Nature Genetics: Does stress make cancer cells stronger?

Mencius said: "Therefore, if the heavens will presume the great responsibility and the human being, he must first suffer his mind, his muscles and bones, hungry his skin, emptied his body, and his behavior is chaotic
.

" Stress and motivation can both oppose each other and transform each other.

But have you ever thought that stress can also make cancer cells stronger and harder to be cured?

But have you ever thought that stress can also make cancer cells stronger and harder to be cured?

Recently, researchers from the University of Connecticut Health Center and Jackson Laboratory published a research paper in the journal Nature Genetics entitled: Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response
.

This study shows that in a stressful environment, such as a chemotherapy drug attack, glioma cells can dynamically modify their genes and change their own gene expression patterns through epigenetic modification, thereby gaining stronger adaptability.
, In order to escape the treatment of anti-cancer drugs
.

Glioblastoma is a very destructive brain tumor.
It originates from glial cells in the brain and is also a common malignant tumor in the brain
.

This kind of brain cancer cells entangle and adhere to normal brain nerve cells, which makes them difficult to remove by surgery

The incidence of glioblastoma is about 3 to 4 cases per 100,000 people.
Based on this estimate, the number of new-haired glioblastoma patients in China each year is about 40,000 to 40,000
.

The treatment of glioblastoma usually includes surgery, radiotherapy and chemotherapy

Drug resistance stems from tumor heterogeneity, and tumor heterogeneity is usually driven by different genetic, epigenetic, and transcriptional aberration sub-cell populations
.

Therefore, it is very important to understand how glioblastoma acquires heterogeneity under stressful conditions and to design new treatment options for this

In this study, the research team first noticed that glioblastoma is prone to changes in epigenetic modifications, especially DNA methylation
.

Previous studies have confirmed that random DNA methylation changes contribute to tumor heterogeneity and cellular plasticity, thereby promoting the evolution of anti-therapeutic phenotypes

Based on this, the research team integrated 914 single-cell DNA methylomes, 55284 single-cell transcriptomes and a large number of multi-omics analyses from 11 glioma patient samples to describe the source of intratumoral heterogeneity.
The definition is The epigenetic state that contributes to tumor evolution
.

Research pattern diagram

Research Mode Diagram Research Mode Diagram

The researchers combined these in vivo analyses with in vitro perturbations to identify gene regulatory regions most susceptible to random DNA methylation changes, epigenetic regulation of transcription networks involved in glioma cell recognition, and DNA methylation disorders The cellular stress response that may be promoted
.

Research results show that in glioblastoma, local DNA methylation disorder is related to cell-cell DNA methylation differences, and it is increased in more aggressive tumors, which is related to transcription interruption, and Change in response to environmental stress
.

Single-cell DNA sequencing highlights the link between heterogeneity within epigenetic tumors and local DNA methylation disorders

Single-cell DNA sequencing highlights the relationship between epigenetic tumor heterogeneity and local DNA methylation disorders Single-cell DNA sequencing highlights the relationship between epigenetic tumor heterogeneity and local DNA methylation disorders

Not only that, glioma cells increase local DNA methylation disorders and change the cell state under conditions of hypoxia and radiation stress in vitro
.

In addition, the researchers also found that there is a positive correlation between the genetic and epigenetic instability of glioma cells, which is supported by a large number of longitudinally collected DNA methylation data

Disorders of DNA methylation of gene regulatory elements are related to cell recognition and stress response pathways

Disorders of DNA methylation of gene regulatory elements are related to cell recognition and stress response pathways .
Disorders of DNA methylation of gene regulatory elements are related to cell recognition and stress response pathways.

More importantly, in a stressful environment, such as chemotherapy drugs or radiation attack, the DNA methylation disorder associated with accelerated disease progression in glioma cells increases, and the survival-related DNA methylation changes will be affected by the environment.
The continuous enrichment in the stimulation pathway will eventually enable the glioma cells to gain stronger adaptability
.

Under the stress of anti-tumor therapy, glioblastoma undergoes adaptive DNA methylation changes

Dr.
Roel GW Verhaak, the main leader of this research, said: “This paper emphasizes a mechanism through which tumor cells may adapt to our treatment methods
.

Understanding these tactics used by tumors allows us to treat more effectively.

Original source:

Original source:

Johnson, KC, Anderson, KJ, Courtois, ET et al.

Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response in this message