Cancer is the second leading cause of death in the US. Except for some germ cell cancers, leukemias and lymphomas, metastatic cancer is generally an incurable disease. Recent work has made great strides in our understanding of the genetic changes that lead to cancer. However, our understanding of the consequences of these oncogenic mutations at the cellular level in tissues in which cancers arise has lagged. This laboratory has begun to apply the principles of stem cell biology to understand the biology of the cancer cells found in solid tumors. Preliminary evidence demonstrates that similar to acute leukemia, solid tumors contain distinct populations of tumorigenic and non-tumorigenic cancer cells. The tumorigenic cancer cells can be prospectively identified based upon marker expression. Self-renewal is critical for both normal stem cells and tumorigenic cancer cells. In a normal tissue, stem cell numbers are under tight genetic regulation resulting in the maintenance of a constant number of stem cells in the organ. By contrast, tumorigenic cancer cells have escaped this homeostatic regulation and the number of cells within a tumor with the ability to self renew is constantly expanding, resulting in the inevitable growth of the tumor. The goal of this grant is to begin to understand the similarities and differences of normal stem cells and tumorigenic cancer cells derived from patients with AML or solid tumors. Specifically we plan:
Specific Aim # 1. To determine whether a single tumorigenic cancer cell can generate the heterogeneous populations of tumorigenic and non-tumorigenic cancer cells.
Specific Aim # 2. To determine whether the proportion of tumorigenic cancer cells in a tumor changes during tumor growth.
Specific Aim # 3. To determine whether the phenotype of the tumorigenic cancer cells changes during passage in the xenograft mouse model.
Specific Aim # 4. To identify the genomic makeup of tumorigenic cancer cells from multiple tumors and to determine whether tumorigenic solid tumor cancer cells and tumor-initiating leukemia cells share expression of """"""""stem cell genes"""""""" with normal stem cells.
| Isobe, Taichi; Hisamori, Shigeo; Hogan, Daniel J et al. (2014) miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. Elife 3: |
| Adorno, Maddalena; Sikandar, Shaheen; Mitra, Siddhartha S et al. (2013) Usp16 contributes to somatic stem-cell defects in Down's syndrome. Nature 501:380-4 |
| Bockhorn, Jessica; Dalton, Rachel; Nwachukwu, Chika et al. (2013) MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Nat Commun 4:1393 |
| Rothenberg, Michael E; Nusse, Ysbrand; Kalisky, Tomer et al. (2012) Identification of a cKit(+) colonic crypt base secretory cell that supports Lgr5(+) stem cells in mice. Gastroenterology 142:1195-1205.e6 |
| Shimono, Yohei; Zabala, Maider; Cho, Robert W et al. (2009) Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138:592-603 |
| Cho, Robert W; Wang, Xinhao; Diehn, Maximilian et al. (2008) Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors. Stem Cells 26:364-71 |
| Dalerba, Piero; Cho, Robert W; Clarke, Michael F (2007) Cancer stem cells: models and concepts. Annu Rev Med 58:267-84 |
| Liu, Ting Xi; Becker, Michael W; Jelinek, Jaroslav et al. (2007) Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. Nat Med 13:78-83 |
| Dalerba, Piero; Dylla, Scott J; Park, In-Kyung et al. (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A 104:10158-63 |
| Lobo, Neethan A; Shimono, Yohei; Qian, Dalong et al. (2007) The biology of cancer stem cells. Annu Rev Cell Dev Biol 23:675-99 |
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