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. This is particularly needed in complex cancers, such as triple-negative breast cancer, where treatment options are limited due to the lack of targeted therapy. The research team makes use of a multicellular spheroid model of triple-negative breast carcinoma to determine the molecular mediators of dormancy, proliferation and chemoresistance as a means to support drug development platforms. The research is sub-divided into two platforms (as per the figure below), namely molecular mediator determination, and drug discovery and development.

Molecular mediator determination

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 BSc.Hons, 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); Charné Scully (MSc candidate); Keith Ncube (PhD candidate)

Resources:
Dissertations: Jie Wang (MSc); Keith Ncube (MSc); Seth-Frerich Fobian (MSc); Melissa Petzer (MSc)
Publications: Seth-Frerich Fobian (2022); Keith Ncube (2023); Melissa Petzer (2025);

Drug discovery and development

Sources for drug discovery are broad, including, but are not limited to phytomedicine (inclusive of indigenous knowledge systems), organic chemistry, and nanomedicine. Although various options are present for drug discovery, a suitable platform is necessary to determine their potential for entering the drug development pipeline. Multicellular spheroids offer such an opportunity. Using the multicellular spheroid model, the research team aims to determine the potential use of various drug sources, such as semi-automated fractions or altered formulations of known compounds, against triple-negative breast carcinoma in isolation or as combination with other chemotherapeutic options.

Applicable research levels: Basic sciences research at BSc.Hons, MSc or PhD level

Minimum skillsets at MSc and PhD levels: Cell culture (preferably three-dimensional culturing); cytotoxicity assessments via spectrometric and/or microscopy; Western blotting (at PhD level)

Collaborators: Prof Vinesh Maharaj (Chemistry, University of Pretoria); Dr Sechaba Bareetseng (CSIR); Dr Eleonor Müller (Chemistry, University of the Free State)

Students: Clarisse Derksen (BSc.Hons candidate); Jessica Pick (BSc.Hons candidate); Ethan Alberts (MSc candidate); Justin Amm (MSc candidate); Sreejarani Kesavan Pillai (PhD candidate)

Resources:
Publications: Seth-Frerich Fobian (2022); Melissa Petzer (2025)