Mathematical Histopathology and Systems Pharmacology of Melanoma

Doctoral thesis (2019)

Treated metastatic melanoma often becomes resistant and relapses whereby resistance mechanisms can be found at the level of biochemical, histological, and pharmacological data. By using this data in a ... [more ▼]

Treated metastatic melanoma often becomes resistant and relapses whereby resistance mechanisms can be found at the level of biochemical, histological, and pharmacological data. By using this data in a mathematical form, an integrative understanding of tumour progression can be gained that reveal the functionality of more complex and hidden recurrence mechanisms. The aims of this thesis were - to investigate how a new engineering concept on tumour growth, based on porous media theory, can be leveraged to support medicine and cancer biology research, - to identify suitable tests for cancer growth model validation, - to study how elements of biochemical cancer pathways are linked to the elements of physical growth, and - to establish a pharmacokinetics module for the melanoma cancer drug dabrafenib. The studied engineering concept is qualitatively suitable to represent late-stage metastatic melanoma in irregular fibrous tissue types, whereby all equations are tested for biological relevance and parametrisation. The framework allows modelling of tissue-specific growth, and the thesis shows that the simulated tumour can shift between compact growth with ECM displacement and invasive growth with ECM circumvention as a consequence of cell plasticity/viscosity change. This is unique among continuous models of tumour growth. However, the investigation also shows that the pressure-saturation relationships are not biologically motivated and can be replaced by a swelling polymer model which captures the water absorbing effect of glycans. The thesis addresses a biologically and computationally reasonable strategy to validate the tumour growth model as complete as possible. A suitable way to validate a part of the tumour growth model is using time course data of spheroid growth in hydrogels of different stiffness values. Spheroids generated from the LU451 melanoma cell line mainly grow due to ECM degradation, have a time-variant growth rate increasing with gel rigidity, and the confined environment renders the melanoma cell line drug-resistant upon dabrafenib dose escalation. This setting reveals the interplay between mechanical and biochemical development over time. The dependency between biological elements of cancer pathways and the mechanical elements of the engineering concept on tumour growth were clarified. Therefore, the literature on mechanoregulation has been reviewed and serves as a computational link between systems biology and physical oncology. Finally, the thesis provides preliminary steps and a concept toward a serious interdisciplinary methodology to understand tumour growth, although this cannot be considered a final model for any of the known melanoma growth settings. Additionally, the thesis provides a novel quantitative systems pharmacology approach to consider liver-enzyme-induction and drug-drug-interaction. The finding is that the potent dabrafenib metabolite desmethyl-dabrafenib accumulates with consequential efficacy loss in a confined tumour environment. [less ▲]

"Stroma-induced phenotypic plasticity offers phenotype-specific targeting to improve melanoma treatment".

in Cancer letters (2018)

Cancer cells' phenotypic plasticity, promoted by stromal cells, contributes to intra-tumoral heterogeneity and affects response to therapy. We have disclosed an association between fibroblast-stimulated ... [more ▼]

Cancer cells' phenotypic plasticity, promoted by stromal cells, contributes to intra-tumoral heterogeneity and affects response to therapy. We have disclosed an association between fibroblast-stimulated phenotype switching and resistance to the clinically used BRAF inhibitor (BRAFi) vemurafenib in malignant melanoma, revealing a challenge in targeting the fibroblast-induced phenotype. Here we compared molecular features and drug sensitivity in melanoma cells grown as co-cultures with fibroblasts versus mono-cultures. In the presence of fibroblasts, melanoma cells switched to the dedifferentiated, mesenchymal-like, inflammatory phenotype that showed reduced sensitivity to the most of 275 tested cancer drugs. Fibroblasts, however, sensitized melanoma cells to PI3K inhibitors (PI3Ki) and particularly the inhibitor of GSK3, AR-A014418 (GSK3i), that showed superior efficacy in co-cultures. The proteome changes induced by the BRAFi+GSK3i combination mimicked changes induced by BRAFi in mono-cultures, and GSK3i in co-cultures. This suggests that the single drug drives the response to the combination treatment, depending on fibroblast presence or absence, consequently, phenotype. We propose that the BRAFi and GSK3i (or PI3Ki) combination exemplifies phenotype-specific combinatorial treatment that should be beneficial in phenotypically heterogeneous tumors rich in stromal interactions. [less ▲]

Thermodynamically constrained averaging theory for cancer growth modelling

in IFAC-PapersOnLine (2016), 49(26), 289-294

In Systems Biology, network models are often used to describe intracellular mechanisms at the cellular level. The obtained results are difficult to translate into three-dimensional biological systems of ... [more ▼]

In Systems Biology, network models are often used to describe intracellular mechanisms at the cellular level. The obtained results are difficult to translate into three-dimensional biological systems of higher order. The multiplicity and time dependency of cellular system boundaries, mechanical phenomena and spatial concentration gradients affect the intercellular relations and communication of biochemical networks. These environmental effects can be integrated with our promising cancer modelling environment, that is based on thermodynamically constrained averaging theory (TCAT). Especially, the TCAT parameter viscosity can be used as critical player in tumour evolution. Strong cell-cell contacts and a high degree of differentiation make cancer cells viscous and support compact tumour growth with high tumour cell density and accompanied displacement of the extracellular material. In contrast, dedifferentiation and losing of cell-cell contacts make cancer cells more fluid and lead to an infiltrating tumour growth behaviour without resistance due to the ECM. The fast expanding tumour front of the invasive type consumes oxygen and the limited oxygen availability behind the invasive front results automatically in a much smaller average tumour cell density in the tumour core. The proposed modelling technique is most suitable for tumour growth phenomena in stiff tissues like skin or bone with high content of extracellular matrix. [less ▲]