgroup (P<0.0001). There was a striking association between PRC2-marked loci and those subjected to significant gene body methylation in CIMP-type cancers (P<1.6xl078). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster specific mutations were observed for genes involved in chromatin remodelling, such as in the SWI/SNF and NuRD complexes, suggesting synthetic lethality.\n\nCONCLUSIONThere are five clinically and molecularly distinct subgroups of colorectal cancer based on genome wide epigenetic profiling. These analyses highlighted an unidentified role for gene body methylation in progression of serrated neoplasia. Subgroup-specific mutation of distinct epigenetic regulator genes revealed potentially druggable vulnerabilities for these cancers, which may provide novel precision medicine approaches.

genomics↗