Biology subjects

McClelland, S.

Publications and source records attributed to McClelland, S..

3 recordsLinked to original sources

bioRxiv2026

ORTHOTOPIC TUMOUR INDUCTION PROTOCOL SHAPES TUMOUR MICROENVIRONMENT

Robust preclinical cancer models are essential for studying tumour progression and evaluating therapeutic strategies. Orthotopic implantation of tumour cells into the mammary gland is widely used to model triple-negative breast cancer (TNBC), yet substantial variation exists in the number of cells used to initiate tumours, often without explicit consideration of how this parameter shapes tumour biology. Here, we systematically assess how tumour cell number at implantation influences the tumour microenvironment using the 4T1 orthotopic TNBC model. Mammary tumours initiated with different cell numbers exhibited comparable early growth kinetics and gross size, yet diverged markedly in cellular density, hypoxia, necrosis, proliferation, vascular integrity, and immune cell infiltration. High-density tumours displayed increased HIF-1 staining and necrosis, alongside differences in vascular-associated markers and increased macrophage recruitment. Conversely, low-density tumours remained highly proliferative, less necrotic and exhibited higher PDGFR{beta} staining. Importantly, tumour cells disseminated systemically within days of implantation across all conditions, although differences in colony recovery and ex vivo expansion were not statistically significant. Together, these findings demonstrate that tumour initiating protocols are powerful determinants of tumour state, with potential implications for dissemination frequency and tumour cell fate at distant sites. Rather than representing a source of experimental variability alone, this understanding provides an opportunity to intentionally tailor orthotopic models to investigate specific stages of disease progression and therapeutic response, thereby enhancing cross-study reproducibility and translational relevance.

cancer biology↗

bioRxiv2026

Conserved Cell Type Signatures Across the Brainstem and Spinal Cord in the Mouse Central Nervous System

Understanding how cell types are organized across the central nervous system (CNS) is key to uncovering neural function. Here, we integrate single-nucleus Multiome (RNA+ATAC) sequencing, spatial transcriptomics, and computational analyses to map conserved cell type signatures in the adult mouse brainstem and spinal cord. We identify a shared core of neuronal and non-neuronal cell types, alongside region-specific specializations reflecting distinct functions. Spatial data reveal conserved cellular niches across the brainstem-spinal cord boundary, indicating a continuous organizational logic. Cross-region comparisons uncover recurrent gene expression modules and signaling programs that may support shared circuit features. Chromatin accessibility profiling highlights cell-type-specific regulatory programs and implicates Hox transcription factors in positional identity. Notably, cell-type and positional identities are largely orthogonal, with varying regional influence across neuronal classes: motor neurons show strong positional coupling, whereas glutamatergic and GABAergic interneurons show minimal entrainment. This work provides a reference for the shared molecular architecture of these CNS regions.

neuroscience↗

bioRxiv2019

Mechanisms of Chromosomal Instability in High-grade Serous Ovarian Carcinoma.

Chromosomal instability (CIN), the continual gain and loss of chromosomes or parts of chromosomes, occurs in the majority of cancers and confers poor prognosis. Mechanisms driving CIN remain unknown in most cancer types due to a scarcity of functional studies. High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynaecological malignancy in the Western world with chemotherapy resistance developing in almost all patients. HGSC exhibits high rates of chromosome aberrations and knowledge of causative mechanisms is likely to represent an important step towards combating the poor prognosis of this disease. However, very little is known about the nature of chromosomal instability exhibited by this cancer type in particular due to a historical lack of appropriate cell line models. Here we perform the first in-depth functional characterisation of mechanisms driving CIN in HGSC by analysing eight cell lines that accurately recapitulate HGSC genetics as defined by recent studies. We show, using a range of established functional CIN assays combined with live cell imaging and single molecule DNA fibre analysis, that multiple mechanisms co-exist to drive CIN in HGSC. These include supernumerary centrosomes, elevated microtubule dynamics and DNA replication stress. By contrast, the spindle assembly checkpoint was intact. These findings are relevant for developing therapeutic approaches to manipulating CIN in ovarian cancer, and suggests that such approaches may need to be multimodal to combat multiple co-existing CIN drivers.

cancer biology↗