A5074607695- Mathematical Biology Tumor Growth
- Cancer Genomics and Diagnostics
- Cancer Immunotherapy and Biomarkers
- Cancer, Hypoxia, and Metabolism
- Gene Regulatory Network Analysis
- Cancer Cells and Metastasis
- Immunotherapy and Immune Responses
- Evolution and Genetic Dynamics
- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- Computational Drug Discovery Methods
- Single-cell and spatial transcriptomics
- Microtubule and mitosis dynamics
- Radiopharmaceutical Chemistry and Applications
- CAR-T cell therapy research
- Immune cells in cancer
- Cancer, Lipids, and Metabolism
- Statistical Methods in Clinical Trials
- Bioinformatics and Genomic Networks
- Cancer Research and Treatment
- Science, Research, and Medicine
- Machine Learning in Materials Science
- Nanoplatforms for cancer theranostics
- T-cell and B-cell Immunology
- Cell Image Analysis Techniques
Moffitt Cancer Center
2016-2025
Trinity College Dublin
2022
ORCID
2021
University of Arizona
2005-2019
Applied Mathematics (United States)
2008-2019
Abstract Histopathologic knowledge that extensive heterogeneity exists between and within tumors has been confirmed deepened recently by molecular studies. However, the impact of tumor on prognosis treatment remains as poorly understood ever. Using a hybrid multiscale mathematical model growth in vascularized tissue, we investigated selection pressures exerted spatial temporal variations microenvironment resulting phenotypic adaptations. A key component this is normal metabolism its...
Significance Glucose is converted to energy through “fermentation” or “oxidation.” Generally, if oxygen available, cells will oxidize glucose CO 2 because it more efficient than fermentation, which produces lactic acid. But Warburg noted that cancers ferment at a “remarkable” rate even O available! This “Warburg Effect” still misunderstood doesn’t make sense cell would when could get much by oxidizing it. The current paper goes the heart of this problem defining microenvironmental conditions...
Tumours rapidly ferment glucose to lactic acid even in the presence of oxygen, and coupling high glycolysis with poor perfusion leads extracellular acidification. We hypothesise that acidity, independent from lactate, can augment pro-tumour phenotype macrophages.We analysed publicly available data human prostate cancer for linear correlation between macrophage markers genes. used zwitterionic buffers adjust pH series vitro experiments. then utilised subcutaneous transgenic tumour models...
Abstract Ongoing intratumoral evolution is apparent in molecular variations among cancer cells from different regions of the same tumor, but genetic data alone provide little insight into environmental selection forces and cellular phenotypic adaptations that govern underlying Darwinian dynamics. In three spontaneous murine cancers (prostate TRAMP PTEN mice, pancreatic KPC mice), we identified two subpopulations with distinct niche construction adaptive strategies remained stable culture:...
It remains unclear how localized radiotherapy for cancer metastases can occasionally elicit a systemic antitumor effect, known as the abscopal but historically, it has been speculated to reflect generation of host immunotherapeutic response. The ability purposefully and reliably induce effects in metastatic tumors could meet many unmet clinical needs. Here, we describe mathematical model that incorporates physiologic information about T-cell trafficking estimate distribution focal...
The Hybrid Automata Library (HAL) is a Java developed for use in mathematical oncology modeling. It made of simple, efficient, generic components that can be used to model complex spatial systems. HAL's broadly classified into: on- and off-lattice agent containers, finite difference diffusion fields, GUI building system, additional tools utilities computation data collection. These are designed operate independently standardized make them easy interface with one another. As demonstration how...
Abstract Cancer growth can be described as a caricature of the renewal process tissue origin, where architecture has strong influence on evolutionary dynamics within tumor. Using classic, well-studied model tumor evolution (a passenger-driver mutation model) we systematically alter spatial constraints and cell mixing rates to show how structure influences functional (driver) mutations genetic heterogeneity over time. This approach explores key mechanism behind both inter-patient intratumoral...
Adaptive therapy aims to tackle cancer drug resistance by leveraging resource competition between drug-sensitive and resistant cells. Here, we present a theoretical study of intra-tumoral during adaptive therapy, investigate under which circumstances it will be superior aggressive treatment.We develop analyse simple, 2-D, on-lattice, agent-based tumour model in cells are classified as fully or resistant. Subsequently, compare this its corresponding non-spatial ordinary differential equation...
Abstract Molecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of renewal in adult tissues. Here, we show fluctuating DNA methylation marks can be used as cells where ongoing and demethylation cause repeated ‘flip–flops’ between methylated unmethylated states. We identify endogenous CpG (fCpG) sites using standard arrays develop a mathematical model quantitatively human stem from these data. Small intestinal crypts were inferred contain slightly...
Interest in spatial omics is on the rise, but generation of highly multiplexed images remains challenging, due to cost, expertise, methodical constraints, and access technology. An alternative approach register collections whole slide (WSI), generating spatially aligned datasets. WSI registration a two-part problem, first being alignment itself second application transformations huge multi-gigapixel images. To address both challenges, we developed Virtual Alignment pathoLogy Image Series...
The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity study transition malignancy as pre-cancers (adenomas) early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary from pre-cancer carcinoma using computational model, ecological analysis digital pathology data, neoantigen prediction 62...
Introduction Metabolism plays a complex role in the evolution of cancerous tumors, including inducing multifaceted effect on immune system to aid escape. Immune escape is, by definition, collective phenomenon requiring presence two cell types interacting close proximity: tumor and immune. The microenvironmental context these interactions is influenced dynamic process blood vessel growth remodelling, creating heterogeneous patches well-vascularized or acidic niches. Methods Here, we present...
Cancers are complex dynamic systems that undergo evolution and selection. Personalized medicine approaches in the clinic increasingly rely on predictions of tumour response to one or more therapies; these complicated by inevitable tumour. Despite enormous amounts data mutational status cancers numerous therapies developed recent decades target mutations, many treatments fail after a time due development resistance The emergence resistant phenotypes is not easily predicted from genomic data,...
Nongenetic variation in phenotypes, or bet-hedging, has been observed as a driver of drug resistance both bacterial infections and cancers. Here, we study how bet-hedging emerges genotype-phenotype (GP) mapping through simple interaction model: molecular switch. We use chemical reaction networks to implement stochastic switches that map gene products investigate the impact structurally distinct mappings on evolution phenotypic heterogeneity. Bet-hedging naturally within this model, is robust...
Abstract The immune system is a robust and often untapped accomplice of many standard cancer therapies. A majority tumors exist in state tolerance where the patient's has become insensitive to cells. Because its lymphodepleting effects, chemotherapy potential break this tolerance. To investigate this, we created mathematical modeling framework tumor-immune dynamics. Our results suggest that optimal scheduling must balance two opposing objectives: maximizing tumor reduction while preserving...
Toxicity and emerging drug resistance are important challenges in PARP inhibitor (PARPi) treatment of ovarian cancer. Recent research has shown that evolutionary-inspired algorithms which adapt to the tumor's response (adaptive therapy) can help mitigate both. Here, we present a first step developing an adaptive therapy protocol for PARPi by combining mathematical modelling wet-lab experiments characterize cell population dynamics under different schedules. Using data from vitro Incucyte...
Purpose: Our study examines tumor growth dynamics and immunosuppression under the presence of immune attack to identify optimal pulsing treatment strategies. Motivation: While immunotherapy has shown remarkable success in treating many cancers like non-small cell lung cancer (NSCLC), not all patients respond well immunotherapy. This mixed response can be attributed complexity tumor-immune system dynamics. TIL therapy is an emerging where activated T cells are injected into patient. fail due...