Seminar Series: extrachromosomal DNA and the metabolic circuits of cancer immune suppression
AuthorScott LaFee
Date
March 25, 2024
The ongoing Sanford Burnham Prebys seminar series will feature a pair of speakers on March 27, from noon to 1p.m., in the Fishman Auditorium. They will be presenting on two topics: extrachromosomal DNA and the tumor microenvironment.
First, Owen Chapman, PhD, a postdoctoral research scientist in the lab of Lukas Chavez, PhD, will discuss clinical and genomic features of circular extrachromosomal DNA (ecDNA) in medulloblastomas, a type of brain tumor.
EcDNA is DNA found off chromosomes, either inside or outside the nucleus of a cell. In a study published last year, Chavez (senior author), Chapman (first author) and colleagues reported that patients with medulloblastomas containing ecDNA are twice as likely to relapse after treatment and three times as likely to die within five years of diagnosis.
The second presentation will be by Kevin Tharp, PhD assistant professor in the Cancer Metabolism and Microenvironment Program. Tharp, who joined Sanford Burnham Prebys in December 2023, studies how tumors manipulate their mitochondria to improve survivability and how those cellular mechanics can be leveraged to create more effective therapies.
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Meet immunologist Jennifer Hope
AuthorMonica May
Date
February 12, 2021
Hope’s research aims to help cancer immunotherapy work for more people
It’s not an overstatement to say that immunotherapy—an approach that uses our own immune system to kill a tumor—has revolutionized the treatment of cancer. Doctors continue to report incredible results, including tough-to-treat tumors seemingly melting away. However, the treatment doesn’t work for everyone, and even if it does work initially, it often stops working as time goes on.
Jennifer Hope, PhD, a postdoctoral researcher in the Bradley lab at Sanford Burnham Prebys, is working to find ways to make cancer immunotherapy work for more people. We caught up with her as she prepared to take the virtual stage at the Diversity and Science Lecture Series at UC San Diego (DASL) to learn more about what she wishes people knew about science and whom she admires.
Did you always know you wanted to be a scientist?
I always had an interest in science, but at first I wanted to go a totally different route. I was an athlete in high school and college—I played tennis—and really wanted to go into sports medicine. Then I had my first real experience being in a lab in college, and I was hooked. I liked how hands-on it was and how I could keep asking questions. As my family knows, I’ve always been one to ask a lot of questions and always ask why. I found that being in the lab that was my opportunity to keep coming up with new questions, and finding answers that will impact people’s lives.
What do you research, and what is your greatest hope for your work?
I’m trying to understand why the immune system—specifically, T cells—seems to turn a “blind eye” to tumors, which it doesn’t do to other foreign invaders like viruses. My ultimate hope is that we use this information to create better cancer immunotherapies, particularly for skin cancer, which is still really deadly.
What do you wish people knew about science?
That it can be a lot of fun! Most people have this perception of science as being very boring. You see X and you do Y. That part can be true. But there’s a lot of opportunity for creativity and to come up with different ways to ask the same question. Some of the best scientists are incredibly creative people.
How would your coworkers describe you?
Motivated and always willing to try new things.
When you aren’t working, where can you be found?
Reading a book. My family started a book club to stay connected during the pandemic. We just read The Food Explorer by Daniel Evan Stone, which was fascinating. It’s about a botanist who is responsible for transforming what food looked like in the U.S. at the turn of the century. I don’t want to give too much away, but it’s because of him that we have cherry blossoms in Washington D.C., and regulations on importing seeds.
Whom do you admire, and why?
My parents. It sounds cliché, but it’s true. They have always been the biggest supporters of my dreams, whether career or personal.
One example that pops into my head is when I was getting my PhD, and my PI moved from Philadelphia to the Netherlands. I had the opportunity to move, too, if I wished. This was obviously a huge step, and I called my parents to talk it through. Immediately, the conversation was about how this would benefit me—the risks and the advantages—and they said they would support me if I wanted to go or not. That meant, and means, the world to me. Ultimately, I did go, and it was an incredible opportunity that I don’t regret at all.
What do you wish people knew about Sanford Burnham Prebys?
That everyone is willing to help each other. You don’t see that everywhere. It is proof that you can do science at an exceptional level without competing with each other.
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Cancer’s final frontier: the tumor microenvironment
AuthorMonica May
Date
September 3, 2019
Cancer researchers are setting their sights on a new kind of cancer treatment that targets the tumor’s surrounding environment, called the tumor microenvironment, in contrast to targeting the tumor directly.
To learn more about this approach, we spoke with cancer experts Jorge Moscat, PhD, director and professor in the Cancer Metabolism and Signaling Networks Program at Sanford Burnham Prebys; and Maria Diaz-Meco, PhD, professor in the Cancer Metabolism and Signaling Networks Program at Sanford Burnham Prebys. Both scientists recently authored a review article centered on a family of cancer-linked proteins that regulate the tumor’s microenvironment. The paper was published in Cancer Cell.
