Michael Clarke lab
In addition to his clinical duties in the division of Oncology, Dr. Clarke maintains a laboratory focused on two areas of research: i) the control of self-renewal of normal stem cells and their malignant counterparts; and ii) the identification and characterization of cancer stem cells. A central issue in stem cell biology is to understand the mechanisms that regulate self-renewal of hematopoietic stem cells, which are required for hematopoiesis to persist for the lifetime of the animal. Until recently, the molecular mechanisms that regulate adult stem cell self-renewal were not known. His laboratory recently found that the proto-oncogene Bmi-1 regulates stem cell self-renewal via an epigenetic mechanism. By investigating the pathways upstream and downstream of Bmi1, the laboratory is actively investigating the molecular pathways that regulate self-renewal.
Cancers arise as a result of a series of genetic mutations. A better understanding of the consequences of these mutations on the underlying biology of the neoplastic cells will help to focus the development of more effective therapies. Solid tumors such as breast cancers contain heterogeneous populations of neoplastic cells. Dr. Clarkes group has developed a technique that allows the isolation and characterization of tumorigenic and non-tumorigenic populations of cancer cells present in human breast, colon and head and neck cancer tumors. Only a small minority of cancer cells had the capacity to form new tumors in a xenograft model. This tumorigenic cell population could be identified prospectively and consistently had definable and identical phenotype. The tumorigenic cells displayed stem cell-like properties in that they were capable of generating new tumors containing additional stem cells as well as regenerating the phenotypically mixed populations of non-tumorigenic cells present in the original tumor. Effective treatment of cancer will require therapeutic strategies that are able to target and eliminate this tumorigenic subset of cells. The laboratory is pursuing the identification of cancer stem cells in other tumors so that they can be studied. Dr. Clarkes laboratory will provide other members of the program with the expertise to identify and isolate cancer stem cells from solid tumors of epithelial origin. Finally, the laboratory is actively pursuing how cancer stem cells self-renew to maintain themselves and escape the genetic constraints on unlimited self-renewal that regulate normal stem cell numbers. Differences in self-renewal pathways between normal and malignant stem cells could be targeted by new therapeutic agents to eliminate cancer stem cells.
Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model.
Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the BMP pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.'
View details for DOI 10.7554/eLife.66037
View details for PubMedID 35311644
LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis.
Cell stem cell
SMAD pathways govern epithelial proliferation, and transforming growth factor beta (TGF-beta and BMP signaling through SMAD members has distinct effects on mammary development and homeostasis. Here, we show that LEFTY1, a secreted inhibitor of NODAL/SMAD2 signaling, is produced by mammary progenitor cells and, concomitantly, suppresses SMAD2 and SMAD5 signaling to promote long-term proliferation of normal and malignant mammary epithelial cells. In contrast, BMP7, a NODAL antagonist with context-dependent functions, is produced by basal cells and restrains progenitor cell proliferation. In normal mouse epithelium, LEFTY1 expression in a subset of luminal cells and rare basal cells opposes BMP7 to promote ductal branching. LEFTY1 binds BMPR2 to suppress BMP7-induced activation of SMAD5, and this LEFTY1-BMPR2 interaction is specific to tumor-initiating cells in triple-negative breast cancer xenografts that rely on LEFTY1 for growth. These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer.
View details for DOI 10.1016/j.stem.2020.06.017
View details for PubMedID 32693087
- Clinical and Therapeutic Implications of Cancer Stem Cells. The New England journal of medicine 2019; 380 (23): 2237–45 Hide More
- Clinical and Therapeutic Implications of Cancer Stem Cells. Reply. The New England journal of medicine 2019; 381 (10): e19 Hide More
Bcl11b maintains the long-term mammary stem cell and is crucial for drug resistance in breast cancer.
AMER ASSOC CANCER RESEARCH. 2018: 23
View details for Web of Science ID 000440602000017