Biology subjects

Dane, M.

Publications and source records attributed to Dane, M..

6 recordsLinked to original sources

bioRxiv2025

Identification of senescence-associated drivers of tumour growth and progression using a novel microarray platform

Senescence and the senescence associated secretory phenotype (SASP) are implicated in promoting early tumorigenesis but due to the complexity of SASP it has been difficult to identify the responsible factors. We used canonical SASP factors on our microenvironment microarray (MEMA) platform to systematically identify SASP-associated drivers of tumorigenesis in breast and lung cancer cells. We found multiple SASP factors enhanced the proliferation and overall cell numbers for both lung and breast cells grown on the MEMA, and that there was significant overlap in SASP-associated growth-promoting factors between the two different cell types. We validated the ability of several factors, including IL-6, TGF-{beta} and EGF, to drive growth in in vitro assays. Interestingly, these factors were effective in driving growth and survival in cells that were altered (either immortalized or fully transformed) but not in normal cells and impacted breast cells differently depending on the age of the patient. RNAseq identified upregulation of wound-healing and stem-cell programs in SASP factor-treated cells. Many of these same SASP factors were present in conditioned media collected from senescent cells, which enhanced the growth of both lung and breast cancer cells, and inhibitors of the specific SASP factors partially reduced growth. Similarly, targeted inhibition of EGF partially reduced lung tumour growth in xenografts when senescent but not normal fibroblasts were co-implanted. Our findings have identified core SASP drivers of tumorigenesis and suggest that effective tumorigenesis driven by SASP is multifactorial and requires alterations in the target cells to achieve maximal response.

cancer biology↗

bioRxiv2025

S-Nitrosylated COX-2 is a TME-regulated breast cancer biomarker of mesenchymal phenotypes

COX-2 is an inducible enzyme key to the production of inflammatory prostaglandins. COX-2 also has tumor intrinsic oncogenic activity in mouse models of breast cancer. Previously, we reported increased expression of Cys-526-nitrosylated COX-2 (SNO-COX-2), but not non-nitrosylated COX-2, with progression of early-stage human breast cancer to invasive ductal carcinoma. Here, we used a 3D culture model of early-stage human breast cancer (MCF10DCIS cells) to investigate the relationship between SNO-COX-2 expression and mesenchymal/invasive tumor cell morphology. We find that SNO-COX-2, but not non-nitrosylated COX-2, closely associated with mesenchymal phenotypes induced by fibrillar type I collagen. Interestingly, invasive phenotypes did not associate with induction of the classic epithelial-to-mesenchymal transition (EMT) markers SNAIL, CDH2 (N-cadherin), and VIM (vimentin). By contrast TGF{beta}-1 strongly induced EMT-related transcripts, but not SNO-COX-2 protein expression or mesenchymal phenotypes. These observations suggest that in MCF10DCIS cells, SNO-COX-2 associates with mesenchymal phenotypes more strongly than non-nitrosylated COX-2 protein, or expression of classic EMT transcripts. In a mouse model with breast tumor heterogeneity, mesenchymal tumor regions also have increased SNO-COX-2 expression. Testing 300 distinct tumor microenvironment conditions, we find SNO-COX-2 protein expression is driven by inflammation, wound resolution, and cancer-associated factors, especially TNC, SPP1, decorin, fibrillar type I and III collagens, INF-{gamma}, and IL-4/13, with evidence for specific extracellular matrix-ligand interactions driving both high and low SNO-COX-2 expression. In sum, in MCF10DCIS cells, expression of SNO-COX-2 is highly microenvironment-dependent and strongly associated with invasive/mesenchymal growth, indicating potential for SNO-COX-2 as a biomarker to assess risk of early-stage breast cancer progression.

cancer biology↗

bioRxiv2022

A tumour-promoting senescent secretome triggered by platinum chemotherapy exploits a targetable TGFβR1/Akt-mTOR axis in lung cancer

Platinum-based chemotherapy is commonly used for non-small cell lung cancer (NSCLC) treatment, yet clinical outcomes remain poor. Cellular senescence and its associated secretory phenotype (SASP) can have multiple tumour-promoting activities, although these are largely unexplored in lung cancer. Here we show that cisplatin-derived SASP enhances the malignant phenotype of lung cancer cells. Using xenograft, orthotopic and KrasG12V-driven murine NSCLC models, we demonstrate that cisplatin-induced senescent cells strongly promote tumour progression. Mechanistically, we find that a TGF-{beta}-enriched SASP drives pro-proliferative effects through TGF{beta}R1 and Akt/mTOR pathway activation. We validate the translational relevance of chemotherapy-induced SASP using clinical NSCLC samples from patients who received neoadjuvant platinum-based chemotherapy. Importantly, TGF{beta}R1 inhibition with galunisertib or senolytic treatment significantly reduces tumour promotion driven by cisplatin-induced senescence. Finally, we demonstrate, using distinct murine NSCLC models, that addition of TGFBR1 inhibitors to platinum-based chemotherapy reduces tumour burden and improves survival, providing pre-clinical proof-of-concept for future trial designs.