What is the tumor microenvironment exactly? Moscat: Just like every person is surrounded by a supportive community—their friends, family or teachers—every tumor is surrounded by a microenvironment. This ecosystem includes blood vessels that supply the tumor with nutrients; immune cells that the tumor has inactivated to evade detection; and stroma, glue-like connective tissue that holds the cells together and provides the tumor with nutrients.
Diaz-Meco: These elements are similar to the three legs of a stool. If we remove all three legs, we can deliver a deadly blow to the tumor. FDA-approved drugs exist that target blood vessel growth and reactivate the immune system to destroy the tumor. The final frontier is targeting the stroma.
When did scientists realize it’s important to focus on the tumor’s surroundings—not the tumor itself? Diaz-Meco: Scientists have known for more than a century that the tumor’s surroundings are different from normal cells. The tissue surrounding a tumor is inflamed—tumors are often called “wounds that never heal”—and their metabolism is radically different from healthy cells.
Moscat: The discovery of oncogenes—genes that can lead to cancer—in the 1970s shifted the field’s focus to treatments that target the tumor directly. These targeted treatments work incredibly well, but only for a short time. Cancer researchers are realizing that tumors quickly adapt to this roadblock and become treatment resistant. In addition, many oncogenes are difficult to target, earning the title “undruggable.” As a result, cancer researchers are returning their focus to the tumor microenvironment—especially the stroma. Only a handful of stroma-targeting drugs are in development. None are FDA approved.
Which cancers could benefit most from a stroma-targeting drug? Moscat: Pancreatic, colorectal and liver cancers stand to benefit most from a stroma-targeting drug. For example, 90% of a pancreatic tumor consists of stroma—not cancer cells. Combined, these cancers are responsible for more than 20% of all cancer deaths in the U.S. each year.
What is the focus of your lab’s research? Diaz-Meco: Our lab studies the cross talk between tumors and their environment. This conversation is very complex. In addition to “talking” with the tumor, the stroma also “speaks” with the immune system. We are working to map these interactions so we can create drugs that silence this conversation—or change it. For example, we recently showed—in a mouse model that faithfully recapitulates the most aggressive form of human colorectal cancer—that by altering the stroma’s interactions with the immune system, we might make tumors vulnerable to immunotherapy.
What do new insights into the tumor microenvironment mean for cancer drug development? Moscat: It’s likely that the ultimate cancer “cure” won’t be just one drug that kills the tumor cells, but a combination of therapies. I expect this will be a three-part combination treatment that stops blood vessel growth, activates the immune system to attack the tumor and targets the stroma.
Additionally, this research shows that experimental models of cancer drug development need to take the tumor microenvironment into account. Many current models use mice that lack an immune system—in order to get the tumor to grow—or focus on the tumor in isolation. Based on our knowledge of the tumor microenvironment, this isn’t an accurate representation of human disease.
Diaz-Meco: In our lab, we have created several animal models of cancers that preserve the immune system and mirror tumor progression. In addition to better modeling human disease, this also allows us to study cancer from its earliest beginnings. This work could lead to early interventions—before the cancer has become large and hard to treat.
Anything else you’d like to add? Moscat:We are truly in the golden age of cancer biology. We understand more than we ever have before. New technologies are allowing us to obtain an unprecedented amount of information—we can even map every gene that is “turned on” in a single cancer cell. I am incredibly hopeful for the future.
Learn more about the future of cancer treatment by attending our next “Conquering Cancer” event at the Fleet Science Center. Details.
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Cancer cells lure in nutrient-rich neighbors, then mug them
AuthorMonica May
Date
August 9, 2018
If your grocery store was out of food, would you still invite your friends to a dinner party?
Unless you happen to have a flourishing garden, probably not.
Our cells would have the same answer. Food is hard to come by, so cells in our body rarely share nutrients. The only product a cell releases is waste.
But cancer cells don’t follow these rules. Despite living in a low-nutrient environment, cancer cells draw neighboring stroma cells—the glue-like cells holding our body together—toward them. In this setting you’d expect cells to keep to themselves, not bring more people to the party.
Petrus R. de Jong, MD, PhD
This odd behavior fascinates Petrus R. de Jong, MD, PhD, research assistant professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), who is studying cancer cells to try to better understand this strange act.
“Scientists are learning more and more about the importance of the tumor’s surrounding environment, called the tumor microenvironment,” says de Jong. “We are finding there are many interactions between stroma and cancer cells. If we could block this cross talk, we might be able to find a new way to treat cancer.”
Many people could benefit from this research, though it is still in its earliest stages. Breast, prostate, ovarian and colorectal cancers are all known to interact with stroma cells. De Jong’s lab is studying pancreatic cancer, which remains one of the deadliest cancers. Less than 10 percent of patients live more than five years after diagnosis. If surgery is not possible, chemotherapy and radiation are the only remaining treatment options.
