Neuroblastoma is the most common solid tumour in infants and young children. Despite constantly improving therapy options, more than half of the patients with a very aggressive form (high-risk neuroblastoma) still suffer from relapses.

“We specifically studied bone marrow metastases because recurrences often originate there. The tumour cells seem to manipulate their environment so that it supports their growth instead of fighting them,” explains Sabine Taschner-Mandl, Head of the Tumor Biology Group at St. Anna Children's Cancer Research Institute (St. Anna CCRI).

How cancer cells manipulate their neighbouring cells

The recently published study, therefore, examined the cell architecture and cell-cell communication of neuroblastoma metastases of two major genetic subtypes (MYCN amplification or ATRX mutations) and those without such changes using single-cell transcriptomics and epigenomics. “Until now, only primary tumours have been studied in such detail, but not neuroblastoma metastases,“ says Irfete Fetahu, PhD, co-first author as well as co-corresponding author of the study and postdoc in the Tumor Biology Group.

The team examined the interaction of metastatic tumour cells with healthy bone marrow cells in more detail. “We developed algorithms that enabled us to analyse different cells in the bone marrow as well as to model their interactions,” emphasises Fortelny, head of the Computational Systems Biology Group, Paris Lodron University of Salzburg. "Our analysis has shown that certain cells, so-called monocytes, react to unwanted invaders. In the course of this, they foster growth processes and release cytokines that stimulate tumour growth,” explains Fetahu. Interestingly, investigations at the epigenetic level showed that although monocytes in the tumour microenvironment are activated to attack cancer cells, they cannot respond appropriately to these signals. “These monocytes receive contradictory messages. As a result, they can no longer fight the tumour,“ Fetahu explains the dilemma.

Interfere with pathological immune cell states

The communication between neuroblastoma cells and bone marrow or monocytes is to a large extent regulated by the proteins MK (midkine), MIF (macrophage migration inhibitory factor) and associated molecules. Signalling pathways controlled by these proteins are upregulated in immune cells. “Drugs targeting MK and MIF disrupt this pathological interaction and are currently under investigation. Through selective inhibition, it could be possible to return these pathologically altered monocytes to their original state,“ says Taschner-Mandl.

Metastases act differently

The scientists also found that cellular plasticity, i.e. the ability of cells to change depending on environmental influences, is retained during metastasis. In addition, the gene expression of metastatic tumour cells depends on the neuroblastoma genetic subtype. For example, neuroblastoma cells that have a MYCN amplification only slightly change when they metastasise from the primary tumour to the bone marrow, whereas tumour cells with ATRX mutation show pronounced differences upon metastasis. “The genetics of the tumour lead to characteristic signals and thus very specific changes in the microenvironment of the bone marrow, which is expressed in individual signatures,” says Taschner-Mandl. “This could explain why neuroblastoma patients with ATRX mutations often respond poorly to therapy.”

Source: St. Anna Children's Cancer Research Institute