Research News

A Tale of Two Proteins

Arman Jahangiri never intended on becoming an MD/PhD student. But during medical school, towards the end of his research fellowship, he made a discovery that would change the trajectory of his career.

During his time as an HHMI Research Fellow, Jahangiri contributed to several key findings in the laboratory of Manish Aghi MD, PhD, Professor of Neurological Surgery at UCSF. Aghi’s group had been investigating why glioblastomas become resistant to bevacizumab, an anti-angiogenic therapy drug that targets a tumor’s ability to grow blood vessels. 

For many patients, bevacizumab is extraordinarily effective at shrinking glioblastomas. But in some cases, the tumor can become resistant to the drug – growing back and becoming an even more invasive cancer. 

UCSF Arman Jahangiri and Manish Aghi
With the guidance of mentor Aghi (left), MD/PhD student Jahangiri (right) has contributed to many of the Aghi Lab's recent research publications.    

The mystery of understanding how and why glioblastomas become resistant has been a driving force for the entire Aghi Lab. Initial efforts revealed that bevacizumab-resistant glioblastomas have increased levels of β1 integrin, a transmembrane protein involved in cell adhesion.1,2 Soon after, they saw that c-Met, another protein, is also found at increased levels in bevacizumab-resistant glioblastomas.3

However, β1 integrin and c-Met only increase by modest amounts in bevacizumab-resistant glioblastomas. Skeptical that that would be enough to cause the drastic changes seen during bevacizumab-resistance, Jahangiri decided to test whether β1 integrin and c-Met interact, causing a larger, compounded effect that could explain invasive resistance. In the spring of 2013, on the cusp of returning to medical school, Jahangiri found out that the proteins do interact, binding to form a C-Met/β1 integrin complex. “This was the discovery that made me apply to the PhD program here. I had to see where this story went,” he explained.

For the next four years, Jahangiri would put his medical degree on hold, investigating the role of the c-Met/β1 integrin complex. This September, in a recent PNAS publication led by Aghi, Jahangiri and colleagues describe how this complex drives not only invasive resistance in glioblastoma, but also metastasis in other cancers.4 

In examining both glioblastoma and brain metastases, the Aghi group found higher levels of c-Met/β1 integrin complex in both bevacizumab-resistant and metastatic tumors. In fact, inducing c-Met/β1 integrin complex formation in glioblastoma cells was sufficient to increase migration and invasion of the tumor cells in culture. Likewise, c-Met/β1 integrin complex formation also increases migration and invasion of breast cancer cells in culture. 

Surprisingly, the c-Met/β1 integrin complex also contributes to metastasis, by allowing tumor cells to exit blood vessels and invade other tissues. Jahangiri and colleagues show that when breast cancer cells are injected into the blood vessels of mice, tumor cells with the c-Met/β1 integrin complex are more likely to exit the circulatory system and metastasize in the lung. “That was the most exciting data I remember getting,” said Jahangiri. 

 

MDA 231 iDim +AC
c-Met/β1 integrin complex (red) in breast cancer cells (green, phalloidin; blue, DAPI) isolated from a brain metastasis. 

 

The key to understanding how the c-Met/β1 integrin complex contributes to invasive processes lies in understanding how cells interact with their extracellular environment. Normally, β1 integrin binds α5 integrin, forming an α5β1 integrin complex that allows cells to bind to fibronectin, a protein in the extracellular matrix. Indeed, cancer cells are able to migrate by binding to, and moving along, fibronectin. Jahangiri and colleagues find that c-Met can replace α5, forming the c-Met/β1 integrin complex which actually binds more strongly to fibronectin – the primary substrate that cancer cells use for migration and invasion. Jahangiri and colleagues further discovered that c-Met and β1 integrin are normally sequestered away from each other, but hypoxic conditions and exposure to bevacizumab promote c-Met/β1 integrin complex formation in glioblastoma cells. This suggests the importance of investigating anti-angiogenic therapies for effective (and perhaps lower) dosages that minimize occurrence of invasive resistance. This may be especially true for specific patient populations, given Jahangiri and Aghi’s observation that glioblastoma patients have worse prognoses if their tumor has higher levels of c-Met/β1 integrin complex at diagnosis – even prior to bevacizumab treatment.  

    Coming up with a small molecule that inhibits this complex – that’s the holy grail.

    Arman Jahangiri

    In finding that the c-Met/β1 integrin complex underlies both invasive resistance in glioblastoma as well as metastasis in breast cancer, the interaction between these two proteins may well represent a universal mechanism, and future target for many cancers. 

    “The biggest hope is being able to stay one step ahead of metastasis and resistance. Disrupting c-Met and β1 integrin interaction could be a viable target for future therapies,” described Aghi. In agreement, Jahangiri added, “Coming up with a small molecule that inhibits this complex – that’s the holy grail.”

     

    Learn more about the c-Met/β1 integrin complex in Aghi, Jahangiri, and colleagues' PNAS publication.