Gene behind highly prevalent facial anomaly found

Whitehead Institute scientists have identified a genetic cause of a facial disorder known as hemifacial microsomia (HFM). The researchers find that duplication of the gene OTX2 induces HFM, the second-most common facial anomaly after cleft lip and palate. The researchers find that duplication of the gene OTX2 induces HFM, the second-most common facial anomaly after cleft lip and palate.

HFM affects approximately one in 3,500 births. While some cases appear to run in families, no gene had been found to be causative. Patients with HFM tend to have asymmetrical faces, --typically with one side of the upper and lower jaws smaller than the opposite side--a smaller or malformed ear on the affected side, and, in some cases, neurological or developmental abnormalities.

 

The genetic cause of this girl's hemifacial microsomia (HFM) was the focus of research conducted by Whitehead Institute Fellow Yaniv Erlich and his lab..

Erlich and lab technician Dina Zielinski began studying the genomes of a five-year-old female member of the family, along with those of her mother, grandmother, and male cousin, who all exhibited traits of HFM. Later, the genetic information from the grandmother's Russian cousin, who resides in the Philadelphia area, was recruited to the study.To find the cause of a family's HFM, Zielinski began by searching for a point mutation, but the five of the study participants held no such mutation in common. Next she looked for sections of the genome that are duplicated. All had an extra copy of one 1.3 megabase pair section of chromosome 14. Duplications this large are frequently detrimental. Within this large piece of DNA, he identified eight candidate genes that could cause the type of HFM running in this family. She then used two algorithms to compare the molecular signatures of these eight genes to other genes known to be responsible for various facial malformations with features similar to HFM. After this analysis, the gene OTX2 that codes for a transcription factor rose above the seven other candidates.

Intriguingly, another, darker role of OTX2 was highlighted during the course of the study. The little girl who was this research's main focus was diagnosed with medulloblastoma, a highly malignant tumor originating at the base of the brain in or near the cerebellum. OTX2 is a known oncogene for her subclass of medulloblastoma, confirming that her OTX2 expression is out of line.

Posted by

Keerti Mishra

 

How diabetes drugs may work against cancer

Summary: A major mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments has been pinpointed by researchers. By identifying cancer cells with defects in this pathway or with impaired glucose utilization, the scientists can predict which tumors will be sensitive to these anti-diabetic drugs known to inhibit this pathway.

For several years, a class of anti-diabetic drugs known as biguanides, has been associated with anti-cancer properties. A number of retrospective studies have shown that the widely used diabetes drug metformin can benefit some cancer patients. Despite this intriguing correlation, it has been unclear how metformin might exert its anti-cancer effects and, perhaps more importantly, in which patients.

 Now, Whitehead Institute scientists are beginning to unravel this mystery, identifying a major mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments. By finding cancer cells with defects in this pathway or with impaired glucose utilization, the scientists can predict which tumor will be sensitive to the anti-diabetic drugs known to inhibit the pathway in question. Their work is described online this week in the journal Nature.

To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, Kıvanç Birsoy and Richard Possemato, postdoctoral researchers in Whitehead Member David Sabatini’s lab, developed a system that circulates low-nutrient media continuously around cells. Of the 30 cancer cell lines tested within this system, most appeared unaffected by a lack of glucose. However, a few of the lines thrived and reproduced rapidly, while others struggled. The varied responses to a glucose shortage were puzzling.

“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” says Possemato, who coauthored the Nature paper with Birsoy. “The cancer-relevance of the alterations that we found as underlying this response to low glucose will still need to be investigated.”

Birsoy and Possemato wondered whether certain cancer cells’ susceptibility to a low glucose environment could be exploited to attack tumors. They screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation, a metabolic pathway in mitochondria. The powerhouses of a cell, mitochondria are membrane-bound organelles with their own DNA, including genes that control oxidative phosphorylation.

Birsoy and Possemato hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer. If true, the hypothesis would suggest that further impairing mitochondrial function, with biguanides—which are known oxidative phosphorylation inhibitors—could push the mitochondria beyond their limits, to the detriment of the cancer cells.

They first tested their hypothesis in vitro on 13 cell lines with glucose utilization defects and mitochondrial DNA mutations. Compared to control cells, those sensitive to low glucose were five to 20 times more susceptible to phenformin, a more potent biguanide than metformin. Birsoy and Possemato then tested phenformin’s effectiveness in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the tumors’ growth.

“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” says Birsoy. “And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.” To confirm the accuracy of their proposed biomarkers, Birsoy and Possemato want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.

Posted by:

Gauri Shah

Faculty (BII)