“I’m introverted by nature,” remarked Sandro Santagata, a physician-scientist who specializes in pathology because of a desire to bridge his interests in mechanisms and medicine together. However, one thing Santagata, the son of Italian immigrants, has not shied away from is his quest to discover solutions to problems in science relevant to human health.
While pursuing his medical and doctorate degrees, Santagata investigated proteins involved in immunodeficiency disorders, such as Ommen syndrome, a disease that affects circulating levels of B and T cells. Then, after his residency at the Brigham, Santagata had a very successful postdoctoral fellowship with Susan Lindquist, PhD, at the Whitehead Institute studying pathways that enable cancer cells to respond to stress. It was this particular work—understanding the mechanisms behind cells under stress—where Santagata has focused much of his research career.
An Ancient Pathway
The malignant transformation of a cell is somewhat of a paradox. For it to occur there must be a series of specific genetic “hits.” These events have an apparent orchestration about them, yet they create chaos in the cell by mutating the genome. Such mutation generates significant stress for the cell. However, it is able to not only survive, but also thrive and proliferate out of control. How is this resilience achieved amidst the chaos? That is the question Santagata seeks to answer.
The specific pathway Santagata studies is known as the heat shock response. Whenever a cell is subjected to high temperatures, the structural integrity of its proteins is compromised. In order to protect its essential proteins from improperly unfolding, or losing the structure necessary for their function, the cell has a regulatory network of special heat-resistant proteins known as chaperones that maintain the structure of essential proteins. These chaperones become active under high temperature, thus the cell remains able to survive and function during stress.
“This is an ancient process for protecting cells from high temperatures,” said Santagata. “The robust chaperone response helps to conserve protein conformation.”
The central node of the heat shock response is a transcription factor known as heat shock factor 1 (HSF1).
“It’s the switch,” according to Santagata.
HSF1 regulates the expression of a host of genes involved in not only the heat shock response, but also cell survivability as a whole.
What do the heat shock response and HSF1 have to do with cancer? Santagata explains that “malignant transformation is stress-inducing,” much like high temperatures. During malignant transformation, there is increased production of proteins, which can result in structural errors during folding. Moreover, the overall ratio of proteins is disrupted, as there are too many of some and too few of others.
Accordingly, the cancer cell has to adapt to the protein stress. One way it does this is by co-opting the heat shock response and HSF1. The primary aim of the Santagata lab is to better understand how early this response turns on and the mechanisms that activate it, and then finding ways to turn it off. Because many different types of cancers co-opt HSF1, understanding this particular protective system could have profound implications as a generalizable approach for treating cancer.
So far, the answers appear to involve chromosomal amplification and mechanisms that disrupt the expression and modification of proteins. Interestingly, this pathway also confers therapeutic resistance on cancer cells, a dilemma for patients. Therapies stress the cancer cell in a manner similar to high temperature, thus engaging the heat shock response. In connecting his research to the clinic, Santagata is looking for compounds that hit chaperones and investigating ways to turn off HSF1 via pathway intermediates.
That a cancer cell can hijack an ancient and typically beneficial pathway to promote its survival and growth in the face of self-induced stress is a testament to the insidiousness of the disease. Inappropriate activation of the heat shock response during transformation is a textbook problem of the seemingly controlled cellular deregulation in cancer. But Santagata and his team are determined to face the challenge head on. He hopes that with the findings he has gathered surrounding this anti-stress mechanism, novel, effective cancer treatments will one day be developed.
“If we could block HSF1 and downstream targets then we could disable the malignant process,” said Santagata.