Advancing the health and well-being of animals and people


Principal Investigator: Robert Weiss

Contact Information: Email: rsw26@cornell.edu; Phone: 607-253-4443
Sponsor: New York State Department of Health-NYSTEM
Grant Number: C026421
Title: Investigating How DNA Damage Response Mechanisms Regulate the
Tumorigenic Potential of Pluripotent Cell Types Using Mouse Models of
Testicular Germ Cell Tumors

Annual Direct Costs: $137,083
Project Period: 09/01/10-08/31/12

DESCRIPTION (provided by applicant):  The tremendous therapeutic potential of pluripotent stem cells is accompanied by a significant cancer risk. The objective of the studies proposed here is to use testicular germ cells as a model for understanding how a key tumor suppressor mechanism, the DNA damage response (DDR), influences the response of pluripotent stem cells to oncogenic signals and impacts the treatment sensitivity of stem cell-derived neoplasms. The DDR provides a potent anti-cancer barrier that prevents mutations that could contribute to malignant transformation. Solid tumors typically exhibit DDR activation, and mutations in critical DDR factors like p53 are common in cancers. Interestingly, DDR activation and mutations are extremely rare in testicular germ cell tumors (TGCTs), which originate from pluripotent germ cells that share many properties with embryonic and induced pluripotent stem cells. TGCTs, the most common cancers in young men, also are unusual in their sensitivity to DNA-damaging chemotherapeutics. We hypothesize that the stem cell-like properties of primordial germ cells, from which TGCTs arise, account for these atypical DDR characteristics and that an intact DDR in TGCTs mediates efficient killing by genotoxic therapeutics. We will test this hypothesis by investigating genomic integrity, DNA damage signaling, and chemotherapeutic sensitivity in an existing mouse testicular teratoma model (Aim 1), as well as in novel mouse TGCT models designed to more closely resemble the human disease (Aim 2). In Aim 3, we will compare DDR signaling and processes in normal testicular germ cells, transformed TGCT cells, embryonic stem cells, and induced pluripotent stem cells, as well as primary somatic cells. These experiments will provide important insights into how unique DDR signaling in TGCTs and pluripotent stem cells influences the initial steps in oncogenic transformation as well as treatment sensitivity in advanced cancers, towards the ultimate goal of developing more effective cancer treatments and safer stem cell therapies.