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Camila dos Santos

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Camila dos Santos. Photo courtesy of CSHL

By Daniel Dunaief

Pregnancy and lactation can alter genes in specific mammary cells, which may have implications in a defense against cancer.

In mouse models, mice that became pregnant at a young age have so-called epigenetic changes that survive for the animal life span and some of those are linked to a decrease in breast cancer.

In a recent study published in Cell Reports, Cold Spring Harbor Associate Professor Camila dos Santos and her graduate student Amritha Varshini Hanasoge Somasundara found that a protein involved in mammary cells in mice, called CD1d, boosts the immune system after a full pregnancy cycle, protecting it against breast cancer.

“Our research demonstrated that increased levels of CD1d in breast cells serve as a signal to recruit higher numbers of specialized immune cells” called natural killer T-cells, or NKT, “to come and reside within the breast tissue after pregnancy,” dos Santos explained in an email. These NKTs are part of mechanisms that reduce breast cancer risk after pregnancy.

Dos Santos would like to understand the molecular changes that occur from pregnancy and hopes one day to adapt them in the form of a vaccination or pill to decrease the risk of breast cancer.

To be sure, numerous questions about the process of using the immune system to prevent cancer remain, which means that the development of such a preventive pill requires considerable additional research.

Dos Santos has spent the last eight years developing model systems that allow her to discover pregnancy-induced changes that could lead to preventive strategies.

Enhancing the communication between epithelial and immune cells could represent a way to decrease breast cancer development and even treat cases of developed cancer.

To get to that point, dos Santos, the members of her lab, and her collaborators plan to make discoveries like this one to understand the dynamic interaction between the cascade of molecular interactions from pregnancy and the genetic and immunological reactions.

Humans have four CD1 genes, which all play a similar role in immunity. Additionally, there are several types of NKT cells, and each of them has a different immunological function, which means that any prevention or treatment that tapped into this system would need to bring the right CD1 molecule and the right NKT cells.

It is not yet clear whether enhancing CD1 signals protect women who might have a predisposition to breast cancer. Dos Santos is currently exploring this question in animals.

While dos Santos is focusing specifically on pregnancy-driven changes in the mammary gland, she acknowledged that altering CD1d levels in other organs might also decrease other types of cancer.

Dos Santos described pregnancy as being akin to turning on a light. First, during the course of gestation, pregnancy brightens that light to the top. After birth, the dimmer goes to the middle, leaving the system in a different state, which is not only more prepared for the next pregnancy but also to defend itself against alterations like cancer.

In most pregnancy mammary cells in mice, the scientists found a 10-fold increase in the abundance of NKT cells when compared to cells from an individual who had never been pregnant.

When the researchers removed the CD1d protein in mice, they found an association between the absence or low expression and the development of tumors in the breast.

Dos Santos and Hanasoge hypothesize that this protein is recruiting immune cells to monitor breast cells after pregnancy. If the epithelial cells develop cancer, the NKT cells may kill them, preventing the development and advancement of cancer.

In addition to working with mouse models of pregnancy, dos Santos is collaborating with Northwell Health to study cells from healthy women who are undergoing cosmetic surgery. They are analyzing that data, which wasn’t in this paper. 

Dos Santos is investigating several questions, including how the age at pregnancy influences breast tissue. She is creating organoids, which are three-dimensional models of breast cells that react to change in their environment

Joining a family

From left, Amritha Varshini Hanasoge Somasundara and Camila dos Santos

Amritha Varshini Hanasoge Somasundara, who has been a part of dos Santos’s lab for over two years, explained that she felt comfortable and supported instantly when she arrived. She described the atmosphere as extremely collegial and felt as if she were included in a scientific family.

Joining dos Santos’s group was “possibly the best decision I’ve ever made,” said Hanasoge. Dos Santos’s lab is a “really special place” where lab members often have lunch together and support each other’s research.

Hanasoge was drawn to Dos Santos’s mentorship and the overall lab dynamic. Scientifically, she was also interested in the immunology project, exploring NKT cells. Her main project has involved trying to characterize NKT cells further. 

Hanasoge sees plenty of opportunities to address additional questions in this field. “We don’t know if the process of lactation is causing more CD1d and increasing expression,” she said. “We are still trying to characterize what T-cell receptors are being expressed after pregnancy.”

A resident of Syosset, Hanasoge enjoys reading and said she was fascinated by science when she was growing up in Mysore, Kamataka in India. She asked her parents for a microscope when she was around seven and used it to looked at flower petals and leaves. That toy microscope, which her parents purchased from a science museum in Mumbai, is still in her parent’s house.

Hanasoge is eager to combine basic and translational work and hopes her research has a clinical benefit. She is looking forward to the next steps in her research in dos Santos’s lab.

“I learn from her every day by watching how she interacts with people she mentors, both inside the lab and out,” Hanasoge explained in an email. “Her passion and commitment to being a good mentor and her drive to ask the right questions in our research are inspiring.”

 

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Camila dos Santos speaks at the Pershing Square Research Alliance’s Fifth Annual Prize Dinner at the Park Avenue Armory on May 23 with Bill Ackman, co-founder of the Pershing Square Sohn Foundation and CEO of Pershing Square Capital Management, and Olivia Tournay Flatto, the President of the Pershing Square Foundation.

By Daniel Dunaief

They aren’t quite wonder twins, but some day the dedicated work of husband and wife scientists Christopher Vakoc and Camila dos Santos may help people batting against a range of cancers, from leukemia to breast cancer.

An assistant professor at Cold Spring Harbor Laboratory, dos Santos recently won the prestigious and highly coveted Pershing Square Sohn prize. Dos Santos, who studies breast cancer, will receive $200,000 in funds per year for the next three years. She won the same prize her husband, an associate professor at Cold Spring Harbor Laboratory, collected two years earlier for his work using the gene-editing technique CRISPR to study the molecular pathways involved in leukemia.

Dos Santos and Vakoc are the first family of prize winners in the Pershing Square Foundation’s five years of supporting research in the New York area.“The board was very much taken by how original her approach is and how thoughtful she is about it,” said Olivia Tournay Flatto, president of the foundation. “There was a lot of early stage data that would say that the observations she’s making are interesting to pursue, but that the National Institutes of Health would not fund. We felt this was something we wanted to be a part of.”

Dos Santos is studying so-called epigenetic changes that protect women from breast cancer if they become pregnant before they are 25. Women who have pregnancies before that cut-off age have a 30 to 40 percent decrease in breast cancer, even decades after their pregnancy.

Dos Santos has been digging into this process, looking at why some women who are pregnant before this age still develop breast cancer later in life.

The Cold Spring Harbor scientist is exploring how infections block the protective effects of pregnancy. She hasn’t defined the panel of infections that could influence cancer risk before or after pregnancy. The hypothesis in her work is that “the whole process that is fighting inflammation could change the breast cells,” which could “take away the advantage that pregnancy brings.”

If she proves her theory — that changes to inflammation could take away benefits of an early pregnancy — she could define changes to proteins and genes as biomarkers to predict the risk of breast cancer, even in the event of an early pregnancy. One of the challenges in the three-step application process for this prize was to explain to a group of experts how what she’s doing was different from what others are pursuing. Her approach is to look at cells before and during the process of turning into cancer cells. That strategy led to the current hypothesis, which was the basis for her application for this prize.

To study breast cancer, dos Santos recently developed a mouse model in her lab, to see how pregnancy changes pre-malignant lesions. When the mice they are studying have a gene that would turn into cancer, some of them don’t develop cancer if they’ve already been pregnant. Those mice that haven’t been pregnant develop cancer. She uses this mouse model to ask questions about how pregnancy changes a cell such that oncogenes cannot operate to change a cell into a cancer.

“We are not only investigating how prevention works, but we are also learning what signals break that prevention,” dos Santos said.

Dos Santos has used the mouse model experiments to test an unusual element to human breast cancer resistance. Women who reach their second trimester before 25, but don’t give birth to a child, have the same resistance, decades later, to breast cancer. Mice whose pregnancies last through the equivalent of the second trimester also experience similar epigenetic benefits.

She has tested mice who have a pseudo-pregnancy —who have higher pregnancy hormone levels without being pregnant — to see if a similar pregnancy environment would convey the same resistance. “Even in those cases, with no fetus, no embryo, no birth and no nursing, we see that the epigenetics changes,” dos Santos said. The scientist plans to use the funds from this award to perform high-tech experiments, such as single-cell, multiple mouse models and human tissue analysis that she wouldn’t have been able to tackle without the funding.

Dos Santos is grateful for the funding, which she said she wouldn’t have been able to secure through other means based on “the stage we are right now,” she said. The work is “risky” and “provocative,” but it’s also “outside of the box ideas and experiments and approaches.”

When she puts all the variants together, the risky outcome could be beneficial, leading to a better understanding of how to copy or, perhaps, understand nature to try to cure or prevent cancer.

Dos Santos said she learned about the award when she was on a train on the way to Jamaica, where she was catching a flight to Washington, D.C. She said she turned into a “texting machine,” sharing the good news with everyone, including her husband Vakoc, who called her as soon as he saw the news. “He was super happy,” she recalled.

She said Vakoc was particularly helpful in discussing the work and in watching their sons Lucas and Marcus who are 8 and 5, respectively. She also received some unexpected help from him before an extensive seven- to eight-minute finalist screening process.

She asked him about the interview, and he remembered that there were five people in the audience and that he didn’t get that many questions. When she appeared for her interview, she saw about 25 people in the audience and received numerous questions. In a way, she said, his memory of his experience may have helped her, because she didn’t have time to worry about the size of the audience or the number of questions.

Dos Santos said their sons are proud of their parents for winning awards for their work on cancer.

When her sons are upset with dos Santos, they sometimes warn, reflecting their parents’ threat to take away TV, that they’re going to “take your epigenetics away.”

Dos Santos said the couple maintains a healthy work-life balance. She is grateful for her husband’s support, as well as for the environment and expertise at Cold Spring Harbor Laboratory.

“Here at the lab, we not only have the technology to move this forward, but we also have a pretty outstanding body of scientists that are very collaborative,” she said.

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Camila dos Santos photo from the scientist

By Daniel Dunaief

Mothers of more than one child have blogged about it for years. When they have their second child, the breastfeeding process is often quicker, with milk available sooner than for the first child. Camila dos Santos, who became an assistant professor at Cold Spring Harbor Laboratory in February, has found a reason.

Cells in the mammary gland go through something called epigenetic changes. That means something affects the genetic machinery, causing them to react differently under the same circumstances. In mouse models, dos Santos discovered changes in cell proliferation and milk production genes to the hormones estrogen and progesterone.

When she was a postdoctoral student in Greg Hannon’s laboratory at CSHL, dos Santos said they “decided to profile the epigenome before and after pregnancy.” At first, she was looking for changes associated with the effects of pregnancy on breast cancer development. The recent work, however, described the presence of epigenetic memory of past pregnancies, which influences milk production in the next pregnancy.

The message from these studies was that those areas where she saw changes “are associated with the genes responsible for lactation and the proliferation of the mammary gland during pregnancy,” said dos Santos.

The implications of this research extend from the potential to enhance breastfeeding in women who struggle during lactation to breast cancer.

Indeed, other studies have shown that women who become pregnant before 25 have a lower risk for all types of breast cancer.

“We believe that such strong protective effect must have an epigenetic basis,” dos Santos said. She would like to “understand how this stable, pregnancy-induced epigenome prevents cancer development,” she continued.

Hannon believes the kind of research dos Santos is conducting holds promise.

“The world of breast cancer prevention is badly in need of very solid underlying molecular biology and I think there’s a fair chance that what [dos Santos] is doing will eventually get us there,” said Hannon, who recently left Cold Spring Harbor Laboratory and is now the Royal Society Wolfson Research Professor at the Cancer Research UK Cambridge Institute at the University of Cambridge.

Dos Santos said her research is exploring ways to turn the changes that occur during pregnancies before the age of 25 into a “preventive strategy to treat women that are high risk and even those that are not.”

To be sure, Hannon and dos Santos cautioned, it’s difficult to know how quickly or even whether this kind of research will lead to any treatment or prevention options.

“The main goal of my lab is to try to understand the effects of pregnancy on normal cells, to devise a strategy to prevent breast cancer from arising,” dos Santos said. She recently published her work in the journal Cell Reports.

Dos Santos and Andrew Smith, a computational biologist from the University of Southern California, along with his postdoctoral fellow Egor Dolzhenko discovered that mice that had been through a single pregnancy had methylation marks that were different from mice of the same age that hadn’t been pregnant. The group connected the changes in the genome to a transcription factor called Stat5a. A transcription factor is a protein that acts like a genetic traffic light, turning on or off genes.

When she joined Hannon’s lab in 2008, dos Santos wanted to study gene regulation throughout cell development. It took her three years to purify stem cells.

Hannon credits dos Santos for developing new techniques.

“She had to build the tools she needed to ask” these questions, Hannon said.

Dos Santos lives in campus housing with her husband, Christopher Vakoc, who is an assistant professor at CSHL. The couple take their young sons hiking and can’t wait for the spring and summer because they hike, swim and kayak. Vakoc and dos Santos met when they were in adjoining labs in Philadelphia.

“We used to have joint lab meetings and one day he asked me on a date,” she recalled.

This summer, dos Santos’ lab will include a premed undergraduate student from Hofstra and high school students from Cold Spring Harbor High School and  Southampton High School. She recently hired a postdoctoral fellow.

“I envision my lab growing according to my needs,” she said. “Right now, I want to continue to work at the bench while training students and postdocs.”

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