My laboratory studies kidney cancer, one of the most common forms of human cancer. The last decade has seen remarkable progress in the management of this disease; however, advanced forms of kidney cancer remain incurable. Therefore, despite major strides in therapy, identifying novel targets remains an urgent clinical need.
To address this need, my laboratory focuses on errors in a kidney tumor cell’s DNA architecture or “chromatin”. “Chromatin” is a complex spooled state in which the DNA thread (our genetic source-code) is wrapped. Spooling DNA into chromatin not only ensures better protection from chemical insults, but also allows exquisite control over turning genes on/off, as per the cell’s needs. Errors in DNA spooling, therefore, can cause undesired (onco)genes to be switched on in kidney tumors.
Using cutting-edge genomics analysis tools, we recently mapped changes in DNA spooling and identified ~100 genes that were erroneously switched-on in kidney cancer cells. We then studied these genes in cultured cells (in petri dishes) and in tumors (grown in mice), to identify which among them were critical for the growth of the kidney tumor. Excitingly, our studies identified a gene named SLC1A1 as a new oncogene in renal cancer.
SLC1A1 resides on the kidney cell’s surface and normally picks up (reabsorbs) important amino acids, such as aspartate and glutamate, before they are excreted in urine. Importantly, these amino acids are also critical nourishment for a cancer cell. Our studies show that kidney cancer cells have hijacked a ‘recycling’ process that was intended to prevent waste, and turned it into a source of building blocks to fuel its metabolic needs.
Interestingly, glutamate itself can be converted into chemical that can modify DNA spooling (chromatin state). Therefore, our idea is that eliminating SLC1A1 can prevent glutamate uptake and thus cause toxic changes in DNA spooling. In this proposal, we interrogate this link between cellular nutrients and DNA architecture, hoping to unravel new ways for us to therapeutically block the growth of kidney cancers.
Our proposed work will identify what genes are turned on/off upon blocking SLC1A1 function. We expect that these genes would be essential for the survival of kidney cancer cells and could, in turn, themselves become valuable targets in the clinic. Therefore, this proposal uses SLC1A1 as a flashlight to illuminate the kidney cancer cell’s most critical survival tactics.
In the short-term, our success would be measured by the identification of how/why SLC1A1 can modify chromatin state. Thus answering the more basic question – how do changes in SLC1A1 (and, as a consequence, Glu) govern the function of key downstream genes by impacting their DNA spooling state?
But, perhaps, more importantly, our work can open clinical avenues that exploit dysfunctional SLC1A1 activity in kidney cancer, as a means to find novel actionable targets. In the long-term, our success would be evident by translating this knowledge into therapeutic strategies that can complement current clinical practice.
100% For The Cure
