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Researchers develop breast cancer spheroid models to study drug response and resistance

04 December 2024 | Story André Damons | Photo André Damons

Breast Cancer Research 2024 — The research team consist of Dr Beynon Abrahams (left), Viwe Fokazi, MMed.Sci student, and PhD student Songezo Vazi.

In an effort to better understand chemotherapeutic treatment response in triple negative breast cancer (TNBC) – known as an aggressive cancer with high recurrence and high mortality rate in breast cancer patients – researchers from the University of the Free State (UFS) developed a drug-resistant TNBC spheroid model that is physiologically more accurate in displaying the complexities involved in drug-resistance development.

Dr Beynon Abrahams, Lecturer in the Department of Basic Medical Sciences within the UFS Faculty of Health Sciences, says breast cancer remains the most frequently diagnosed cancer in women. It is also the most debilitating type of cancer responsible for the highest cancer mortality rates in women. Though various subtypes of breast cancer exist, TNBC is one that is of particular interest to his research team.

“TNBC is one of the most difficult cancer types to treat, due to lack of treatment targets. This often leads to treatment failure in TNBC patients, with drug resistance being a common occurrence, contributing to high death rates. TNBC is classified based on its lack of expression of common receptors such as the estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, which are commonly expressed in other cancer subtypes.

“Characteristically, TNBC is known as an aggressive cancer with high metastatic potential (spreading of cancer), resulting in a poor prognosis for these patients. The current prescribed therapies for TNBC, entails multidrug combination systemic therapy including chemotherapeutic agents such as doxorubicin and cisplatin as adjuvant therapy. However, despite these therapeutic interventions, drug resistance is a common occurrence,” says Dr Abrahams.

The best available preclinical cell-based models should be used

For effective drug treatments to be developed for TNBC therapeutics, he continues, the best available disease models should be used to not only improve our understanding of the disease physiology and its numerous mechanisms involved in chemotherapeutic resistance development but also to provide accurate results when determining how safe and effective newly developed drugs are, before they may be considered for further development and testing on humans.

According to him, in preclinical cancer research the conventional methods employed to study disease mechanisms, drug action and drug resistance is ineffective. Firstly, the traditionally used preclinical 2-dimensional (2-D) cell culture models do not accurately recapitulate the architectural biology observed in vivo, second, the drug responses assessed in these models may provide inaccurate results and limit its translational potential, explains Dr Abrahams. Thus, more advanced cell-based models such as 3-dimensional (3-D) spheroids and organoids to name a few, should be considered as alternatives.

The UFS research team, in collaboration with the Centre of Excellence for Pharmaceutical Sciences (Pharmacen™) at the North-West University (NWU), recently took the undertaking to establish two triple negative breast cancer 3-D spheroid models, using the clinostat rotating bioreactor ClinoStar™ system, designed by CelVivo in Denmark. The project is funded by the National Research Foundation.

The ClinoStar™ system promotes the self-aggregation of single cells, and natural formation of 3-D spheroids, through slow rotation within a cell growth chamber known as an incubator. There are various techniques and methods available to develop spheroids and organoids, however the ClinoStar™ systems allow for the development of metabolically stable spheroids, over a longer period of time, as opposed to other methods. It also eliminates the sheer-stress conditions that are normally encountered when using 2-D cell culture models.

“We successfully established one chemotherapeutic-sensitive triple negative breast cancer spheroid model and one novel cisplatin-resistant triple negative breast cancer spheroid model. The chemo-sensitive TNBC spheroid model was evaluated for responsiveness against two clinically used chemotherapeutic agents, doxorubicin and cisplatin. We suggest that this model may be useful to screen novel compounds including traditionally used phytomedicinal material for anticancer activity.

“In our second model, the cisplatin-resistant TNBC spheroid model was also exposed to cisplatin and doxorubicin and demonstrated a resistant response in terms of growth and viability. We believe that this model may be useful to further explore drug resistance mechanisms and may also be used as a tool to assess the drug reversal potential of novel compounds. The value and impact of these models lies in that they may offer predictive drug responses that are closer to that observed in in vivo (animals), as opposed to 2-D cell cultures. This however needs to be assessed. We are currently in the process to fully characterise these spheroids models.”

Aim of the research

Dr Abrahams explains their research aims to merge the gap between conventionally used 2-D cell models and in vivo models, by providing a model that is physiologically more accurate in mimicking the in vivo conditions and complex pathways associated with drug resistance, which is otherwise not observed or accurately expressed in 2D models. “Although our research is preclinical and considered fundamental basic research, the translational potential of our spheroid models may provide options for exploring and testing alternative drugs that may be considered for translational research,” Dr Abrahams says.

