Cancer Cell 26, 851-862, December 8,2014

The research from the group of Dr. Kevin Jones from the university of Utah was published in December 2014. It gives very important information on the metabolism of ASPS. It demonstrates that lactate drives proliferation of ASPS.

The full paper is available here.

The researchers initiated the study by creating transgenic mice carrying the ASPS gene in all of their cells. In patients this gene (ASPSCR1-TFE3) is found only in tumor cells. As expected this gene induced the formation of rapidly growing tumors. Unexpectedly, the ASPS tumors formed only in the heads of these mice. Every transgenic mouse developed a tumor within the skull, but never in the extremities (legs or hands) where usually patient ASPS tumors form. Close analysis of the tumors showed that these tumors had the same histopathology of human ASPS.

Next, the researchers identified the 500 most abundant genes expressed in the mice tumors and found them to be similar to those that were reported in human ASPS. As expected some of the genes are in pathways as “cell division” and “cell cycle”. However some of these genes belong to the “carbohydrate metabolism” pathway. This was another unexpected finding.

The surprise did not ended here: In addition to the fact that the ASPS in mice developed only in their heads, the researches found these tumors within skeletal muscles, although it was clear that the tumor origin did nor arise from muscle.

Then the researchers made few important findings explaining the above-unexpected observations. They found that the normal cells in the microenvironment of the tumors drove the formation of the tumors in the mice heads. The researchers discovered that ASPS tumors need the metabolite lactate for growth. Both brain and muscle are producing lactate flux. ASPS tumor cells then absorb this lactate and use this metabolic substrate as their energy source. Helping the ASPS tumors to uptake lactate are the MCT1 transporters and their binding partner CD147 protein. Those transporters are highly expressed by ASPS cells.
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Finally, the researchers found that when they inhibited the lactate transporters MCT1 with a specific drug inhibitor namely CHC they could inhibit lactate signaling effects.

The researchers concluded that their research opened the door for exploring possible metabolic treatments for ASPS patients that could reduce the ability of ASPS to benefit from lactate which is available in their microenvironment.

 
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Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com