Mehdipour Group Research Overview
Epigenetic modifications are extensively altered in cancer cells compared with normal cells. Drugs that alter epigenetic modifications –termed ‘epi-drugs’– such as DNA methyltransferase inhibitors (DNMTi), are often designed to restore the expression of silenced genes, such as tumour suppressors. However, an intriguing recent discovery is that epigenetic therapies can mediate anti-tumour effects by activating repetitive sequences, such as retroelements. Active retroelements generate double-stranded RNAs (dsRNAs), which the immune system interprets as a viral infection, and initiating tumour antiviral signalling that fights against cancer cells.
For example, we made the pioneering discovery that DNMTi can reactivate Inverted-Alu (IR-Alu) repeat elements, leading to intrinsic activation of anti-viral pathways in cancer cells, decreasing the cancer cells’ fitness and stemness (Mehdipour, P. et al. Nature. 2020). Based on this work, our group aims to identify immunogenic nucleic acids induced by a variety of cancer treatments across different cancer types. These immunogenic nucleic acids can act as novel biomarkers for predicting the cancer patient’s response to cancer therapy. We will explore whether different types of cancer treatment might reactivate distinct classes of repeat elements with various configurations and then activate different pattern recognition receptors (Figure).
Figure: Tumour antiviral sensing pathway or viral mimicry. During viral infection, dsRNAs accumulate due to viral replication and can be detected by dsRNA-binding proteins, RIG-I, MDA5, PKR and OAS (left panel). Activation of RIG-I like receptors, MDA5 and RIG-I induce Type I/III IFNs. Protein kinase R (PKR) activation results in phosphorylation of eukaryotic initiation translation factor 2-⍺ (eIF2⍺) and inhibition of protein synthesis. Upon binding of an interferon-inducible enzyme, oligoadenylate synthase (OAS), to dsRNA, RNase L is homodimerized and act as an endoribonuclease to degrade RNA. In cancer cells, drugs targeting epigenetic modifiers that are involved in silencing repeat elements (e.g. LINEs, SINEs, LTRs), result in the activation of dormant repeat elements and formation of dsRNAs with various configurations (left). These endogenous dsRNAs mimic a viral infection and can be recognized by cytoplasmic pattern recognition receptors, such as MDA5, leading to induction of type I/III interferons and subsequent activation of interferon stimulated genes (right panel) (ISGs) with interferon-stimulated response elements (ISREs). Activation of the interferon response pathway is associated with loss of cancer cell fitness. The figure was created by smart.servier.com.
We use a variety of molecular biology methods to identify the source of immunogenic nucleic acids that are generated by different cancer therapies, including epigenetic therapies. We are developing a non-invasive screening approach to assess immunogenic nucleic acids and the feasibility of applying them as biomarkers for stratification of cancer patients. As well as linear dsRNAs , we are exploring other types of nucleic acids such as circular RNAs (circRNAs) and how they might be linked to tumour anti-viral responses.
Our previous work has demonstrated that combination of epigenetic therapies, such as DNMTi, with targeting the RNA modifier enzyme ADAR1 led to a significant reduction in cancer-initiating cells in colorectal cancer. We are investigating other combinations of epigenetic modifiers and RNA modifiers that might reduce other types of cancer stem cells.
In our research we will focus mainly on colorectal cancer and acute myeloid leukaemia (AML).
