Check out “What’s New in Research” to find out about discoveries and advancements from Brigham researchers. This month, we feature new research from Brigham researchers on creating 3D tumor spheroids to find new anti-cancer drugs, merkel cell carcinoma, preventing a complication from bacterial sepsis more.  

Using Vibrator Found in Cell Phones, Researchers Develop 3D Tumor Spheroids to Screen for Anti-Cancer Drugs  

Hae Lin Jang

Bumseok Namgung

Depending on their location, cancer cells within a three-dimensional (3D) tumor structure can have different microenvironments. Cells in the core of the tumor receive less oxygen (hypoxia) and nutrients than those in the periphery. These varying conditions can drive differences in cell growth rates and drug sensitivities, highlighting the need to study 3D tumor models in lab settings. Until recently, conventional methods used to create such tumor spheroids were time-consuming, produced inconsistent results and involved high setup costs.

Investigators at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, developed a low-cost, high-throughput device that can reliably generate uniform tumor spheroids. The study describes how to assemble the ‘Do-It-Yourself (DIY)’ device from parts totaling less than $7, including a coin-vibrating motor commonly found in cell phones.

By vibrating a suspension of cancer cells flowing rapidly out of a fine nozzle, the team was able to create nearly 4000 equally sized droplets per minute. They found that cancer cells within the droplets aggregated to form tumor spheroids with hypoxic cores and exhibited proliferation markers typical of in vivo tumors.

The tumor spheroids also demonstrated clinically typical responses to chemotherapy, with cancer cells at the hypoxic core driving tumor survival and drug resistance. These findings, the authors suggest, could help overcome the limitations of traditional two-dimensional cancer cell cultures and provide insights for improved drug development.

“We developed a simple, DIY method for reliable preclinical testing of anti-cancer drugs,” said corresponding author Hae Lin Jang, PhD, of the Center for Engineered Therapeutics. “The cost of devices often acts as a barrier to cancer research. Low-cost, simple-to-operate systems like ours are essential to democratize cancer research and make science more accessible.”

First author Bumseok Namgung, PhD, of the Center for Engineered Therapeutics added, “Our simple and low-cost system facilitates the anti-cancer drug research by enabling high-throughput drug screening.”

Read more in Device.

Study Identifies New PD-1 Immune Checkpoint Mechanism Promoting Merkel Cell Carcinoma Growth

Tobias Schatton

Programmed cell death 1 (PD-1) is an important target for immune checkpoint inhibitor therapies that block its signaling and boost T-cell activity. PD-1 inhibitors have been approved for treating various types of cancer.

But PD-1 functions can vary between different cell and cancer types, either promoting or suppressing disease progression. Merkel cell carcinoma (MCC), a rare and aggressive form of skin cancer, responds well to immune checkpoint inhibitor therapy. However, it was previously unknown if MCC cells express PD-1 themselves, and unclear how exactly cancer cell-intrinsic PD-1 contributes to tumor growth.

A study led by investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, identified a new mechanism through which PD-1 promotes MCC progression. Through a series of experiments, the researchers demonstrated PD-1 expression on MCC cells in preclinical models and patient tumor samples. They found that MCC-PD-1 receptor binding to its ligands accelerated tumor growth by activating the mammalian target of rapamycin (mTOR) pathway and generating mitochondrial reactive oxygen species (mtROS) to promote MCC growth.

The authors subsequently showed that inhibiting mTOR signaling and neutralizing mtROS suppressed MCC-PD-1-mediated tumor proliferation in mice. These findings, they suggest, might help in the development of new treatments to halt MCC progression even in patients lacking T-cell immunity.

“For the first time, our work identifies PD-1 as an MCC-intrinsic receptor that promotes tumor growth via downstream mTOR signaling and mitochondrial reactive oxygen species production,” said corresponding author Tobias Schatton, PharmD, PhD, of the Department of Dermatology. “Targeting this tumor-intrinsic PD-1 signaling network could help optimize immune checkpoint therapy regimens and improve MCC patient outcomes.”

Read more in Science Advances.

Researchers Find Anti-HIV Drugs May Prevent Complications from Bacterial Sepsis

Matthew Waldor and Karthik Hullahall

Bacterial infections can lead to the formation of abscesses — pockets of dead cells and debris surrounded by inflammatory immune cells. Bacteria multiply within abscesses, causing more inflammation and further damage to surrounding tissues. In severe cases, these immune reactions spread across the body, resulting in life-threatening organ failure, or sepsis. But how these abscesses form and what can be done to prevent them were previously not well understood.

Using preclinical models, investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, identified a key mechanism that may be driving liver abscess formation: a process known as reverse transcription, in which DNA is synthesized from RNA. Using RNA-sequencing, the researchers examined liver gene transcripts from mice infected with Escherichia coli. They found that abscess formation was associated with increased expression from endogenous retroviruses (ERVs), remnants of viruses that integrated into the mouse genome following past infections.

The authors hypothesized that DNA produced by ERVs can stimulate inflammatory immune responses, which damage surrounding cells and thus drive abscess development. If so, preventing the activity of the ERVs might prevent abscesses from forming. To test this, the team treated mice with a cocktail of reverse transcriptase inhibitors — antiretroviral drugs also used to manage HIV infections — to block ERV DNA expression. They found that a single dose of the inhibitor cocktail was enough to prevent abscess formation, if delivered quickly after bacterial infection.

“Our findings suggest that drugs used to treat HIV can be used to prevent inflammatory complications of bacterial sepsis,” said corresponding author Matthew Waldor, MD, PhD, of the Division of Infectious Diseases.

“In mice, abscess susceptibility varies by sex and between tissues, so further work is needed to understand how antiretroviral drugs can prevent complications like bacterial sepsis in different individuals. But our study shows promise and points to a new way of thinking about treatment and prevention of deleterious consequences following bloodstream infection,” said first author Karthik Hullahalli, a Harvard graduate student in the Waldor lab at the Brigham.

Read more in PNAS.

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