A team at the MD Anderson Cancer Center in the University of Texas found a gatekeeper protein that could prevent the transformation of pancreatic cancer cells into particularly aggressive cell types that could help prevent the lack of such a housekeeping Protein of cancer cells transferred.
The study was published in the Feb. 8 issue of Nature magazine, where researchers passed a series of patient-derived tumor xenografts (PDX) models and mouse models for rapid deterioration and resistance to cancer cells Treatment pointed out the new square.
"Pancreatic cancer cells are characterized by significant plasticity, and cell transformation makes this malignancy difficult to treat," said Dr. Giannicola Genovese, the first author of the article.
Genovese et al. Found that a subgroup of tumor cells, after the original carcinogenic factor did not work, a gene called SMARCB1 would be depleted, leading to cell transformation into a mesenchymal state, that is, migration and invasive cell status. They also found a weakness of mesenchymal cells, that is, in order to meet the increased metabolic needs, overly dependent on accelerating proteins.
The researchers further analyzed the discovery of a heat shock protein 90 inhibitor called AUY922 that blocks protein homeostasis, including protein production, folding, distribution and degradation. Whether used alone or in combination with chemotherapy gemcitabine, are able to increase the efficacy of drugs to extend the lives of sick mice.
One of the keys to cancer treatment is cancer cell molecules and genomic variability, which can lead to functional differences in drug-resistant cancer cells. "We are trying to resolve the cell population within the tumor, hoping to understand the functional weakness of each cell, and then design a more rational combination of treatment," the article's author, MD Anderson Cancer Center genetics professor Giulio Draetta said.
He noted that identifying subgroups of invasive cells and establishing their protease inhibitory weaknesses can help to find the relevant matching cell type, "This is the true functional definition of personalized care."
Reduce the SMARCB1 level, shorten the life
In order to explore the clinical relevance of these findings, the researchers analyzed 134 patients with surgical tumors, which found a group of low levels of SMARCB1 expression, these patients do not rely on KRAS signaling, the prognosis is not good.
Researchers later found that the removal of the SMARCB1 gene in the mouse model resulted in rapid amplification of mesenchymal subpopulations with strong growth and metastasis characteristics, whereas the recovery of SMARCB1 could reverse the mesenchymal cells back to the non-active epithelium , So they point out that SMARCB1 is a housekeeping factor for epithelial cells.
At the same time, the researchers also found that the lack of SMARCB1 cells will accelerate the rate of protein synthesis, activation of many protein-related stress response pathway, in which the expression of oncogene MYC is to maintain SMARCB1 deletion of cell mesenchymal state necessary.
"This work is the first step in understanding why malignant cells have to attack specific genetic programs for stress and survival.Now we have a detailed understanding of the genetic map that drives the occurrence and progression of cancer, but we have a table on the transition state of cancer cells View genetics, metabolism and molecular procedures are still poorly understood, "Genovese said.
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