Characterising other advanced cell-based cancer models

The team is currently in the process of further characterising the TNBC spheroid model based on protein and genetic expression profiles to elucidate potential therapeutic biomarkers for drug treatment as well as screening various phytomedicinal plants, to assess their antiproliferative and drug-resistance reversal potential. In addition, the researchers recently commenced a new research project that aims to develop a drug-resistant prostate cancer spheroid model using the Clinostar™ system with their collaborators at the NWU.

Advanced cell-based model research is still relatively ‘new’ in South Africa and Africa, compared to the global North. As a result, says Dr Abrahams, their NWU collaborators together with other stakeholders, initiated the establishment of the Society for Advanced Cell Culture Modelling for Africa (SACCMA) in 2021, which aims to develop the fields of advanced cell modelling, three-dimensional (3D) cell cultures, 3D bioprinting and stem cell research, in Africa. Our current inter-departmental collaboration include researchers from the Pharmacology department, but we hope to build and expand our collaboration network in the near future.

News Archive

UFS Department of Physics offers unique learning experience with on-campus radio telescope

2015-12-14

Athanasius Ramaila, an Honours student in the Department of Physics, and Dr Brian van Soelen, a lecturer from the same department, in the laboratory where the radio telescope is housed in the new wing of the Physics Building on the Bloemfontein Campus of the UFS. The telescope will be used to expose graduate students to the basic techniques of radio astronomy.
Photo: Charl Devenish

The university this year added a four-storey wing to the existing Physics Building on the Bloemfontein Campus. The new development, which includes four lecture halls and four laboratories, complements other world-class facilities such as the X-ray photoelectron spectroscope and the scanning electron microscope.

A unique asset that distinguishes the UFS Department of Physics from other similar institutions, is the Boyden Observatory situated approximately 27 km northeast of Bloemfontein. The observatory houses a powerful 1.5 m optical telescope, and several smaller, but well equipped telescopes.

According to Pieter Meintjes, Professor in the Department of Physics, the observatory has acquired a new addition - a 0.5 m optical telescope donated by the South African Astronomical Observatory (SAAO) and the National Research Foundation (NRF) to the UFS Astrophysics Group. This optical telescope is one of two powerful optical telescopes used to introduce students to techniques such as photometry and spectroscopy.

“The telescope at Boyden forms an integral part of the Department of Physic’s student training and research programme. Because the UFS is the only university in South Africa operating such a facility, and one of only a few globally, Astrophysics students at the UFS have the unique privilege of having unrestricted access to these telescopes for their MSc and PhD studies,” says Prof Meintjes. In addition, the department has also built a radio telescope as part of a post-graduate student project. The telescope, housed in the new wing of the Physics Building at the Bloemfontein Campus of the UFS, will be used to expose graduate students to the basic techniques of radio astronomy, especially in light of the fact that the SKA is nascent. Prof Meintjes would like to act proactively by grounding his students in the relevant techniques of radio astronomy. The telescope will be used to introduce students to the manner in which radio flux calibrations are performed in order to determine the energy output of an emitting source.

At undergraduate level, the radio telescope will be used, together with optical telescopes in the Astrophysics laboratory, to place students at a high baseline regarding the level of multi-wavelength astrophysics training received at the UFS.

Third-year and Honours students will also have the opportunity of practical training in a research laboratory with 15 computers. The laboratory is equipped with software used to reduce and analyse multi-wavelength data.

“My goal is for the UFS to become the major centre of multi-wavelength astrophysics in South Africa and a key role player in the international arena. To be able to do this, our training should be world class,” Prof Meintjes said.

Aided by its world-class facilities and research, the Department of Physics is competing with the best in the world. Research-wise, a group from the Department of Physics is intensively involved with the SKA Project (Square Kilometre Array), with 3 000 dishes reaching from Carnavon in the Karoo to Mauritius in the Indian Ocean. According to Prof Meintjes, many detailed studies can be conducted with the SKA system of sources, showing major eruptions and mass effluent from the systems. Athanasius Ramaila, a BSc Honours student in Astrophysics at the UFS, has also received a two-year SKA internship, where he will be engaged in the SKA software engineering programme to help with developing software for the telescope.

The UFS Astrophysics Group is focusing on the multi-wavelength study of high-energy astrophysics sources. “This multi-wavelength approach to astrophysics is in line with the recent announcement by government that multi wavelength astrophysics will be the main focus for astrophysics research in South Africa. It is also a very important focus for research in the international arena, as can be seen from the large number of international conferences having a multi-wavelength character,” Prof Meintjes said.

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