Hope alive as Kenyan leads study on cancer

From lecturing Biochemistry and Biomedical Sciences at the Department of Biochemistry at Kisii University, Sospeter Njeru is now leading a promising cancer research in Germany. 

The research, published in the Springer Journal in October 2019, could lead to the development of a cure for lymphoma, a cancer of lymphoid immune cells, and several others such as breast, bladder, testicular and pancreatic cancers.

The research, which Dr Njeru and his peers in Germany conducted by experimenting on mice, aims to find a cancer cure by analysing the role of aneuploidy in shaping the human genome during the development of cancer.

Aneuploidy occurs when chromosomes fail to separate properly between two cells during the process of cell division, leading to an abnormal number of chromosomes. Aneuploidy can, in turn, lead to the formation of cancerous tumours, thereby leading to cancer.

“We were looking at novel molecular and biochemical mechanism that promotes cancer development. The rationale was that the reason there are no effective cancer drugs to date may be because we have been working on the wrong or non-effective therapy target,” Njeru says of the premise of the study.

The research brought together experts, all of whom brought unique expertise ranging from computational work to pathology and lipidomics investigations.

Njeru said: “In our study, we screened the entire human genome, targeting 16,500 genes by manipulating cells to express a low amount of the targeted gene products through an shRNA gene knockdown technology.”

Through this technique, Njeru says, the researchers knocked down three of the most robust selected candidate genes (ORP3, GJB3 and RXFP1) and consequently induced aneuploidy in mice.

By inducing aneuploidy in the mice, the researchers thereby enhanced the transformation of healthy human fibroblast cells into cancerous cells, thereby causing cancer.

Progenitor cells

Njeru added: “Further investigation of an Orp3 knockout mouse model (a mouse deficient of Orp3 expression) showed that loss of Orp3 results in an abnormal expansion of bone marrow immune stem cells, specifically the lymphoid stem and progenitor cells.”

He said during the experiment, the mature lymphoid cells from these mice exhibited a deregulated phospholipid metabolism and an abnormal induction of proliferation regulating molecular pathways.

Njeru says aging mice from the Orp3 knockout mouse model developed B cell lymphoma that spread to all organs except the brain and muscles.

Further analysis by the researchers demonstrated that the B cell lymphoma could have originated from a limited number of cells that multiplied abnormally and spread to other parts of the body.

The Orp3 knockout mouse model characterised in the study can be used to decode the molecular mechanisms used by drug-resistant cancer cells, Njeru says, signaling progress in finding a cancer cure.

The model opens an avenue for the de?nition of new therapeutic approaches to the prevention and treatment of human cancer.

Widespread debate

While there has been widespread debate on whether aneuploidy leads to cancer development or protection, the study confirmed this using an in vitro (culture-based experiments) as well as in vivo (experiment in living animals) that aneuploidy indeed leads to the development of cancer.

According to them, the mouse model will lead to new therapeutic approaches that can be applied in preventing and treating human B cell lymphoma. While many scientists across the world are involved in cancer research, Njeru says this particular study is different in a couple of ways.

“What was different from all other studies was identification of gene sets that had not been associated with cancer development,” he says.

His study was the first to show that the loss of ORP3 leads to the development of B cell lymphoma, as well as the first to demonstrate that genes not directly associated with cell division can indeed interfere with cell division, leading to the development of cancer.

Njeru conceived the research at the Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) – in 2014 in Jena, Germany, being supervised by two professors.

But it was not until he joined the Friedrich-Schiller University for his doctorate studies.

“On joining the laboratory for my PhD studies, I worked on one of the top candidate genes (ORP3) identified in the screen. I characterised the phenotypic and molecular consequences of loss of ORP3 using cells manipulated by CRISPR/Cas9 technology and an Orp3 knockout mouse model,” he says.

Interestingly, Njeru not only introduced the technology among his research group but was also among the first scientists to learn and use the technology at the institute.

He anticipates that the research model will be critical in defining new therapeutic approaches that will be used to prevent and treat human B cell lymphoma.

He speculates that the model will be valuable in studying other types of cancer such as breast, bladder, testicular and pancreatic.