Therapeutic non-coding RNAs and integrated stress in cancer
"RNA is the medicine of the future. It is time to study the code that allows us to predict a function from an RNA sequence and how cellular stress influences it".
DRA. Mª PURIFICACIÓN FORTES ALONSO AND DR. JOSEPMARIA ARGEMI BALBE
RESEARCHERS. RESEARCH GROUP ON THERAPEUTIC NON-CODING RNA AND INTEGRATED STRESS IN CANCER
Microproteins, non-coding RNAs and antitumor biotechnology
Cells, especially tumor cells, evolve to produce thousands of different RNAs that fold into specific structures and bind to proteins, DNAs or other RNAs to perform functions that, sometimes, contribute to the malignancy of the cell.
These RNAs, called non-coding, are unused therapeutic targets with enormous potential.
If we manage to identify and block them, we will have treatments that prevent tumor malignancy and/or facilitate tumor destruction.
"Cellular stress dramatically modulates how RNA is translated, and the integrated stress response is the Achilles heel of the cancer cell".
We study non-coding RNAs from 4 different aspects:
We identify RNAs that are produced in the most prevalent liver cancer: hepatocellular carcinoma. We study those that are essential for the survival of the tumor cell and that are related to the treatments that are currently used in the clinic, such as tyrosine kinase inhibitors, immunotherapy or chemo or radiotherapy. For example, NIHCOLE, an RNA that works like a staple that repairs DNA broken by radiotherapy. We think that blocking NIHCOLE while giving radiotherapy would increase the levels of broken DNA, leading to tumor cell destruction.
We identified RNAs from hepatocellular carcinoma and triple negative breast cancer that are capable of producing small proteins. We are interested in microproteins important for tumor generation and growth, because they would also be excellent therapeutic targets and drugs. In addition, we have found that many of them are tumor-specific. This allows us to develop vaccines against these tumors based on microproteins. RNA vaccines like COVID, but against cancer.
We can imitate the strategies that the cell uses to make these non-coding RNAs... in the laboratory! Using this, we have identified synthetic non-coding RNAs that, when introduced into the cell, are capable of controlling the levels of a therapeutic gene. If the gene is beneficial... great. If the gene produces unwanted side effects... with this RNA we can prevent the expression of the therapeutic gene until the patient recovers from the unwanted effects and can continue with the therapeutic treatment.
We also study how different states of cellular stress, especially that which triggers the so-called integrated stress response, impact the translation of microproteins. For example, we are seeing how if we decrease the ability of cancer cells to organize their stress response, the cell ends up completely changing its proteome and becomes more sensitive to immunotherapy.
Getting to know RNAs better
This photo could represent a small primitive horse running. In reality, it is a picture of NIHCOLE obtained by atomic force microscopy. NIHCOLE is an RNA that acts as a staple to join DNA molecules broken by radiotherapy. Each image represents a single NIHCOLE molecule. When NIHCOLE binds to the DNA repair machinery, the image changes drastically.
Meet the research team
Scientific activity of the Therapeutic non-coding RNAs and integrated stress in cancer Research Group
Latest scientific publications
- Prognostic Value of Ultra-Low-Pass Whole-Genome Sequencing of Circulating Tumor DNA in hepatocellular carcinoma under systemic treatment Dec 29, 2023 | Magazine: Clinical Molecular Hepatology
- Engineering U1-Based Tetracycline-Inducible Riboswitches to Control Gene Expression in Mammals Dec 12, 2023 | Magazine: ACS Publications
- ISR8/IRF1-AS1 Is Relevant for IFNα and NF-κB Responses Jul 4, 2023 | Magazine: Frontiers in Immunology
- U1A is a positive regulator of the expression of heterologous and cellular genes involved in cell proliferation and migration Jun 14, 2023 | Magazine: Molecular Therapy Nucleic Acids
Rational to modulate the Microbiome-induced Endoplasmic Reticulum stress as tool to avoid the immune evasion in Hepatocellular Carcinoma (RETO)
Immune4ALL. Exploring the feasibility of predictive and pharmacodynamic biomarkers of immunotherapy in solid tumors
14 Jun 2022