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MIT study: High-fat diets make liver cells more likely to become cancerous

Fatty diet rewires liver cells and makes them more prone to becoming cancerous.

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One of the biggest risk factors for developing liver cancer is a high-fat diet. A new study from MIT reveals how a fatty diet rewires liver cells and makes them more prone to becoming cancerous.

The researchers found that in response to a high-fat diet, mature hepatocytes in the liver revert to an immature, stem-cell-like state. This helps them to survive the stressful conditions created by the high-fat diet, but in the long term, it makes them more likely to become cancerous.

“If cells are forced to deal with a stressor, such as a high-fat diet, over and over again, they will do things that will help them survive, but at the risk of increased susceptibility to tumorigenesis,” says Alex K. Shalek, director of the Institute for Medical Engineering and Sciences (IMES), the J. W. Kieckhefer Professor in IMES and the Department of Chemistry, and a member of the Koch Institute for Integrative Cancer Research at MIT, the Ragon Institute of MGH, MIT, and Harvard, and the Broad Institute of MIT and Harvard.

The researchers also identified several transcription factors that appear to control this reversion, which they believe could make good targets for drugs to help prevent tumor development in high-risk patients.

Shalek; Ömer Yilmaz, an MIT associate professor of biology and a member of the Koch Institute; and Wolfram Goessling, co-director of the Harvard-MIT Program in Health Sciences and Technology, are the senior authors of the study, which appears today in Cell. MIT graduate student Constantine Tzouanas, former MIT postdoc Jessica Shay, and Massachusetts General Brigham postdoc Marc Sherman are the co-first authors of the paper.

Cell reversion

A high-fat diet can lead to inflammation and buildup of fat in the liver, a condition known as steatotic liver disease. This disease, which can also be caused by a wide variety of long-term metabolic stresses such as high alcohol consumption, may lead to liver cirrhosis, liver failure, and eventually cancer. 

In the new study, the researchers wanted to figure out just what happens in cells of the liver when exposed to a high-fat diet — in particular, which genes get turned on or off as the liver responds to this long-term stress.

To do that, the researchers fed mice a high-fat diet and performed single-cell RNA-sequencing of their liver cells at key timepoints as liver disease progressed. This allowed them to monitor gene expression changes that occurred as the mice advanced through liver inflammation, to tissue scarring and eventually cancer.

In the early stages of this progression, the researchers found that the high-fat diet prompted hepatocytes, the most abundant cell type in the liver, to turn on genes that help them survive the stressful environment. These include genes that make them more resistant to apoptosis and more likely to proliferate.

At the same time, those cells began to turn off some of the genes that are critical for normal hepatocyte function, including metabolic enzymes and secreted proteins.

“This really looks like a trade-off, prioritizing what’s good for the individual cell to stay alive in a stressful environment, at the expense of what the collective tissue should be doing,” Tzouanas says.

Some of these changes happened right away, while others, including a decline in metabolic enzyme production, shifted more gradually over a longer period. Nearly all of the mice on a high-fat diet ended up developing liver cancer by the end of the study.

When cells are in a more immature state, it appears that they are more likely to become cancerous if a mutation occurs later on, the researchers say.

“These cells have already turned on the same genes that they’re going to need to become cancerous. They’ve already shifted away from the mature identity that would otherwise drag down their ability to proliferate,” Tzouanas says. “Once a cell picks up the wrong mutation, then it’s really off to the races and they’ve already gotten a head start on some of those hallmarks of cancer.”

The researchers also identified several genes that appear to orchestrate the changes that revert hepatocytes to an immature state. While this study was going on, a drug targeting one of these genes (thyroid hormone receptor) was approved to treat a severe form of steatotic liver disease called MASH fibrosis. And, a drug activating an enzyme that they identified (HMGCS2) is now in clinical trials to treat steatotic liver disease.

Another possible target that the new study revealed is a transcription factor called SOX4, which is normally only active during fetal development and in a small number of adult tissues (but not the liver).

