Biology subjects

Skinner, L.

Publications and source records attributed to Skinner, L..

5 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↗

bioRxiv2024

Chemical mate choice copying in Drosophila melanogaster

Mate choice is a critical decision especially for females that requires time and energy to assess potential partners genetic quality. Consequently, in many species, females have evolved the ability to utilize social information by copying the mate choices of others, usually based on visual cues. However, many species, especially invertebrates, primarily rely on chemical not visual cues. Using chemical rather than visual cues provides several advantages such as not requiring active observation of copulations. Despite of that, empirical evidence for the existence of chemical mate choice copying is scarce. Using Drosophila melanogaster, we provide the first demonstration of chemical mate choice copying. Females exposed to a recently mated select the same male genotype as the teacher female mated with at a higher frequency than expected by chance. Chemical mate choice copying requires sensing both male and female cues, which might indicate that other females have chosen that male genotype. Our work suggests that females, in the presence of mated females, increase choosiness at the virgin stage, elevating sexual selection on male traits. This study provides novel evidence that exploiting social information is more prevalent in flies than previously assumed.

animal behavior and cognition↗

bioRxiv2024

A multi-institutional study to investigate the sparing effect after whole brain electron FLASH in mice: Reproducibility and temporal evolution of functional, electrophysiological, and neurogenic endpoints

PurposeUltra-high dose-rate radiotherapy (FLASH) has been shown to mitigate normal tissue toxicities associated with conventional dose rate radiotherapy (CONV) without compromising tumor killing in preclinical models. A prominent challenge in preclinical radiation research, including FLASH, is validating both the physical dosimetry and the biological effects across multiple institutions. MethodsWe previously demonstrated dosimetric reproducibility of two different electron FLASH devices at separate institutions using standardized phantoms and dosimeters. In this study, we compared the outcome of FLASH and CONV 10 Gy whole brain irradiation on female adult mice at both institutions to evaluate the reproducibility and temporal evolution of multiple endpoints. ResultsFLASH sparing of behavioral performance on novel object recognition (4 months post-irradiation) and electrophysiologic long-term potentiation (LTP, 5-months post-irradiation) was reproduced between institutions. Interestingly, differences between FLASH and CONV on the endpoints of hippocampal neurogenesis (Sox2, doublecortin), neuroinflammation (microglial activation), and electrophysiology (LTP) at late times were not observed at early times. ConclusionsIn summary, we demonstrated reproducible FLASH sparing effects between two beams and two institutions with validated dosimetry. FLASH sparing effects on the endpoints evaluated manifested at late but not early time points.

cancer biology↗

bioRxiv2023

FLASH-RT does not affect chromosome translocations and junction structures beyond that of CONV-RT dose-rates

The molecular and cellular mechanisms driving the enhanced therapeutic ratio of ultra-high dose-rate radiotherapy (FLASH-RT) over slower conventional (CONV-RT) radiotherapy dose-rate remain to be elucidated. However, attenuated DNA damage and transient oxygen depletion are among several proposed models. Here, we tested whether FLASH-RT under physioxic (4% O2) and hypoxic conditions ([≤]2% O2) reduces genome-wide translocations relative to CONV-RT and whether any differences identified revert under normoxic (21% O2) conditions. We employed high-throughput rejoin and genome-wide translocation sequencing (HTGTS-JoinT-seq), using S. aureus and S. pyogenes Cas9 "bait" DNA double strand breaks (DSBs), to measure differences in bait-proximal repair and their genome-wide translocations to "prey" DSBs generated by electron beam CONV-RT (0.08-0.13Gy/s) and FLASH-RT (1x102-5x106 Gy/s), under varying ionizing radiation (IR) doses and oxygen tensions. Normoxic and physioxic irradiation of HEK293T cells increased translocations at the cost of decreasing bait-proximal repair but were indistinguishable between CONV-RT and FLASH-RT. Although no apparent increase in chromosome translocations was observed with hypoxia-induced apoptosis, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in their junction structures. Thus, Irrespective of oxygen tension, FLASH-RT produces translocations and junction structures at levels and proportions that are indistinguishable from CONV-RT.

molecular biology↗

bioRxiv2019

FLASH irradiation enhances the therapeutic index of abdominal radiotherapy in mice

Peritoneal metastases are the leading cause of morbidity and mortality in ovarian cancer. Despite current surgery, chemotherapy and targeted therapies, the majority of patients diagnosed with advanced epithelial ovarian cancer develop recurrent disease and overall survival rates remain poor. It is known that ovarian cancer is a radiosensitive tumor. Historically, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of chemotherapy sensitive and resistant ovarian cancer. However, TAI fell out of favor due to high toxicity, particularly of the gastrointestinal tract. We have developed a preclinical irradiation platform that allows for total abdominal ultrahigh dose rate FLASH irradiation. We demonstrate that TAI-FLASH reduces radiation-induced intestinal injury in both healthy and tumor-bearing mice compared to conventional dose rate (CONV) irradiation. Single high dose TAI-FLASH reduced mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and decreased cell death in crypt base columnar cells. Importantly, FLASH and CONV irradiation had similar efficacy in the reduction of ovarian cancer peritoneal metastases. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of radiotherapy for the treatment of metastatic ovarian cancer in women.

cancer biology↗