Scientists at the University of Missouri and Yale University have discovered that one of the mutations in the RAS family of genes, which impede treatment options, is also responsible for allowing tumour regrowth following genotoxic therapy.
Genotoxic therapies cause DNA damage inside cancer cells in order to destroy them . To avoid being eliminated, cells will stop replicating and try to repair the damage, but if they fail to do so, they will trigger cell death, relying on a protein called “p53”.
While RAS gene mutations have been studied for over three decades, scientists today have a better understanding of how they work. However, many of them still consider these mutations to be “undruggable” or resistant to therapeutic treatment, according to the National Cancer Institute.
“Most of our knowledge of how cells respond to DNA damage is mainly derived from studies looking at the single cell level,” said Yves Chabu, an assistant professor in the MU College of Arts and Science. “Therefore, we don’t know much about how tumour cells respond to DNA damage in the broader context of the tissue level, and what possible implications these responses might have on a tumor’s relapse following genotoxic therapies. To address this, we looked at how tissues containing patches of cells carrying oncogenic RAS mutations respond to DNA damage. We focused on oncogenic RAS because it is associated with cancers relapse and resistance to genotoxic therapies in humans. This approach has allowed us to identify novel cell-to-cell communication within the tissue that instructs tumour cells in tissues to regrow. It’s something we would not have identified if we were only looking at the single cell level.”
“We found that in oncogenic RAS tissues, cells elevate the levels of the p53 protein to varying degrees in response to DNA damage,” said Prof Chabu, whose appointment is in the Division of Biological Sciences. “Further analyses revealed that cells with high p53 protein levels, or more extensive DNA damage, do not simply die in response to the DNA damage. Instead, they release a growth signal called interlukin-6 into the tumor environment. Interlinkin-6 instructs cells with low p53 levels, or cells with less DNA damage, to activate JAK/STAT, a growth-amplifying signal, and drive tumor regrowth after treatment. We essentially have a situation where cells that are vulnerable to the treatment are instructing the more robust cells to take over and grow.”
Prof Chabu, who has been studying oncogenic RAS mutations for more than a decade, said that this further suggests that adding JAK/STAT inhibitors to genotoxic therapies inhibit the regrowth ability of RAS tumours. He said another interesting aspect of their findings is that p53 is traditionally considered as a tumour suppressor protein.
“A loss of p53 activity, due to genetic mutation, causes cells to grow uncontrollably while accumulating even more DNA mutations,” said Prof Chabu. “So, naturally one would think that having more p53 activity is a good thing because it prevents pre-cancerous cells from growing and forming cancers. Yet, here we find that too much of a normal, not mutated, p53 can signal the surrounding RAS tissues to overgrow.”
Source: Medical Xpress
Journal information: Yong-Li Dong et al, Cooperation between oncogenic Ras and wild-type p53 stimulates STAT non-cell autonomously to promote tumor radioresistance, Communications Biology (2021). DOI: 10.1038/s42003-021-01898-5
