Cancer

Research Projects

Alon Kahana, MD, PhD

Cancer Stem Cells

The paradigm that has dominated cancer research over the past 30 years is that cancer is a genetic disease driven by mutation and subsequent selection of malignant cell clones. This has resulted in a massive effort to characterize the mutational spectrum in each type of cancer and to apply this knowledge to specifically target these mutations in individual patient tumors – “targeted therapy.” Despite the potential promise of “personalized oncology treatment,” this approach has led to only modest benefits characterized by short-lived responses for the majority of cancer patients. At the same time, there is growing appreciation that epigenetic mechanisms play a key role in cancer development and treatment resistance. These epigenetic mechanisms in cancer mimic embryologic development and generate tumors that display a hierarchical organization, at the apex of which are tumor cells that demonstrate stem cell-like properties. These cancer stem cells (CSCs) mediate tumor metastasis and play a pivotal role in treatment resistance. The transformative goal of this project is to cure cancer by targeting CSCs.

Cancer stem cells can arise from dysregulation of normal tissue stem cell pathways that regulate their self-renewal, or from reprogramming of more differentiated cells through activation of core transcription factors resembling those activated in induced pluripotent stem (IPS) cells. A unifying concept behind these observations is that cancer is a disease of “aberrant stemness,” which is achieved through a unique stem cell epigenetic state and maintained via a combination of intrinsic and extrinsic signals that also involve the tumor microenvironment. According to this model, rapid development of resistance to molecularly targeted therapies may result from the plasticity of the stem cell state with activation of alternate pathways to maintain the “aberrant stemness.” This suggests that rather than targeting specific mutations, which are but one pathway to “aberrant stemness,” we should develop strategies to target “stemness” itself, i.e. the shared downstream consequence of these mutations.

In order to elucidate the fundamental molecular mechanisms that drive and maintain “stemness” in CSCs, we propose to utilize a novel model of dedifferentiation in adult zebrafish that is robust and results in a large population of reprogrammed dedifferentiated progenitor cells.  Our preliminary data reveal high-level concordance between the molecular genetic and epigenetic pathways in dedifferentiated zebrafish cells and human CSCs. An advantage of this approach is that it permits the de-coupling of “stemness” from other secondary changes driven by oncogenesis and genetic instability in tumors.  Utilizing this concordance, we propose to identify shared candidate pathways and nuclear states that define the stem cell state in dedifferentiated cells. Using genome wide conformation capture (Hi-C), 3D-FISH, RNA sequencing (RNA-Seq), non-coding RNA analysis, and chromatin immunoprecipitation-sequencing (ChIP-Seq), we will probe the nuclear architecture alterations and chromatin remodeling that underlie reprogrammed stemness. Further experimental and computational comparisons with zebrafish embryonic neural crest and human embryonic stem cells will add fundamental insights into the differences between the embryonic versus reprogrammed stem cell states, to further narrow putative targets for therapeutic targeting. These putative targets would be validated utilizing in vitro human and transgenic mouse models of breast cancer stem cells. Once validated, the zebrafish dedifferentiation model would be utilized to screen through and develop drugs that target “stemness,” taking advantage of the ease of genetic manipulation and drug delivery as well as the physiologically relevant microenvironment of the zebrafish. At the conclusion of the full project, we would identify key molecular pathways and develop drugs that  directly target cancer “stemness”.

 

Related Faculty Bios

Dr. Alon Kahana

Alon Kahana, MD, PhD

Associate Professor, Ophthalmology and Visual Sciences
Academic Office: 734-763-8097