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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

Historians must place African history on world stage – Dr Zeleza

2017-05-30

From the left: Panellists Rev Henry Jackson,
Prof Irikidzayi Manase and Arno Van Niekerk at a book
launch and panel discussion on Africa Day hosted by the
UFS Sasol Library.
Photo: Mamosa Makaya

“African historians must take seriously the challenge of placing African history in world history, and in the history of our species, Homo sapiens.”

With these words, Dr Paul Tiyambe Zeleza, Vice Chancellor of the United States International University-Africa in Nairobi, Kenya, stressed the continent’s challenge.

According to him the contest should continue to recover and reconstruct Africa’s long history. Liberating African knowledges can be done by: “Provincialising Europe that has monopolised universality, universalising Africa beyond its Eurocentric provincialisation, and engaging histories of other continents on their own terms.”

University celebrates Africa Month in various ways
Dr Zeleza delivered the ninth Africa Day Memorial Lecture, titled The Decolonisation of African Knowledges, at the University of the Free State (UFS). The lecture, hosted by the Centre for Africa Studies (CAS), took place on 24 May 2017 in the Equitas Auditorium on the Bloemfontein Campus and was one of the ways in which the UFS celebrated Africa Month.

Scholars should immerse themselves in these thoughts
Dr Zeleza focused on two issues, which he said were interconnected. They were the unfinished project of decolonising African knowledges and the continent's positioning in global knowledge production.

He said Africa’s scholars and students should “immerse themselves in the rich traditions of African social thought going back millennia”. According to him the continent’s research profile still remains weak in global terms.

“It is imperative that the various key stakeholders in African higher education from governments to the general public to parents, and to students, faculty, staff, and administrators in the academic institutions themselves, raise the value proposition of African higher education for 21st century African societies, economies, and polities.”

“Colonialism is associated with injustice
and inequality, but what happens when
our liberators become our oppressors?”

Library celebrates with panel discussion and book launch
The UFS Sasol Library celebrated Africa Day by presenting a book launch and panel discussion on 25 May 2017, on the pertinent and current political theme of land redistribution with a comparative basis of land invasions in Zimbabwe.

Prof Irikidzayi Manase discussed his book White Narratives: The Depiction of Post-2000 Land Invasions in Zimbabwe, accompanied by Rev Henry Jackson who wrote Another Farm in Africa. A perspective of the economic implications of land redistribution in South Africa was discussed by panellist Arno Van Niekerk: Senior Lecturer of Economics at the UFS Faculty of Economic and Management Sciences.

Inequality still an African problem
The content of the books are a stark reminder of the burning issues of inequality and loss of identity of those who lost their farms in Zimbabwe, a collection of memoirs by white farmers and their families. Rev Jackson gave a religious perspective on reconciliation, forgiveness and the question of land ownership, saying that healing of injustice begins with forgiveness of past transgressions.

Van Niekerk highlighted that while land issues were important, “social cohesion is affected by the economic decisions that will be made”. In closing, Prof Manase called for serious consideration of what the future may hold. “Colonialism is associated with injustice and inequality, but what happens when our liberators become our oppressors?”

The panel discussion was attended by staff and students of the university, and was lit up by robust discussions on possible historical and future solutions to the question of land, decolonisation and political power struggles in Southern Africa and lessons to be learned from Zimbabwe.

UFS celebrates Africa Month (24 May 2017)

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