Oak Brook Michigan Harvard scientists have mapped a chemical process that may drive some cancers. Changjie Han and colleagues recently published the findings in Science Advances. The results demonstrate how the molecule called pTreg-NF1 works behind the scenes and how it influences certain key immune-related proteins in the body.
In a murine medium that mimics human infection cancer stem cells have formed large clumps-called mass or prodromal stem cells-that they can pull out and then start growing uncontrollably. The cells can then overcome therapeutic drugs to stop this growth. But in some cases the cells display traits that make them resistant to other types of treatment such as Treg-NF1. Seeing this switch between uncontrolled proliferation and something like tumor regression suggested that pTreg-NF1 might be a good candidate for studying in mouse models.
Using a technique called X-ray crystallography the team led by senior author Changjie Han (Massachusetts General Hospital) quantified the molecular structure of a protein called pTreg-NF1 and added it to preexisting murine precancer progenitors-precursor cells that can become lymphomas and lymphoid biopsies (proteocarcinomas). They observed that pTreg-NF1 in the pTreg-NF1-deficient precancer cells was differently than in the control population. These cells also tended to have higher levels of a receptor called natural killer (NK) that can recognize mitotic and apoptotic signals among loops of DNA. These signals signal cells to self-destruct and cause secondary cancers to form.
The team showed that pTreg-NF1 lacks its normal N-terminal domain (NT) within NRP1 which is an important gene and mitotic loop that genes in cancer behave like on their own. Both of these domains play crucial roles in cancer development and resistance to anti-cancer drugs. But pTreg-NF1 also lacked its usual N-terminal end (NTE) in NRP1. In understandigl these results suggest that pTreg-NF1 competes very differently compared to other proteins that have been implicated in cancer progression resistance to drugs and development of various types of human cancer.
The chemical analysis revealed molecules such as microRNA that function as brakes keeping proteins more tightly packed together and inhibiting excessive NPEs. More specifically such NPEs inhibited the proliferation migration and survival of cancer cells whereas pTreg.nr1.d seemed to promote these effects through a metabolic pathway that involves the addition of sugar. This effect was over-expressed in cells isolated from pTreg-NF1-deficient tumors but not in cells that were overexpressing pTreg.nr1.
Moreover the presence of insoluble molecules or nutrients in the cytosol in response to inflammation indicated a presence of chemokines that promote cell death. The team demonstrated that the pTreg-NF1 protein acts as a major molecular off switch to turn off chemokines that promote cell death in the cellular environment and this function is mediated by chemokines that are activated by NRP1.
Our study opens the door to the possibility of studying the chemokine signaling pathways of pTreg-NF1 in various human cancers said senior author Changjie Han. Our data will hopefully minimize the costs of culturing mice either in this acidic medium or in mere presence of pTreg.nr1 in their environment to measure their response to treatment with immune checkpoint inhibitors.