10 October 2022

First step towards precision medicine for sarcoma using mini tumors

Bianca-Olivia Nita

Bianca-Olivia Nita

The team of Oncode Investigator Jarno Drost together with other scientists at the Princess Máxima Center have cultured organoids from rhabdomyosarcoma, an aggressive soft tissue tumor, for the first time. The organoids, 3D mini tumors grown in the lab, mimic the genetic and molecular abnormalities much better than the research models used until now. ‘In future we hope to use the organoids to find the best therapy for every child with rhabdomyosarcoma' says Dr. Michael Meister, who led the project. The new study was published last month and is now featured on the cover of the October issue of the journal EMBO Molecular Medicine.

Some 25 children in the Netherlands are diagnosed with soft tissue tumor rhabdomyosarcoma every year. Despite intense treatment with chemotherapy and surgery, less than half of children with high-risk rhabdomyosarcoma survive their disease. Research into better, targeted therapies is desperately needed to improve the survival rates for these children.

Mini tumors

The advantage of organoids is that scientists can grow them from tumor tissue with high efficiency, while the characteristics of the child’s tumor are well preserved. But developing mini tumors can be different for each form of cancer: they can require a different environment to grow properly.

Scientists from the Princess Máxima Center for paediatric oncology collected tumor tissue from 46 children who had been treated there for rhabdomyosarcoma. They tested different methods to grow the mini-tumors and managed to successfully culture an organoid in 41 percent of the samples, 19 in total.

‘Rhabdomyosarcoma can develop anywhere in the body, and there are several subtypes of the disease,’ says clinical researcher Dr. Michael Meister, who led the project. ‘That makes it important to build up a diverse collection of organoids from this form of cancer. Our work certainly doesn’t stop here: we’re continuing to add subtypes to the collection for research to improve treatment for as many children with rhabdomyosarcoma as possible.’

Addition to the arsenal

The researchers in the Holstege and Drost groups analyzed the entire DNA of the organoids and compared it with the DNA of the child from whom the tissue was collected. They found that the genetic code matched, and that the organoids mimicked the disease well. Next, the team looked at the organoids’ sensitivity to existing drugs: organoids with DNA changes known as a drug target did indeed respond well to the associated targeted therapy.

‘Our organoid library forms an important addition to the arsenal of preclinical models of rhabdomyosarcoma. It will allow us to significantly speed up our research into this rare form of childhood cancer and look into entirely new research questions. In the future, we hope to use the organoids to find the best therapy for every child with rhabdomyosarcoma’ says Dr. Meister.

World leader

The rhabdomyosarcoma organoids are the second collection of childhood cancer mini-tumors. They are also the first organoids of a cancer type that arises from the mesenchyme, a cell type that occurs in connective tissue, cartilage and blood vessels.

Group leader and Oncode Investigator Jarno Drost was involved in the research and cultured the first pediatric cancer organoids, from kidney tumors. ‘The first organoids were made from healthy tissue and adult cancers, but childhood cancers are fundamentally different. This likely mesenchyme-derived tissue posed a new challenge, requiring a completely different approach. Our new study strengthens the position of the Princess Máxima Center as a world leader in organoids for paediatric cancer research’ he says.

Team effort

Prof. dr. Frank Holstege, group leader and closely involved in the research: ‘We owe a lot to the children with rhabdomyosarcoma and their parents who made their tissue available for the research. This collection of organoids is truly a team effort, made possible by the integration of care and research expertise at the Máxima. Colleagues from the Biobank, research nurses, oncologists, surgeons, pathologists, diagnostic laboratory and facilities including the big data core, single cell genomics, imaging and high-throughput screening all contributed to this study.’

Rhabdomyosarcoma, like all childhood cancers, is rare. That’s why international collaborations are essential. ‘We’ve been told that the new organoid library is a valuable addition to international research. We have already shared the protocol to grow the organoids with six different institutes around the world, as a starting point to improve treatment for rhabdomyosarcoma in a whole variety of different ways’ says Dr. Meister.

The research was supported by core funding from KiKa to the Princess Máxima Center, with further funding from the Deutsche Forschungsgemeinschaft.

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