At the USP IQ (Institute of Chemistry), research identified genes associated with the spread of pancreatic cancer tumors, which are highly resistant to treatment. Through computational techniques, scientists have been able to pinpoint possible functions in genes such as tumor cell growth and migration to be confirmed in laboratory experiments.
The results of the work will help define new targets for cancer therapy, as well as markers of residual or recurrent disease in treated patients. The study’s findings are presented in an article published in a scientific journal Cellular oncology Last May 14.
“Pancreatic cancer is the seventh leading cause of cancer death in Brazil and the world, and one of the deadliest: patients have a survival rate of less than 5% five years after diagnosis. Currently, the only therapeutic treatment is surgical removal. Professor Eduardo Mores Rego Reis reported to the Journal da USP. “However, the lack of symptoms is difficult to diagnose early and, when it is detected, it often spreads to other parts of the body. It is still a cancer resistant to chemotherapy and immunotherapy.”
The aim of the research was to generate a high-resolution catalog of active genes in pancreatic tumors, focusing on the identification of long non-coding RNAs (IncRNAs). “The functions of incRNAs are still poorly understood by scientists, for example, messenger RNAs, responsible for the synthesis of proteins that express the genetic information contained in DNA,” says the professor.
“We have identified lncRNA genes that play an oncogenic role, that is, they contribute to tumor malignancy-related traits such as high proliferation in tumor cells, substrate-independent growth potential, migration and invasion,” says the professor.
The study analyzed a set of genes (transcriptomes) of 14 pancreatic tumors and non-tumor pancreatic tissues from samples taken from patients.
“For this, all RNAs were isolated, then libraries were prepared for high-capacity sequencing,” Reiss explains. “Data obtained from sequencing were subjected to bioinformatic analysis to reconstruct the sequence of RNAs expressed in the pancreas and to identify lncRNAs with abnormal expression in tumors compared to normal tissue.”
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“From high-resolution sequencing of active RNAs in tumors and normal pancreatic tissue, we identified ‘signatures’ of lncRNAs that produce abnormal expression in tumors, hundreds of them unpublished, not described in the literature. Many of them are related to patient survival. Price to “, says Professor.
“Functional analysis of a set of lncRNAs in pancreatic tumor cell lines showed that the mutation of these RNAs reduced tumor characteristics, such as proliferation, migration and invasion, confirming that they are oncogenic lncRNAs.”
Using a computational approach based on gene co-expression networks, research has identified the role of many oncogenic lncRNAs, indicating potential biological processes where they function and which can be confirmed experimentally. “We demonstrated this approach by demonstrating that one of these RNAs, lncRNA UCA1, is required for DNA repair in tumor cells exposed to ionizing radiation,” says Reiss.
The study will continue with research into the effects of individual and combined silence of oncogenic lncRNAs described in the work, now being used in vivo tumor models.
“For this, we will use a collection of xenotumors already available in our laboratory, implanted in immunosuppressed mice that originate from pancreatic tumors and removed from patients,” the professor pointed out. “We also want to evaluate the presence of lncRNAs in the biological fluids of patients with pancreatic cancer, exosomes of lncRNAs secreted by tumor cells, and pancreatic cancer during treatment.”
“These experiments will be important to evaluate lncRNAs as therapeutic targets or as markers for detecting residual or recurrent diseases in patients undergoing treatment for pancreatic cancer,” Reiss emphasizes. “In this way, in addition to increasing the knowledge about the biology of these RNAs, the work contributes to new molecular targets for diagnostic and potential therapeutic interventions to control the disease.”
The research was conducted in collaboration with a multi-disciplinary team consisting of biochemists, molecular and cellular biologists, bioinformatics specialists and physicians from various units at the USP in the Department of Biochemistry, IQ. FAPESP (Sao Paulo State Research Support Foundation).
The clinical samples analyzed in the study were obtained from the biobank of the AC Camaro Cancer Center in Sao Paulo, which also contributed to the work of the institute’s physicians.