Exploring the Role of Neurons in the Tumor Microenvironment that Drive Cancer Growth

Cancer researchers increasingly are recognizing the role that different cell types within the tumor microenvironment play in advancing disease growth. In recent years, research discoveries in angiogenesis and immunotherapy have led to the approval of drugs that slow the growth and spread of cancer by targeting cells within the tumor microenvironment, validating this approach. Yet the role of neurons and the nervous system has remained largely unexplored.

Humsa Venkatesh, PhD, a cancer biologist in the Department of Neurology at Brigham and Women’s Hospital, is studying the neural regulation of cancer and how nerve cells found within the tumor microenvironment drive malignant growth. Her research has implications for primary brain tumors such as gliomas as well as for other types of cancers both in and outside of the brain.

“My work lays the foundation for a new field focused on the neurobiology of cancers,” Dr. Venkatesh says. “We’ve found that the nervous system plays a fundamental role in tumor growth and that this dependency on neural input is a huge vulnerability for a number of cancers.”

How Brain Cancer Hijacks Normal Growth Mechanisms

Dr. Venkatesh began this area of inquiry as a postdoctoral fellow at Stanford, with a focus on pediatric high-grade gliomas. She hypothesized that since neurons are a large component of the brain tumor microenvironment and neural activity plays such a strong role in development, the cancer cells may similarly rely upon activity for progression.

Using techniques such as optogenetics and single-cell sequencing, she and her colleagues showed that interactions between neurons and glioma cells include activity-dependent secretion of mitogens and, perhaps more importantly, electrochemical communication that occurs via direct neuron-to-glioma synapses.

“It is interesting because cancer cells seem to hijack normal mechanisms of neural signaling,” Dr. Venkatesh says. “Our findings make it clear that these tumor cells physically and functionally integrate into the brain’s normal, healthy neural circuits.”

The work, published in Nature, utilized preclinical models of glioma to further demonstrate that blocking this electrochemical signaling either with drugs or by inducing genetic changes slowed tumor growth.

“This electrical aspect of cancer biology has been completely underappreciated, and it gives us a new strategy to attack these tumors therapeutically,” Dr. Venkatesh says.

This research led to the development of clinical trials of repurposed neuromodulatory drugs for the treatment of some forms of primary brain cancer.

Shifting Focus to Brain Metastasis

Since joining the Brigham, Dr. Venkatesh’s work has expanded to study the role that neurons within the tumor microenvironment play in the progression of metastatic brain cancers.

“We know that a lot of cancers tend to be innervated, including prostate, lung and pancreatic cancers,” she says. “This got me thinking about whether these non-glial derived cancers also respond to neuronal cues.”

Although many cancers have the ability to spread to the brain, they are different from brain cancers in that they do not originate in glial cells. “But what is fascinating is that these metastatic cells upregulate similar neuronal gene expression profiles,” Dr. Venkatesh says.

Currently, Dr. Venkatesh’s research is largely focused on small cell lung cancer. Her team is looking at how these cancer cells have the ability to use signals from neurons in the tumor microenvironment and leverage them to communicate with neighboring cells. This integration and communication appear to be essential for the growth and spread of tumors.

“We know there may be different mechanisms and different neural populations involved,” she says. “But what’s become quite clear is that neuronal communication is a critical component of the tumor microenvironment for a large number of different cancers.”

Uniting Disciplines to Study Cancer Neuroscience

Dr. Venkatesh explains that she came to the Brigham to help grow a new program in cancer neuroscience. She’s looking forward to collaborating with other investigators at the Brigham as well as with colleagues at Massachusetts General Hospital, Harvard Medical School and MIT.

“We’re at a critical juncture where there have been so many advances in technology as well as in interdisciplinary science,” she says. “Neuroscientists, molecular biologists, cancer biologists and others have all worked together to advance this interesting and exciting new field.”

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