Project Details
Projekt
Small non-coding RNAs in lung cancer metastasis
Subject Area
Hematology, Oncology
Term
from 2021 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 455258845
Lung cancer remains the leading cause of cancer death worldwidewith an estimated 1.6 million deaths each year. Even recentimprovements in clinical care based on small molecule inhibitors and immunotherapy have not altered the dismal outcome for the majority of patients. Non-small cell lung cancer (NSCLC) is the dominant form of lung cancer which accounts for 85% of all cases. Cure of NSCLC is possible in patients with resectable disease but despite complete resection of stage I and stage II NSCLC, up to half of these patients ultimately die, most frequently from development of distant metastasis. Non-coding RNAs (ncRNAs) have recently gained increased attention in cancer pathogenesis as they have been shown to be associated with metastasis formation and disease severity. Long non-coding RNAs (lncRNAs) such as MALAT1 are well recognized for important roles in lung cancer pathogenesis and prognosis prediction. Beyond lncRNAs, small RNA species exist with less well understood functions in lung cancer. Small nucleolar RNAs (snoRNAs), constitute a group of intron-encoded ncRNAs which range from 60-300 nucleotides in length. SnoRNAs are prominently located in the nucleolus and are required for post-transcriptional modifications of ribosomal RNA (rRNA). Several studies demonstrate that snoRNAs are frequently altered in hematological disorders and solid tumors including lung cancer. In previous experiments we discovered an impact of H/ACA box snoRNAs/RNPs on tumorigenicity and prognosis of NSCLC. We identified, that increased expression of the H/ACA box protein NOP10 was associated with a poor prognosis of NSCLC patients and its deletion inhibited cell growth, proliferation and invasion of lung cancer cells via dysregulation of distinct snoRNAs. Based on these results we aim to determine the function of snoRNAs in the process of metastasis development in Non-Small Cell Lung Cancer (NSCLC). We will perform expression analyses in primary NSCLC patients and CRISPR/Cas9 snoRNA knockout library screenings in metastasis-prone lung cancer cells to identify snoRNAs, which affect metastasis and survival in early stage NSCLC. Candidate snoRNAs will be investigated regarding the mechanisms that determine metastatic capacity using cutting edge technologies.Finally, using antibody-coupled siRNAs we will test new therapeutic approaches to target metastasis- associated snoRNAs in vitro and in mouse models in vivo. These studies will contribute to our understanding of how small non-coding RNAs affect metastasis formation and lead to the development of therapeutic strategies to inhibit growth and metastasis formation in NSCLC.
DFG Programme
Research Grants
