This is how metastasis is generated in childhood cancer and how it could be reversed with drugs

2023-06-26 14:45:24

Cancer cells prevent cells around them from fighting the tumor. It has been seen by a team from the Research Institute of Childhood Cancer St. Anna and of the University of Salzburg Paris Lodron (Austria), who is the first to analyze bone marrow metastases from childhood nervous system tumors using modern single cell sequencing analysis. Scientists claim that this process could be reversed with drugs. The findings are published in the journal «Nature Communications».

Neuroblastoma is the most common solid tumor in infants and young children. Despite existing therapeutic options today, more than half of patients with a very aggressive form (high-risk neuroblastoma) still relapse. “We have studied bone marrow metastases because recurrences originate there in most cases. Tumor cells seem to manipulate their environment to support their growth rather than fight them,” explains Sabine Taschner-Mandl, head of the Tumor Biology Group at the Research Institute of Childhood Cancer St. Anna.

The study examined the cellular 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 tumors have been studied in detail, but not neuroblastoma metastases,” says Irfete Fetahu, co-author of the study.

The team looked in more detail at the interaction of metastatic tumor cells with healthy bone marrow cells. “We developed algorithms that allowed us to analyze different cells in the bone marrow, as well as model their interactions,” says Nikolaus Fortelny, head of the Computational Systems Biology Group at University of Salzburg Paris Lodron. ‘Our analysis has shown that certain cells, called monocytes, react to unwanted invaders. In the course of this, they promote growth processes and release cytokines that stimulate tumor growth,” explains Fetahu.

Interestingly, investigations at the epigenetic level showed that although monocytes in the tumor microenvironment are activated to attack cancer cells, they cannot respond appropriately to these signals. “These monocytes receive mixed messages. As a result, they can no longer fight the tumor,” Fetahu explains.

Gene expression of metastatic tumor cells depends on the genetic subtype of neuroblastoma

Communication between neuroblastoma cells and bone marrow or monocytes is largely regulated by MK (midkine) proteins, MIF (macrophage migration inhibitory factor) and associated molecules. Signaling pathways controlled by these proteins are activated in immune cells. “Drugs that target MK and MIF disrupt this pathological interaction and are currently under investigation. Through selective inhibition, it might be possible to return these pathologically altered monocytes to their original state,” says Taschner-Mandl.

The scientists also discovered that cellular plasticity, that is, the ability of cells to change based on environmental influences, is maintained during metastasis. Furthermore, gene expression in metastatic tumor cells depends on the genetic subtype of neuroblastoma. For example, neuroblastoma cells that have MYCN amplification change little when they metastasize from the primary tumor to the bone marrow, whereas ATRX-mutant tumor cells show pronounced differences when they metastasize.

“The genetics of the tumor lead to characteristic signals and therefore very specific changes in the microenvironment of the bone marrow, which are expressed in individual signatures,” explains Taschner-Mandl. This could explain why neuroblastoma patients with ATRX mutations often respond poorly to therapy.”