Arturo Araujo, PhD

Araujo, A., Cook, L.M., Frieling, J.S., Tan, W., Copland, J.A., Kohli, M., Gupta, S., Dhillon, J., Pow-Sang, J., Lynch, C.C. and Basanta, D. (2021). Quantification and optimization of standard-of-care therapy to delay the emergence of resistant bone metastatic prostate cancer. Cancers, 13(4), p.677.

Intestinal glands in the small intestine and colon, or intestine crypts, are an important example of tissue homeostasis regulated by the extracellular environment. The crypts are invaginated structures made of a layer of cells that help absorb nutrients from passing food. However, they are continuously worn away by this process and are being continually renovated by Stem Cells at the bottom of the crypt. These Stem Cells divide to replace worn cells and may even displace other stem cells so that at a given time the whole crypt becomes monoclonal- a descendant of one single Stem Cell. Colorectal Cancer, the second leading cause of cancer-related death in Europe and North America, is thought to start with a mutation of one Stem Cell at the base of the intestinal crypt; which then expands within the crypt until the crypt is composed of monoclonal cells. The time to monoclonality therefore offers a key metric for the successful establishment of mutations; however, the biggest biological contributor to this feature is highly debated. To tackle this, we have abstracted key biological features and modelled them in a bottom-up Agent-Based Model that allowed us to study the biological first principles that rule the fixation of mutations, offering key spatial and temporal understanding of this process. Our results show that the number of basal Stem Cells have a direct influence on the fixations of mutations and suggesting a lesser role for extracellular influences, while proposing the existence of a threshold to the contribution of cell side displacement. Our results have been published as:

• Araujo, A., Zhang, H., Rübben, A., & Bentley, P. J. (2019). Investigating the Origins of Cancer in the Intestinal Crypt with a Gene Network Agent Based Hybrid Model. ALife (pp. 195-202).
• Araujo, A., Rübben  A., Bentley, P. J., & Basanta, D. (2018). Testing Three Hypotheses of the Contribution of Geometry and Migration Dynamics to Intestine Crypt Evolution. ALife (pp. 420-427). doi:10.1162/isal_a_00080
• Rübben A., Araujo, A. (2017) “Cancer Heterogeneity: Converting a Limitation into a Source of Biologic Information” Journal of Translational Medicine. 2017;15:190. doi:10.1186/s12967-017-1290-9.

Bone metastasis is common in prostate cancer progression. In bone, prostate cancer cells derive factors necessary for progression by manipulating bone forming osteoblasts and bone resorbing osteoclasts, resulting in areas of excessive osteogenesis and osteolysis, respectively. Transforming growth factor beta (TGFBeta) is a key factor in the progression of bone metastases. Therapeutic inhibition of TGFBeta however, presents a dilemma since it can have differential effects on various cell types in the tumor-bone microenvironment. In our current study, we have utilised an integrated approach using mathematical and in vivo models to test the impact of TGFBeta inhibition on prostate to bone metastases as a possible therapy. For this, we developed an agent-based mathematical model where the interactions between key cell types and their role on the evolutionary dynamics of the tumour can be studied. Our work has been published in:

• Araujo, A., Cook, L.M., Frieling, J.S., Tan, W., Copland, J.A., Kohli, M., Gupta, S., Dhillon, J., Pow-Sang, J., Lynch, C.C. and Basanta, D. (2021). Quantification and optimization of standard-of-care therapy to delay the emergence of resistant bone metastatic prostate cancer. Cancers, 13(4), p.677.
• Araujo, A., Cook, L. M., Lynch, C. C., & Basanta, D. (2018) Establishment of prostate cancer metastases in the bone. Bulletin of Mathematical Biology. https://doi.org/10.1007/s11538-018-0416-4
• Cook, L. M., Araujo, A.., Pow-Sang, J. M., Budzevich, M. M., Basanta, D., & Lynch, C. C. (2016). Predictive computational modeling to define effective treatment strategies for bone metastatic prostate cancer. Scientific reports, 6.
• Gallaher J, Cook LM, Gupta S, Araujo, A., Dhillon D, Park JY, Scott, J, Basanta, D and Lynch CC. (2014). Improving Treatment Strategies for Patients with Metastatic Castrate Resistant Prostate Cancer through Personalized Computational Modeling. Clinical & Experimental Metastasis, 31(8), 991-999.
• Cook, L. M., Shay, G., Araujo, A., & Lynch, C. C. (2014). Integrating new discoveries into the “vicious cycle” paradigm of prostate to bone metastases. Cancer and Metastasis Reviews.
• Araujo, A.., Cook, L. M., Lynch, C. C., & Basanta, D. (2014). An Integrated Computational Model of the Bone Microenvironment in Bone-Metastatic Prostate Cancer. Cancer Research, 74(9), 2391-2401.

Many cancers are aneuploid (have chromosomal aberrations). However, the precise role that chromosomal instability plays in the development of cancer and in the response of tumours to treatment is still hotly debated. To explore this question from a theoretical standpoint we have developed an agent-based model of tissue homeostasis in which to test the likely effects of whole chromosome mis-segregation during cancer development. In stochastic simulations, chromosome mis-segregation events at cell division lead to the generation of a diverse population of aneuploid clones that over time exhibit hyperplastic growth. Significantly, the course of cancer evolution depends on genetic linkage, as the structure of chromosomes lost or gained through mis-segregation events and the level of genetic instability function in tandem to determine the trajectory of cancer evolution. As a result, simulated cancers differ in their level of genetic stability and in their growth rates. We used this system to investigate the consequences of these differences in tumour heterogeneity for anti-cancer therapies based on surgery and anti-mitotic drugs that selectively target proliferating cells. Our model highlights the difficulties of predicting the outcome of a given anti-cancer treatment, even in cases in which it is possible to determine the genotype of the entire set of cells within the developing tumour. This work was published in :

• Araujo, A., Bentley, P. (2020) Untangling role of chromosome mis-segregation from mutation in cancer initiation. ALife.
• Araujo, A.., Baum, B., & Bentley, P. (2013). The Role of Chromosome Missegregation in Cancer Development: A Theoretical Approach Using Agent-Based Modelling. PloS one, 8(8), e72206.
• Araujo, A., Bentley, P. J. and Baum, B. (2010) Modelling the Role of Chromosome Missegregation in Cancer Therapies. 3rd Complex Systems Modelling and Simulation Workshop. 2010. Luniver Press. 
• Araujo, A., Bentley, P. J. and Baum, B. (2010) Modelling the Role of Aneuploidy in Tumour Evolution. 12th International Conference on the Synthesis and Simulation of Living Systems. 2010. MIT Press. 

And on my science outreach efforts when organising the Pint of Science Festival in Tampa, FL USA: