Catalyzing Translational TSC Research: Novel LAM and AML Cell Culture Models
Abstract
The limited number of cellular models of TSC that are derived from human tissue represents a critical unmet need. Most investigators in our field rely on cell lines derived from mouse and rat models of TSC. While these rodent cellular models have been pivotal in the success of TSC research to date, cellular models derived from human angiomyolipomas (AML) and lymphangioleiomyomatosis (LAM) could catalyze future breakthroughs in translational and preclinical TSC research. This is especially important as we move from understanding the fundamental biology and signaling functions of the TSC proteins (which is similar in rodents and humans) to elucidating the tissue-specific and tumor-specific features that lead to the clinical manifestations of TSC, which are not easily recapitulated in rodents. We and others have tried for many years to establish cell lines from AML and LAM. We have had one major success: 621-101 cells, derived from an angiomyolipoma with inactivation of both copies of the TSC2 gene. This cell line has been sent to at least 20 research laboratories, all over the world, and used in at least 10 research publications to date. The goal of this project is to use state-of-the-art techniques to develop additional cellular models of TSC. The availability of rapid "next-generation" DNA sequencing to rapidly detect somatic (i.e., not inherited) TSC1 and TSC2 mutations in tissue specimens gives us the chance to develop cultures with established mutational inactivation of both alleles (copies) of TSC1 or TSC2 (the "gold standard" for a patient-derived cell line). We will partner with the Cell Line Factory initiative at the Broad Institute of MIT and Harvard to develop both primary and immortalized cultures derived from human LAM and angiomyolipoma specimens. This project involves a team that is perfectly positioned to accomplish our goals: Dr. Henske, who has a bank of early-passage cultures from LAM and AML; Dr. Kwiatkowski, who is an expert in detecting TSC gene mutations even when they are present in only a few cells within a mixed population; and Dr. Boehm, who leads the Cell Line Factory at the Broad Institute of MIT and Harvard. This project will lead to novel and unique scientific resources that can be readily shared with other investigators, worldwide. We expect these cell lines to catalyze and even transform translational and preclinical TSC and LAM research.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510285
Entities
People
- Elizabeth P Henske
Organizations
- United States Army