Nature Cancer: Why do some people recover from deadly brain tumors without treatment?

Neuroblastoma is the most common extracranial tumor in children and the most common tumor in infants and young children, also known as the king of childhood canc.

MYC genes are a group of common oncogenes (divided into C-MYC, N-MYC, L-MYC), and many cancers rely on the abnormal expression of MYC as a transcription factor to promote the uncontrolled growth and proliferation of cancer cel.

Recently, a research team from Heidelberg University in Germany and the German Cancer Research Center published a research paper entitled: MYCN mediates cysteine ​​addiction and sensitizes neuroblastoma to ferroptosis in Nature Cancer , a sub-journal of Natur.

This study shows that MYCN-amplified neuroblastoma is highly dependent on cysteine ​​and sensitive to ferroptosis, and blocking cysteine ​​can promote ferroptosis in cancer cells and significantly inhibit tumor grow.

The study also explains why a subset of infants and young children with neuroblastoma heal spontaneously without treatment -- when the cancer cells are rapidly dividing, they deplete cysteine ​​and trigger ferroptosis, thereby eliminating the cancer cel.

It is well known that during the development of multicellular organisms, there are a variety of predetermined and precisely controlled programmed cell death, such as apoptosis (Apoptosis), programmed necrosis (Necroptosis), cell pyroptosis (Pyroptosis), and iron Death (Ferroptosis),e.

Ferroptosis is a novel iron-dependent programmed cell death method discovered by the laboratory of Bre.

At the same time, there are multiple defense pathways against ferroptosis in cells, the most important one of which is mediated by glutathione peroxidase 4 (GPX4), which is specifically catalyzed by glutathione (GS.

Cancer cells are strongly dependent on certain amino acids due to their strong metabolic deman.

Therefore, when cysteine ​​uptake is limited, cysteine ​​is used in large quantities for protein synthesis, which triggers ferroptos.

Neuroblastoma cells with high MYCN expression have a strong demand for cysteine, but restricting the intake of cysteine ​​does not completely block cysteine, because the intracellular can also be removed from methionine through transsulfati.

Therefore, the research team adopted a three-pronged approach to simultaneously block cystine uptake, transsulfuration, and inhibit GPX4 in an orthotopic mouse tumor model of neuroblastoma with high MYCN expression, thereby completely blocking cysteine acid source and inhibited GPX4-mediated ferroptosis inhibiti.

At the same time, the study provides an explanation for the puzzle that some infants and young children with neuroblastoma heal on their own, said Hamed Alborzinia, lead author of the pap.

This study demonstrates that triggering ferroptosis significantly inhibits lethal neuroblastoma, suggesting that MYCN-driven tumor cells' high dependence on cysteine ​​is a novel therapeutic avenue that could be exploited to induce cancer cell dea.

Original source:

Alborzinia,.

, Flórez, AF, Kreth,.

et .

MYCN mediates cysteine ​​addiction and sensitizes neuroblastoma to ferroptosi.

Nat Cancer 3, 471–485 (202
https://d.

org/11038/s43018-022 -00355-