Cancer progression

After the researchers identified these changes in mice, they sought to discover if something similar might be happening in human patients with liver disease. To do that, they analyzed data from liver tissue samples removed from patients at different stages of the disease. They also looked at tissue from people who had liver disease but had not yet developed cancer.

Those studies revealed a similar pattern to what the researchers had seen in mice: The expression of genes needed for normal liver function decreased over time, while genes associated with immature states went up. Additionally, the researchers found that they could accurately predict patients’ survival outcomes based on an analysis of their gene expression patterns.

“Patients who had higher expression of these pro-cell-survival genes that are turned on with high-fat diet survived for less time after tumors developed,” Tzouanas says. “And if a patient has lower expression of genes that support the functions that the liver normally performs, they also survive for less time.”

While the mice in this study developed cancer within a year or so, the researchers estimate that in humans, the process likely extends over a longer span, possibly around 20 years. That will vary between individuals depending on their diet and other risk factors such as alcohol consumption or viral infections, which can also promote liver cells’ reversion to an immature state.

The researchers now plan to investigate whether any of the changes that occur in response to a high-fat diet can be reversed by going back to a normal diet, or by taking weight-loss drugs such as GLP-1 agonists. They also hope to study whether any of the transcription factors they identified could make good targets for drugs that could help prevent diseased liver tissue from becoming cancerous.

“We now have all these new molecular targets and a better understanding of what is underlying the biology, which could give us new angles to improve outcomes for patients,” Shalek says.

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Stress, BMI, and hormones linked to earlier puberty in girls

Higher levels of key steroid hormones—combined with elevated stress and body mass index (BMI)—are associated with earlier onset of puberty in girls.

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Higher levels of key steroid hormones—combined with elevated stress and body mass index (BMI)—are associated with earlier onset of puberty in girls, according to a new study at Columbia University Mailman School of Public Health.

The findings are published in The Journal of Clinical Endocrinology & Metabolism.

 Elevated prepuberty urinary levels of glucocorticoids, androgens, and progesterone were strongly linked to accelerated breast development (thelarche). Girls with high glucocorticoid levels alongside high BMI and stress entered puberty an average of seven months earlier than peers with lower levels.

“While stress and BMI have long been recognized as independent predictors of puberty, few studies have examined how they interact with a girl’s hormones,” said Lauren Houghton, PhD, assistant professor of Epidemiology at Columbia Mailman School, and first author. “Our findings challenge conventional research that has largely focused on estrogen and body size, highlighting instead the role of stress and androgens – typically thought of as male hormones– in shaping pubescent development.”

The strongest associations were observed for progesterone, androgens, and glucocorticoids, indicating that multiple hormonal pathways—not just estrogen—play a critical role in the timing of puberty.

For example:

  • Higher glucocorticoid, androgen, and progesterone metabolites were associated with earlier onset of puberty
  • Elevated androgens and progesterone were also linked to a longer duration of puberty
  • Estrogen metabolites were associated with delayed onset, not acceleration
  • The effects of hormones on puberty timing were significantly modified by BMI and stress levels.

 Notably, the associations were consistent regardless of family history of breast cancer.

“Our objective was to identify the full set of hormonal patterns linked to accelerated puberty and test whether BMI and stress modify this relationship,” said Houghton, who is also assistant professor at the Herbert Irving Comprehensive Cancer Center at Columbia. “We predicted that girls with elevated BMI and stress would experience the earliest onset—and that the stress response shifts during this key time for girls.”

The researchers drew on data from the LEGACY Girls Study, a cohort of 1,040 girls ages 6 to 13 recruited across the U.S. States and Canada. Participants were followed every six months with clinical assessments, questionnaires, and biospecimen collection.

The analysis included 327 girls who were at the pre-puberty stage at baseline and provided urine samples at least one year before the onset of puberty. Houghton and colleagues measured a comprehensive panel of steroid metabolites using first-morning urine samples and tracked puberty development using validated clinical scales.

