Eliminating cancer stem cells: an interview with CCR’s Steven Hou

Steven Hou, Ph.D.

Steven Hou, Ph.D. in his lab.

Often when patients receive treatment for cancer — through surgery, radiation and/or chemotherapy — after an initial regression, tumors grow back. Scientists believe this is due to the presence of cancer stem cells that are resistant to the initial treatments. These cells can immediately give rise to new tumors or remain dormant for years or even decades.

To understand why and how this happens, Steven Hou, Ph.D., senior investigator in the Basic Research Laboratory at the Center for Cancer Research, is exploring the molecular mechanisms that regulate self-renewal, differentiation, survival, and death of stem cells and cancer stem cells using a fruit fly (Drosophila) model.

In this interview, Dr. Hou discusses his study, “The Lipolysis Pathway Sustains Normal and Transformed Stem Cells in Adult Drosophila”, which was published in Nature. The results of this research have uncovered potential ways to eliminate cancer stem cells and may offer hope to patients with reoccurring tumors.

What is exciting about your new findings?

Cancer stem cells, or CSCs, are usually localized to a storage niche surrounded by a dense cellular environment, which may make them less accessible to the sugar and amino acid nutrition from the body’s circulatory system. Most normal cells rely on sugar and amino acids for their energy supply with lipolysis (fat) playing only a minor role in their survival.

Our results show that CSCs are metabolically unique. Like hibernating animals, they mainly rely on lipid reserves for their energy supply, and blocking a process called COPI/Arf1-mediated lipolysis can starve them to death. We also discovered that CSC-like stem cells were more sensitive than normal stem cells to Arf1 inhibition. So we think that by selectively blocking lipolysis, we may be able to kill CSCs without severe side effects. Further, targeting the COPI/Arf1 complex or the lipolysis pathway appear to be novel approaches for eliminating CSCs.

How did results from this study build upon your lab’s previous work?

We have been studying the regulation of stem cells for more than 10 years. Using adult fruit flies, we were able to identify kidney stem cells in a 2007 study.  In 2015, we identified the networks involved in the intestinal stem cell regulation of fruit flies using a genome-wide RNA interference (RNAi) screen.

What challenges did you overcome to successfully complete this study? 

In the above mentioned genome-wide RNAi screen, my former postdoctoral fellow, Xiankun Zeng, Ph.D., found that knockdowns of the COPI/Arf1 complex selectively killed stem cells. The COPI and COPII complexes are essential components of the trafficking machinery for vesicle transportation between the endoplasmic reticulum (ER) and the Golgi complex. We questioned how such a basic cellular process selectively affected stem cells. Later, we realized that the COPI complex also regulated the transport of lipolysis enzymes to the surface of lipid droplets for lipid droplet usage. We also noted that our RNAi screen identified many components of the COPI/Arf1 complex but none of the COPII complex. Other experiments confirmed that rather than regulating the general trafficking machinery between the ER and Golgi, the COPI/Arf1 complex sustained stem cells through regulating lipolysis.

We further investigated the intracellular pathway that directly regulates stem cell death induced by knockdowns of the COPI/Arf1 complex. Our data suggested that neither caspase-mediated apoptosis nor autophagy-regulated cell death was induced by the COPI/Arf1 knockdowns. We were puzzled about how the stem cells were killed. Until one day, staff scientist, Shree Ram Singh, Ph.D., found that the dying stem cells showed a very unique cell membrane rupture phenotype. Further experiments confirmed that knockdowns of the COPI/Arf1-lipolysis pathway killed stem cells through necrosis. We also found that the dying stem cells were engulfed by neighboring differentiated cells.

What are your next steps?

Findings from our study open new avenues in both stem cell research and in identifying novel molecular markers for cancer treatments. We are following this new direction by investigating the molecular mechanism of the COPI/Arf1-regulated lipolysis in stem cells in different models. We are studying the function of Arf1 in regulating normal stem cells and CSCs in mice. We are also testing Arf1 and other lipolysis inhibitors to eliminate CSCs and see the effects on tumors in mouse tumor models.  Finally, we are screening new anti-CSC drugs in whole fly stem cell tumor models and will test promising agents in mouse tumor models.

Summary Posted: Thu, 09/01/2016