cancer biology↗

bioRxiv2021

ME-VAE: Multi-Encoder Variational AutoEncoder for Controlling Multiple Transformational Features in Single Cell Image Analysis

Image-based cell phenotyping relies on quantitative measurements as encoded representations of cells; however, defining suitable representations that capture complex imaging features is challenged by the lack of robust methods to segment cells, identify subcellular compartments, and extract relevant features. Variational autoencoder (VAE) approaches produce encouraging results by mapping an image to a representative descriptor, and outperform classical hand-crafted features for morphology, intensity, and texture at differentiating data. Although VAEs show promising results for capturing morphological and organizational features in tissue, single cell image analyses based on VAEs often fail to identify biologically informative features due to uninformative technical variation. Herein, we propose a multi-encoder VAE (ME-VAE) in single cell image analysis using transformed images as a self-supervised signal to extract transform-invariant biologically meaningful features, including emergent features not obvious from prior knowledge. We show that the proposed architecture improves analysis by making distinct cell populations more separable compared to traditional VAEs and intensity measurements by enhancing phenotypic differences between cells and by improving correlations to other analytic modalities.

bioinformatics↗

bioRxiv2020

Centennial clonal stability of asexual Daphnia in Greenland lakes despite climate variability

Climate and environmental condition drive biodiversity at many levels of biological organisation, from populations to ecosystems. Combined with palaeoecological reconstructions, palaeogenetic information on resident populations provides novel insights into evolutionary trajectories and genetic diversity driven by environmental variability. While temporal observations of changing genetic structure are often made of sexual populations, little is known about how environmental change affects the long-term fate of asexual lineages. Here, we provide information on obligately asexual, triploid Daphnia populations from three Arctic lakes in West Greenland through the past 200-300 years to test the impact of a changing environment on the temporal and spatial population genetic structure. The contrasting ecological state of the lakes, specifically regarding salinity and habitat structure may explain the observed lake-specific clonal composition over time. Palaeolimnological reconstructions show considerable environmental fluctuations since 1700 (the end of the Little Ice Age), but the population genetic structure in two lakes was almost unchanged with at most two clones per time period. Their local populations were strongly dominated by a single clone that has persisted for 250-300 years. We discuss three possible explanations for the apparent population genetic stability: (1) the persistent clones are general purpose genotypes that thrive under broad environmental conditions, (2) clonal lineages evolved subtle genotypic differences that are unresolved by microsatellite markers, or (3) epigenetic modifications allow for clonal adaptation to changing environmental conditions. Our results will motivate research into the mechanisms of adaptation in these populations, as well as their evolutionary fate in the light of accelerating climate change in the polar regions.

ecology↗

bioRxiv2020

Invasion of homogeneous and polyploid populations in nutrient-limiting environments

Breast cancer progresses in a multistep process from primary tumor growth and stroma invasion to metastasis. Progression is accompanied by a switch to an invasive cell phenotype. Nutrient-limiting environments promote chemotaxis with aggressive morphologies characteristic of invasion. It is unknown how co-existing cells differ in their response to nutrient limitations and how this impacts invasion of the metapopulation as a whole. We integrate mathematical modeling with microenvironmental perturbation-data to investigate invasion in nutrient-limiting environments inhabited by one or two cancer cell subpopulations. Hereby, subpopulations are defined by their energy efficiency and chemotactic ability. We estimate the invasion-distance traveled by a homogeneous population. For heterogeneous populations, our results suggest that an imbalance between nutrient efficacy and chemotactic superiority accelerates invasion. Such imbalance will spatially segregate the two populations and only one type will dominate at the invasion front. Only if these two phenotypes are balanced do the two subpopulations compete for the same space, which decelerates invasion. We investigate ploidy as a candidate biomarker of this phenotypic heterogeneity to discern circumstances when inhibiting chemotaxis amplifies internal competition and decelerates tumor progression, from circumstances that render clinical consequences of chemotactic inhibition unfavorable.Significance A better understanding of the nature of the double-edged sword of high ploidy is a prerequisite to personalize combination-therapies with cytotoxic drugs and inhibitors of signal transduction pathways such as MTOR-Is.Competing Interest StatementThe authors have declared no competing interest.View Full Text

systems biology↗