Mothers of the girls completed an Internalizing Composite Scale, which includes subscales for anxiety, depression, and other at-risk status. They also provided information on girls’ family history of all cancers as well as on pregnancy and infancy, including birth weight and their child’s race and ethnicity. Trained research staff measured height and weight twice every 6 months. 

“Unlike prior research, this study simultaneously examined hormonal patterns, BMI, and psychosocial stress—captured through standardized behavioral assessments—within the same cohort,” said senior author Mary Beth Terry, PhD, professor of Epidemiology at Columbia Mailman School, and the Herbert Irving Cancer Center, and Silent Spring Institute.  “Interestingly, we also learned that the associations were consistent regardless of family history of breast cancer.”

The findings may help explain the ongoing trend toward earlier puberty and point to actionable prevention strategies, observed the authors.

 “Stress-reducing interventions and healthy lifestyle changes may help delay early puberty and improve long-term health outcomes,” said Houghton. ‘Because early puberty is linked to increased breast cancer risk later in life, the results have important implications for both pediatric care and public health.”

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Cancer risk is significantly higher for adults who never married, large study finds

Adults who were never married had substantially higher rates of developing cancer compared with those who were or had been married. For some cancers, the association was even stronger: adult men who were never married had approximately five times the rate of anal cancer compared with married men.

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Adults who have never been married face a significantly higher risk of developing cancer than those who have been married, according to a study of more than 4 million cases.

The increased risk spans nearly every major cancer type and is especially pronounced for preventable cancers—those linked to infections, smoking and reproductive factors. Led by researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, the study appears in the April 8 issue of Cancer Research Communications.

link to the article is here.

“These findings suggest that social factors such as marital status may serve as important markers of cancer risk at the population level,” said Paulo Pinheiro, Ph.D., study co-author and a Sylvester physician-scientist whose lab conducts population-based cancer epidemiology.

The novel observation does not mean that getting married prevents cancer or that people need to get married.

“It means that if you’re not married, you should be paying extra attention to cancer risk factors, getting any screenings you may need, and staying up to date on health care,” said Frank Penedo, Ph.D., associate director for population sciences and director of the Sylvester Survivorship and Supportive Care Institute (SSCI).

“For prevention efforts, our findings point to the importance of targeting cancer risk awareness and prevention strategies with attention to marital status,” he added.

Marriage is already associated with earlier cancer diagnosis and better survival. Married individuals often, but not always, have stronger support systems, greater economic stability and are more likely to adhere to cancer treatment regimens.

But previous work on the links between marriage and cancer focused almost entirely on what happens at and after diagnosis. Only a few small, older studies explored whether marriage affects the odds of getting cancer in the first place.

“We wanted to know who is more likely to get cancer: married people or unmarried people?” Pinheiro said.

To find out, the researchers analyzed a large dataset covering 12 states that included demographic and cancer data from more than 4 million cancer cases in a population of more than 100 million people, collected between 2015 and 2022. They examined cases of malignant cancers diagnosed at age 30 or older and compared rates of various cancers by marital status, further broken down by sex and race and adjusted for age.

The researchers categorized marital status into two groups: those who were or had been married, including married, divorced and widowed individuals, and those who had never been married. The study began in 2015 because that year, the U.S. Supreme Court legalized gay marriage, allowing same-sex couples to be included in the married category. One in five adults in the study had never married.

Pinheiro expected to see some associations, given established relationships between marriage and lifestyle factors such as smoking, routine medical care and having children. But the strength of some findings surprised him.

Adults who were never married had substantially higher rates of developing cancer compared with those who were or had been married. For some cancers, the association was even stronger: adult men who were never married had approximately five times the rate of anal cancer compared with married men. Adult women who were never married had nearly three times the rate of cervical cancer compared with women who were or had been married.

Both anal and cervical cancers are strongly related to HPV infection, so these differences likely reflect variation in exposure, and for cervical cancer, also differences in screening and prevention. In contrast, for cancers such as endometrial and ovarian, differences by marital status may partly reflect the protective effect of parity, which is more common among married individuals.

