Reference : Mathematical Histopathology and Systems Pharmacology of Melanoma
Dissertations and theses : Doctoral thesis
Life sciences : Anatomy (cytology, histology, embryology...) & physiology
Physical, chemical, mathematical & earth Sciences : Multidisciplinary, general & others
Business & economic sciences : Multidisciplinary, general & others
Human health sciences : Oncology
Human health sciences : Pharmacy, pharmacology & toxicology
Human health sciences : Multidisciplinary, general & others
Systems Biomedicine; Physics and Materials Science; Computational Sciences
http://hdl.handle.net/10993/39977
Mathematical Histopathology and Systems Pharmacology of Melanoma
English
Albrecht, Marco mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > >]
29-Apr-2019
University of Luxembourg, ​Belvaux, ​​Luxembourg
Docteur en Biologie
200 + 108
Sauter, Thomas mailto
Kreis, Stephanie mailto
Bordas, Stéphane mailto
van den Oord, Joost mailto
Sciumé, Giuseppe mailto
[en] Melanoma ; Tissue ; Cancer growth ; TCAT ; Polymer physics ; Quantitative Systems Pharmacology
[en] 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.
European Commission - EC
Researchers ; Professionals ; Students
http://hdl.handle.net/10993/39977
H2020 ; 642295 - MEL-PLEX - Exploiting MELanoma disease comPLEXity to address European research training needs in translational cancer systems biology and cancer systems medicine

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