Our mission is to gain an insight into the mechanisms driving tumorigenesis, drug resistance, metastasis, and to develop personalized targeted therapies and precision medicine to treat both drug resistance and metastasis.
Tumor microenvironment regulates cancer cell survival, metastasis, inflammation, and immune surveillance. There is growing evidence that the lymph node (LN) microenvironment, especially lymph node stromal cells (LNSCs), play a significant role in solid tumor growth, drug resistance, and subsequent extra-nodal metastasis of many types of cancer. A comprehensive understanding of the associated molecular mechanisms and pathways that are involved in tumor progression and metastasis would have substantial benefits for high-risk cancer patients.
Cancer stem cell and tumor microenvironment
Recently, a new class of cancer cells has been identified that may be responsible for tumor recurrence. Referred to as tumor initiating cells (TICs), these cells represent a small population within the original tumor that are resistant to conventional chemotherapeutic and radiation treatments. They also have the ability to produce new (recurrent) tumors that possess all the phenotypic features of the original tumors. We have identified such drug resistant TICs in colon cancer, bladder cancer, and follicular lymphoma cells. These cells are dependent on the LN microenvironment provided by LNSCs. Some of the communication between the LNSCs and TICs may occur by the transfer of exosomal vesicles, small membrane-bound particles containing proteins, siRNAs and mRNAs which have been shown to form functional signaling pathways between cells in vivo. We have recently shown a positive effect of stromal cell exosomal vesicle-derived mRNAs and miRNAs on tumor progression.
Patient-derived orthotopic xenograft models for combination including immune check point inhibitory therapies
To examine the role of LNSCs in tumor progression and metastasis, we established both in vitro cell culture models and in vivo human-in-mouse orthotopic xenograft models using patient tumor specimens, tagged with optical reporter genes. These models recapitulate human cancer features and provide a useful platform for investigating major TIC/LN microenvironment-specific mechanisms of cancer resistance to chemotherapeutic agents in various cancers, such as solid tumor Colorectal Cancer, Renal Cell Carcinoma, Bladder Cancer, Esophageal Adenocarcinoma, Pancreatic Cancer, and B Cell Lymphoma. With noninvasive imaging approaches, the labeled tumor cells can be tracked in vivo, which permits both macroscopic and microscopic analysis of tumor progression and metastasis. Thus, our models provide a powerful mammalian experimental system to elucidate the mechanisms of cancer initiation, maintenance, progression, and provide platforms for combination including immune check point inhibitory therapies.
Prognostic and predictive biomarkers and translate preclinical discoveries into effective cure for cancer patients
The established in vitro and in vivo xenograft models will be used as platforms for dissecting the molecular mechanisms underlying the dissemination of cancer and for preclinical drug development to constitute an integrated bedside to bench approach. As supported by our recent data on renal cell cancer studies, these models can lead to support identification of biomarkers, optimization of clinical candidate selection, and explore novel therapeutic strategies targeting tumor microenvironment in general or to evaluate individual patient tumor cells and predict their response to therapies in an Avatar style approach.