A new study shows that liver cell stress can lead to cancer, yet it also can make tumors less resistant to immunotherapy. The findings may lead to new treatments and help physicians determine which patients will benefit from existing immunotherapies. Image credit: crystal light/Sanford Burnham Prebys.
Cell stress response protein implicated in cancer progression, yet it also weakens resistance to immunotherapies
Metabolic disorders such as obesity and type 2 diabetes place extra stress on the liver. Liver cells try to protect themselves from the accompanying surge in dysfunctional proteins by activating factors that help restore an appropriate protein balance.
One of these factors is a protein called activating transcription factor 6 alpha (ATF6α) that was recently shown to drive the onset of liver cancer if left permanently active. In a Nature study published February 4, 2026, an international team of scientists demonstrated that activating ATF6α in mice caused liver disease that progressed to liver cancer.
In data from human liver cancer patients, ATF6α activation was linked with more aggressive tumors, a suppressed immune system surrounding tumors and reduced patient survival.
The researchers also uncovered ways that ATF6α might be used to advance the treatment of liver cancer. Liver cells with ATF6α switched off developed fewer tumors. While high ATF6α activity levels were associated with cancer progression, they also were found to make tumors more susceptible to certain immunotherapies.
These findings suggest the need for future clinical trials to test drugs that directly target ATF6α to treat the disease. Additionally, it might prove advantageous to screen liver cancer patients for ATF6α activity to find those most likely to benefit from existing immunotherapies.
Randal Kaufman, PhD, is a professor in the Center for Metabolic and Liver Diseases at Sanford Burnham Prebys and a co-corresponding author of the study. Image credit: Sanford Burnham Prebys.
Xin Li, PhD, a postdoctoral fellow at the German Cancer Research Center (DKFZ), shares first authorship of the study with co-corresponding author Cynthia Lebeaupin, PhD, principal scientist at Pfizer and former postdoctoral researcher at Sanford Burnham Prebys Medical Discovery Institute.
The other co-corresponding authors are Dirk Haller, PhD, Technische Universität München; Randal Kaufman, PhD, Sanford Burnham Prebys; and Mathias Heikenwälder, PhD, University of Tübingen and DKFZ.
Institute News
How scientists turned plant poisons into medicines
Sanford Burnham Prebys scientists Ani Deshpande and Pamela Itkin-Ansari recently released episode six of the Discovery Dialogues Podcast focused on Metformin and other medications with origins as plant poisons.
Scientists and science communicators detail how caustic compounds meant to deter eaters of plants were harnessed to treat diabetes
The US Food and Drug Administration approved Metformin for use as a diabetes drug more than 30 years ago. This medicinal compound—prescribed to patients to help control high blood sugar—was discovered in nature through a toxic herb found in a variety of medieval remedies.
Sanford Burnham Prebys scientists Ani Deshpande, PhD, and Pamela Itkin-Ansari, PhD, recently released episode six of the Discovery Dialogues Podcast focused on Metformin and other medications with origins as plant poisons. The podcast features surgeon and writer Ambarish Satwik, MD, as well as endocrinologist David Nathan, MD, and Nir Barzilai, MD, a geneticist and longevity researcher.
A human donor central retinal artery was cannulated (intubated) and perfused with Lectin FITC, a specific protein chemically linked to a fluorescent dye. The microvasculature of the optic nerve head area at the center is visible.
Image courtesy of Dong An, Lions Eye Institute, Australia.
Institute News
Q & A with Postdoctoral Researcher Ambroise Manceau, PhD, from the Commisso Lab
Meet one of our early-career scientists at Sanford Burnham Prebys Medical Discovery Institute: Ambroise Manceau, PhD, a postdoctoral researcher in the lab of Cosimo Commisso, PhD. Manceau studies pancreatic ductal adenocarcinoma — the most common form of pancreatic cancer with only a 13% five-year survival rate.
When and how did you become interested in science? When I was very young, I was a bit of a nerd when it came to reading reviews of new scientific studies written for kids. Especially anything related to biology.
