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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

Sites of memory. Sites of trauma. Sites of healing.

2015-04-01

Judge Albie Sachs – human rights activist and co-creator of South Africa’s constitution – presented the first Vice Chancellor’s Lecture on Trauma, Memory, and Representations of the Past on 26 March 2015 on the Bloemfontein Campus.

His lecture, ‘Sites of memory, sites of conscience’, forms part of a series of lectures that will focus on how the creative arts represent trauma and memory – and how these representations may ultimately pave the way to healing historical wounds. This series is incorporated into the five-year research project, led by Prof Pumla Gobodo-Madikizela, and funded by the Mellon Foundation.

Sites of memory and conscience – and healing

“Deep in solitary confinement, I read in the Bible: ‘the lion lay down with the lamb … swords will be beaten into ploughshares.’” And with these opening words, Judge Sachs took the audience on a wistful journey to the places in our country that ache from the past but are reaching for a better future at the same time.

Some of the sites of memory and conscience Judge Sachs discussed included the Apartheid Museum, Liliesleaf, District Six Museum, and the Red Location Museum. But perhaps most powerful of them all is Robben Island.

Robben Island

“The strength of Robben Island,” Judge Sachs said, “comes from its isolation. Its quietness speaks”. Former prisoners of the island now accompany visitors on their tours of the site, retelling their personal experiences. It was found that, the quieter the ex-prisoners imparted their stories, “the gentler and softer their memories; the more powerful the impact,” Judge Sachs remarked. Instead of anger and denouncement, this reverence provides a space for visitors’ own emotions to emerge. This intense and powerful site has become a living memory elevated into a place of healing.

After Judge Sachs visited the National Women’s Memorial in Bloemfontein some years ago, he came to an acute realisation as he read the stories, experienced the grief, and saw the small relics that imprisoned commandoes from Ceylon and St Helena sculpted. “It’s so like us,” he thought, “our people on Robben Island making a saxophone out of seaweed, our people carving little things. It was so like us. It was another form of inhumanity to human beings in another period.”

The Constitutional Court

The Constitutional Court next to the Old Fort Prison is also a profound site of trauma and healing. Bricks from the awaiting trial lock-up were built into the court chambers. “We don’t suppress it, we don’t say let’s move on. We acknowledge the pain of the past. We live in it, but we are not trapped in it. We South Africans are capable of transcending, of getting beyond it,” Judge Sachs said.

Transforming swords into ploughshares

Judge Sachs had great praise for Prof Gobodo-Madikizela’s research project on Trauma, Memory, and Representations of the Past. “You convert and transform the very swords, the very instruments, the very metal in our country. In a sense, you almost transform the very people and thoughts and dreams and fears and terrors into the ploughshares; into positivity.”

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