Role of the RNA Modifier METTL3 in Lung Cancer

2023

Health Equity and Inclusiveness Research Fellow Award

Maria Trovero, PhD

Boston Children's Hospital

Boston

In this project, Dr. Trovero will study the role of METTL3, an RNA modifying protein that is thought to promote tumor initiation and progression. She will evaluate the function of METTL3 by increasing or decreasing its activity in vivo. Results from this study will help establish METTL3 as a possible therapeutic target for lung cancer, and pave the way for understanding the relationship between RNA modifiers and cancer biology.

Research Summary

Lung adenocarcinoma (LUAD) is the leading cause of death from cancer worldwide. The survival rate for lung cancer is only about 18%, highlighting the need for more effective treatments. DNA is encoded in our genomes to make RNA, which encodes proteins. However, RNA can have important functions in our cells independent of making proteins, such as exquisite regulation of gene expression. RNA can also undergo chemical modifications. However, the role of RNA modifications in cancer is still poorly understood. METTL3, a protein that modifies RNA, has emerged as a possible oncogene, a gene that promotes tumor growth. Our collaborator Dr. Richard Gregory discovered that METTL3 activity benefits the growth, survival, and invasion of human cancer cell lines (what we call “in vitro”). I aim to explore the role of METTL3 in LUAD initiation and progression in models that more closely resemble reality (“in vivo”). I will evaluate the function of METTL3 in a LUAD mouse model, by studying the effects of decreasing or increasing METTL3 activity on tumor development. I also want to test how METTL3 impacts early stages of lung cancer. Thus, I will manipulate METTL3 expression in a lung tumor organoid system (a simplified 3-dimensional version of an organ generated from stem cells, that recapitulates in vivo tumor growth). The results of this proposal will help to establish METTL3 as a possible future therapeutic target for lung cancer. This investigation could also pave the way for understanding the links between RNA modifiers and cancer biology.

Technical Abstract

Among mRNA modifications, N6- Methyladenosine (m6A) is the most abundant, catalyzed by a complex that includes methyltransferase-like 3 (METTL3). Although the function of m6A in cancer remains understudied, Gregory’s lab provided functional evidence of METTL3 as an oncogenic protein, promoting translation of oncogenes to promote lung cancer cell growth, survival, and invasion in human cancer cell lines. Lung adenocarcinoma (LUAD) is the most common form of lung cancer, with a survival rate of about 18%, highlighting the need for more effective treatments and understanding LUAD biology.

Our hypothesis: METTL3 is a novel oncogenic factor in lung cancer and plays a key role in tumor initiation and progression. I will test the role of METTL3 in a LUAD mouse model, and in tumor organoid culture system.

Aim 1: Determine the effects of METTL3 manipulation on tumor progression in a LUAD mouse model. Lentivirus will be used to knockdown or overexpress METTL3 simultaneously with activation of oncogenic Kras in the LUAD mouse model for comparison of tumor number, size and histopathological features.

Aim 2: Test the effects of METTL3 on early-stage lung cancer by manipulating METTL3 expression in a tumor organoid model of cancer initiation. Alveolar epithelial (AT2) cells from Kras mice will be infected with Cre and shMETTL3 or METTL3 cDNA to initiate early-stage lung cancer in organoid cultures, to assess organoid size, proliferation and differentiation features.

This proposal could establish METTL3 as a therapeutic target for lung cancer and pave the way for understanding links between epitranscriptome and cancer biology.

Key words

Acquired resistance

Adenocarcinoma

Metastatic

Non-small cell lung cancer (NSCLC)

Stage III

Stage IV

Targeted therapy

Role of the RNA Modifier METTL3 in Lung Cancer

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