Till & McCulloch Meetings 2012: Lessons to learn from leukemic stem cells

 

by Alexey Bersenev

The first plenary session of the Till & McCulloch Meetings was dedicated to cancer stem cells. John Dick opened the session by asking a question: “Stem cells in cancer: do they matter?” He is always ahead of time, very precise and innovative and I think cancer stem cell researchers can learn a lot from the Dick’s studies of leukemia and hematopoiesis.

Dick’s group has showed that cancer stem cell properties ultimately govern survival of patients with acute myelogenous leukemia (AML). Stem cell expression signatures can stratify patients and direct the treatment strategies. In Dick’s study, high expression of “leukemic stem cell signatures” was tightly associated with poor prognosis and decreased patient survival. He said: “If cancer stem cells are only cell type within the tumor capable to sustain clonal growth, we should study them.” So, the first take home message — cancer stem cells are relevant, if their properties precisely govern clinical outcome.

The cancer stem cell field is full of scientific controversies. Dick pointed out that the most controversies are coming from lack of our understanding of normal stem cells. He spent a great amount of time for studying normal hematopoietic stem cells and developing assays. His work progressed from prospective isolation and defining the markers to functional assays, from normal to leukemic stem cells. Comparing markers and gene expression signatures, his team was able to tackle similarities and differences between normal hematopoietic and leukemic stem cells. So, in order to succeed in studying of cancer stem cells, look at their normal equivalent and understand it first.

It turns out that the normal stem cell surface markers do not apply in leukemia. Ultimately, any sorted AML cell population possesses leukemic stem cell properties in functional assays. Dick said: “Surface markers are all about differentiation, but differentiation in cancer is totally screwed up”. To solve this problem, they have developed a new approach. Before profiling the gene expression signature, they validated each AML population, sorted by different combination of surface markers in functional (transplantation) assays. So, the lesson to learn — don’t trust surface markers, do functional validation!Well, surface markers could mislead cancer stem cell researchers, but functional validation is very laborious and time-consuming. Dick believes that we should look for new better markers. Intracellular or “metabolic” markers could be promising. He pointed to one of such marker – miR-126.

Till & McCulloch 2012 Award winner Aaron Schimmer presented a data on therapeutic targeting of AML stem cells metabolism. His team demonstrated that AML cells have much more mitochondria than normal hematopoietic cells and that mitochondrial translation could be selectively inhibited by the antibiotic tigecycline. This drug was discovered by chemical screening of thousands compounds. The advantage of Schimmer’s approach is using FDA-approved drugs for screening and leukemic cell lines, established in Dick’s lab. Because tigecycline was already approved for other indications, it took much less time to submit for clinical trial in AML and to get an approval. Nine patients have been treated in the trial so far. So, the take home message is that if you’re screening for drugs targeting cancer stem cells, start from the approved ones.

I think, applying of these lessons to other cancer stem cells could help to overcome some technical hurdles and accelerate the clinical translation.

Follow Alexey Bersenev on his blog at www.stemcellassays.com or on Twitter @cells_nnm