Drug development platforms are generally hindered by using unrepresentative preclinical models, such as traditional monolayer culturing systems that fail to reproduce the in vivo or disease state accurately. This leads to a high rate of drug attrition in the developmental pipeline. By using three-dimensional culture systems, such as multicellular spheroids, cells are grown in a more complex representative state, affording them greater physiological relevance, a heterogenous phenotype, differential gradients of drug, nutrient and waste exchange, proteomic fluctuations, and extracellular matrix formation. In doing so, multicellular spheroids display reduced susceptibility to antineoplastic agents, phenotypic gradients throughout the spheroid, and greater relevance to biological studies. The research team focuses on establishing multicellular spheroid models of cancer, including triple-negative breast carcinoma and alveolar carcinoma, and assessing their molecular mediators of dormancy, proliferation and chemoresistance as a means to support drug development platforms. The research is sub-divided into three platforms, namely model establishment and molecular mediators, drug discovery using indigenous knowledge systems, and drug discovery using nanoparticles.

Given the complex three-dimensional architecture, multicellular spheroids develop gradients of nutrient and waste exchange (among others), which in turn also modulates the degree in which certain proteomic ques are regulated. In doing so, multicellular spheroids in different regions develop specific phenotypic characteristics that afford them different functionalities, strengths, and weaknesses. As the exterior of the multicellular spheroid has a high level of nutrient supply, it is highly proliferative, however, also subjected to a higher exposure to chemotherapeutics and their anti-proliferative properties. Cells in the interior of the spheroid reduce their proliferative capacity, entering a state of quiescence to focus on survival rather than mitosis, and tend to be more resistant to anti-neoplastic activity. The sub-division of this research focuses on determining the molecular mediators and functional characteristics between these different regions of the zones to better characterise their dormancy, proliferation and chemoresistance factors. Additionally, new multicellular model development also occurs in this sub-division as needed.

Collaborators: Prof Iman van den Bout (Physiology, University of Pretoria); Dr June Serem (Anatomy, University of Pretoria); Prof Chrisna Gouws (Pharmacen, North-West University)

Applicable research levels: Basic sciences research at MSc or PhD level

Minimum skillsets at MSc and PhD levels: Cell culture (preferably three-dimensional culturing); spectrometric methods; microscopy (preferably fluorescence); Western blotting (at PhD level)

Students: Cara de Moura (MSc candidate); Keith Ncube (PhD candidate); Vacancy available