Therapeutic long non-coding RNAs and integrated stress in Cancer

We identify long non-coding 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, a long non-coding 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 long non-coding 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. Long non-coding RNAs vaccines like COVID, but against cancer.

The strategies that the cell uses to make these long non-coding RNAs can be mimicked in the laboratory. For example, we have identified synthetic non-coding RNAs that, when introduced into the cell, are able to control the levels of a therapeutic gene. If the gene is beneficial... great. If the gene produces unwanted side effects... with this RNA we prevent its expression until the patient is well again and can continue with the 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.