Dr. Justilien's Molecular Mechanisms of Tumorigenesis Laboratory has several ongoing research projects.
CSC mechanisms of pathogenesis and therapeutic targeting
The cancer stem cell (CSC) population within non-small cell lung cancer (NSCLC) tumors has been shown to be involved in the factors that contribute to poor outcomes, including metastasis and relapse. Therefore, understanding the mechanisms by which cancer stem cells mediate the aggressiveness of NSCLC may provide insights for developing better therapeutic interventions.
Our lab is working to understand interactions among cancer stem cells and non-cancer stem cells and other cells (such as immune, fibroblast and endothelial cells) of the tumor microenvironment. These cells might promote pro-inflammatory changes, angiogenesis, metastasis and drug resistance. Our goal is to uncover therapeutically targetable interactions between cancer stem cells and other cells of NSCLC tumors.
Recent studies have provided evidence that although current conventional therapies eliminate the bulk of tumor cells, they fail to eradicate the CSC population that is able to initiate new tumors, resulting in relapse after therapy. Interestingly, NSCLC cancer stem cells also exhibit intrinsic resistance to conventional therapeutic agents commonly used to treat lung cancer.
These findings have led to the hypothesis that NSCLC cancer stem cells must be effectively targeted to elicit effective and long-lasting therapeutic treatment. Our lab has identified novel signaling pathways that are important in lung cancer stem cell biology and promote their aggressive behavior. With this knowledge, our research team is designing and testing rational and novel combination therapies to eliminate NSCLC cancer stem cells to effectively block the growth and relapse of non-small cell lung cancer tumors.
Oncogenic Ect2 signaling in cancer
Epithelial cell transforming sequence 2 (Ect2) is a guanine nucleotide exchange factor that activates the Rho family of GTPases to elicit cellular processes, such as cell division. Ect2 is frequently aberrantly expressed in cancer cells, including in non-small cell lung cancer and pancreatic ductal adenocarcinoma (PDAC).
We have shown that:
- Ect2 is frequently amplified and overexpressed in cancer and is required for the transformed phenotype of lung and pancreatic cancer cells.
- The oncogenic function of Ect2 is distinct from its well-characterized role in cytokinesis.
- Ect2 localizes to the nucleolus, where it regulates ribosomal RNA (rRNA) synthesis in NSCLC cells, suggesting a novel mechanism by which Ect2 drives tumorigenesis.
- Ect2 is required for lung cancer formation, providing the first demonstration that Ect2 is required for tumorigenesis in vivo.
- Genetic loss of Ect2 impairs growth of lung tumor initiating cells (TICs), suggesting a novel role for Ect2 in tumor initiation and TIC maintenance.
Our goal is to elucidate oncogenic Ect2 signaling mechanisms that contribute to cancer and translate these mechanistic insights into better cancer treatment strategies.
Modeling of lung cancer
Human solid carcinomas develop through stepwise pathological progression. This stepwise development presents an opportunity to therapeutically intervene at a clinically meaningful, early point in the progression of cancer.
In order to identify critical events triggering different stages of cancer progression, more information is needed about the cellular and molecular events associated with the distinct histopathological stages of cancer. Lung cancer provides a good model to study the morphological and molecular changes in cancer progression.
Before invasive lung cancer develops, there are distinct histologic premalignant lesions. For example, carcinogenesis for lung squamous cell carcinoma, a major subtype of lung cancer, includes progression of premalignant lesions from squamous metaplasia to various levels of dysplasia, followed by carcinoma in situ and finally invasive squamous cell carcinoma.
Despite advances in targeted treatments and immunotherapies, lung cancer continues to be the leading cause of cancer deaths worldwide, according to the World Health Organization. Survival of lung cancer has not dramatically improved, mainly because most patients are diagnosed at an advanced stage of disease, when the cancer has already spread, making a cure more difficult.
Our research team is targeting prevention and early detection to help decrease lung cancer mortality. We're developing novel 3D ex vivo organoid cultures to transform lung stem cells to study the earliest steps in lung cancer development. We are also engineering novel mouse models that carry alterations identified in human tumors to study the stepwise pathological progression of tumors. This work will allow us to identify critical cellular and molecular events associated with the distinct histopathological stages and uncover drivers that initiate different stages of cancer progression.
Our goals are to:
- Uncover signaling events critical for cells to progress through the tumorigenesis spectrum.
- Develop biomarkers for early detection of preneoplastic lesions and cancer diagnosis.
- Identify therapeutically actionable targets to prevent the progression to malignant disease.