I lost sight of that interest at some point in my teenage years. I tried going into computer science, but I realized very quickly that it wasn’t a good fit for me. That forced me to do some deeper self-reflection about what I really wanted to do, and that brought me back to biology.
I started studying biology at college, and everything just clicked into place. I really found my way when I went to college.
What brought you to the Commisso lab at Sanford Burnham Prebys? I have an uncle that I always admired who is a researcher here in California. From talking with him, it sounded like a great place to work and live as a scientist. When I was an undergraduate in France, I decided to do a four-month internship abroad in Los Angeles at the University of Southern California.
I absolutely loved it, and I knew I wanted to return when I could. Because you can finish your graduate school program a bit faster in France, I decided to go back to France to earn my doctorate and then apply for postdoctoral positions in Southern California.
I was looking for labs conducting interesting research in the region, and that is when I found the Commisso lab. It has been a terrific fit for me.
What are the key areas of research you focus on? My broad focus is on metabolism and organelle biology in pancreatic cancer. My main project looks at macropinocytosis, which is a cellular process that allows cells to gather extra resources from their surrounding environments. Pancreatic cancer cells use this process as an adaptation because they exist in an environment where resources are scarce, and they need to find fuel for their expansion.
I study the contents taken in when pancreatic cancer cells contort their cell surfaces to create pockets called macropinosomes. By analyzing every single protein located on macropinosomes, I found that calcium and zinc transporter proteins present in macropinosomes also are required for macropinocytosis.
These proteins have never been targeted before in pancreatic cancer. By continuing to research them, our long-term goal is to use this strategy to cut the nutrient supply to tumors and see if we can inhibit tumor growth.
What motivates you about your research? One thing I enjoy is how you adjust your hypothesis based on what you are learning from the experiments. You need to adapt your hypothesis as you gain knowledge, but you don’t always realize it because it can happen one little step at a time.
Then you look at your project a year later, and it is very satisfying to see how much it evolved and how much you changed your mind by following the data.
Also, now that I have attended pancreatic cancer conferences and met with physicians and patients, I have more appreciation for the need to improve upon available therapies.
What do you like about working here? The people at Sanford Burnham Prebys embrace collaboration. They also are very curious, knowledgeable and kind. With the core facilities, workshops and other opportunities for learning and networking, we have so many resources available to us.
Then add on top of that the location in San Diego, which is a great hub for biomedical research and the biotech industry. And we have the Southern California coast, culture and weather for when we aren’t working.
Have you had an influential mentor? In addition to my uncle, my thesis mentor and principal investigator back in France were very influential in my professional development. Here, I feel like Cosimo is doing everything he can to get the best out of me, including supporting me to go to workshops and conferences.
What do you enjoy doing when you’re not in the lab? I’m a bit addicted to rock climbing, and San Diego is a great place to be a climber. I have access to an incredible indoor climbing gym, but I also can go climbing outdoors within a 15-minute drive from where I live.
I also play a bit of tennis, go running and relax at the beach. And I’m painting some, which is something I used to do on rainy days in France. We don’t have many rainy days here, though, so I always want to be outside.
Postdocs at Sanford Burnham Prebys are pushing the boundaries of science every day through curiosity, collaboration, and innovation. This series highlights their unique journeys, what inspires their work, and the impact they’re making across our labs.
A confocal micrograph of fluorescently marked mouse colon.
Image courtesy of Marius Mählen, Koen Oost, Prisca Liberali and Laurent Gelman, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
The intricate architecture of the endoplasmic reticulum, the largest organelle in most cells, is depicted in this mouse brain cancer cell. The actin cytoskeleton in cyan and the endoplasmic reticulum in red.
Image courtesy of Halli Lindamood and Eric Vitriol, Augusta University.
A cell’s cytoskeleton provides structural support, maintains cell shape and is involved in processes like cell movement and intracellular transport of substances. Actin and tubulin are primary components of two main types of cytoskeleton protein. In this micrograph of rat liver cells, actin is shown in orange and tubulin in white.
Image courtesy of Francisco Lázaro-Diéguez, Albert Einstein College of Medicine.