Using pancreatic cancer cells, including cells isolated from patients after surgery, de Jong and his team designed an experiment to better understand why the cancer cells draw stroma cells near. They placed the cancer and stroma cells in a special container that separated the two but still allowed them to interact. After two days, they removed the cells and used special dyes to visualize different parts of the cells. DNA shows up bright blue. Cancer cells, a vibrant red. And a nutrient cells crave—fats, called lipids—shows up an intense green. [To learn more about how fluorescence microscopy works, read our primer.]
Peering under the microscope, de Jong and his team saw green lipids emerge from the stroma and taken up by the red cancer cells.
Green lipids emerged from the stroma
and were taken up by the red cancer
cells.
“Lipids are a valuable source of energy, so it is unusual for the stroma cells to release this nutrient to the cancer cells,” says de Jong. “It appears the cancer cell is sending out a signal that tells the stroma cells to give them this food.”
To try to determine how the cancer cells were taking up these lipids, de Jong used chemicals to halt autophagy—a process that allows cells to destroy and recycle their own guts. Cancer cells are known to use autophagy to break down elements that aren’t useful any longer and reuse the material as building blocks for growth.
“When the autophagy process was halted, the exchange of lipids stopped,” explains de Jong. “This finding indicates the pancreatic cancer cells forced the stroma cells to start eating themselves, then took up the resulting nutrients.”
De Jong’s team is now focused on the next mystery: how the pancreatic cancer cells are taking up these nutrients. If scientists can identify this process, they might be able to find a medicine that halts cancer cells while leaving healthy cells unharmed, the goal for any cancer treatment.
In other words, they could stop cancer cells from mugging their unsuspecting neighbors.
Read the AACR 2017 abstract detailing this research. For the full poster, contact de Jong at pdejong@sbpdiscovery.org.
Interested in keeping up with SBP’s latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.
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SBP presents at American Association for Cancer Research’s annual meeting
Moscat presented at the session titled “Metabolic Interplay between Tumor and Microenvironment.”
“Cancer cells have to adapt their metabolism to survive nutrient deprivation and several stress conditions in their tumor microenvironment. For this they put in motion a process called autophagy whereby they get rid of toxic intracellular molecules and organelles and generate nutrients that allow them to survive,” said Moscat.
“Central to this process is a protein called p62 that was discovered in collaboration with my SBP colleague Maria Diaz-Meco. This protein is upregulated in, for example, liver cancer, whose mortality has increased dramatically over the last 10 years, in marked contrast to many other neoplasias that have shown a significant decrease in mortality.
“We presented new compelling data from human patients, mouse models and cell culture studies demonstrating that inactivation of p62 in cancer liver cells dramatically reduced the incidence and aggressiveness of hepatocellular carcinoma. Therefore, p62 is a novel and potentially actionable therapeutic target in liver cancer,” added Moscat.
Moscat said he was impressed at AACR by the number and quality of research studies linking the possibility of treating patients by a combined strategy of targeting cancer metabolism and the immunological tumor microenvironment.
He also spoke to ecancer.tv, an online provider of oncology news, about his research. Watch the video here.
Moscat is co-chair of a symposium on related research in cancer metabolism to that will be held June 22-23 at SBP’s La Jolla campus.
Commisso’s presentation was featured in a special session on pancreatic cancer that aimed to stimulate opportunities for collaboration between Pancreatic Cancer Action Network-AACR grantees and others in the field.
“The research that I presented was focused on a novel drug target in pancreatic cancer discovered recently by my lab,” said Commisso.
“We have found that an ion transporter that regulates pH homeostasis is critical to pancreatic cancer cell survival. This previously uncharacterized transporter plays a role in maintaining amino acid supply in tumor cells that harbor a mutation in the oncogene known as Ras, which is mutated in >90% of pancreatic tumors.
“Our future work is focused on exploring the role of this transporter in preclinical models and developing new approaches to inhibit this druggable target,” added Commisso.
He called the AACR meeting “a remarkable opportunity for cancer researchers to come together and share their exciting discoveries.” Dr. Commisso also said it was a good opportunity to connect with colleagues and friends to develop and nurture scientific collaborations, to create, progress and build.
Commisso will also present at the 2016 PancWest Symposium in September at the Moores Cancer Center at UCSD.
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Upcoming symposium: Cancer Immunology and the Tumor Microenvironment
Authorjmoore
Date
March 10, 2016
On March 17, SBP La Jolla is hosting a symposium on the interactions between the immune system and tumors, including how they can be leveraged for cancer treatment. The symposium is organized by Carl Ware, PhD and Robert Rickert, PhD, the directors of the Inflammatory and Infectious Disease Center and the Tumor Microenvironment and Cancer Immunology Program, respectively, and features presentations by leaders in the field:
Adam Godzik, PhD, Sanford Burnham Prebys Medical Discovery Institute
The symposium will be held from 9-4:30 in Fishman Auditorium (overflow seating in the Building 12 auditorium), with a reception to follow. If you plan to attend, please register here.