“It’s a clear and powerful signal that some individuals are at a greater risk,” Penedo said.

Men and women showed slightly different patterns. Men who were never married were about 70% more likely to develop cancer than married men, while women who never married were about 85% more likely to develop cancer than women who were or had been married.

This represents a small but noteworthy reversal of a broader trend: Men often benefit more from marriage than women in terms of health and social factors. In this case, women appeared to benefit slightly more from marriage than men.

The strongest associations between marriage and cancer were seen for cancers related to infection, smoking or alcohol use, and, for women, cancers related to reproduction, such as ovarian and endometrial cancer.

The researchers found weaker associations for cancers with robust screening programs, including breast, thyroid and prostate cancers.

They also observed patterns across race and marital status. Black men who were never married had the highest overall cancer rates. However, married Black men had lower cancer rates than married White men, indicating a strong protective association with marriage in that group.

The study has limitations. People who smoke less, drink less, take better care of themselves and are more socially integrated may also be more likely to get married.

Still, the researchers found that associations between marriage and cancer were stronger in adults older than 50, suggesting that as people age and accumulate cancer risk exposures, the benefits associated with marriage may become more pronounced.

The study also excluded individuals who are unmarried but in committed partnerships. That group is likely small relative to the size of the dataset, Pinheiro said, but worth exploring in future research.

Future studies could further subdivide the married category into married, divorced and widowed individuals and follow people over decades to better understand how marital transitions affect cancer risk.

Overall, getting married does not magically prevent cancer, both authors stressed.

“But the association between marriage status and cancer risk is an interesting, new observation that deserves more research,” Pinheiro said.

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Social support, sleep, pain management linked to mental health in later life

Older people who are socially connected, physically healthy, and spiritually engaged are significantly more likely to experience complete mental health.

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Older people who are socially connected, physically healthy, and spiritually engaged are significantly more likely to experience complete mental health.

This is according to a new study, “Flourishing older Canadians: What characteristics are associated with complete mental health?”, that was published in PLOS One.

Using data from 2,024 respondents in Statistics Canada’s 2022 Mental Health and Access to Care Survey (MHACS), researchers examined factors associated with both the absence of psychiatric disorder (APD) and complete mental health (CMH), a broader measure that combines freedom from mental illness with high emotional, psychological, and social well-being.

“Our findings shift the conversation away from mental illness alone and toward understanding what helps older adults truly flourish,” said first author Daniyal Rahim, PhD Candidate, Ontario Institute for Studies in Education, University of Toronto. “Complete mental health reflects not just the absence of disorders, but the presence of meaning, satisfaction, and strong social connections.”

The study found that older adults were more likely to experience APD and CMH if they were married or in a common-law relationship, had strong social support, rated their physical health as fair or better, and reported no chronic pain, sleep problems, or limitations in daily activities. Social support emerged as one of the strongest predictors, more than doubling the odds of achieving complete mental health.

“Social relationships appear to be a cornerstone of mental well-being in later life,” said coauthor Shannon Halls, Research Coordinator, Institute for Life Course & Aging, University of Toronto. “Having people to rely on during stressful times may buffer against psychological distress and promote resilience, happiness, and a sense of purpose.”

Spirituality was also strongly associated with mental well-being. Older adults who reported that religion or spirituality was important in their daily lives had significantly higher odds of both APD and CMH.

“Spiritual beliefs may help older adults cope with adversity by providing meaning, hope, and a sense of community,” said co-author Ying Jiang, a senior epidemiologist in the Applied Research Division, Centre for Surveillance and Applied Research, Public Health Agency of Canada. “These factors can be particularly relevant during periods of declining health or life transitions.”

Physical health factors played a critical role. Freedom from chronic pain, sleep problems, and limitations in instrumental activities of daily living was consistently associated with better mental health outcomes. Conversely, living in a large urban center was linked to lower odds of complete mental health compared to rural living.

“These findings underscore that mental health in aging is shaped by a complex interplay of social, physical, and environmental factors,” said senior author Esme Fuller-Thomson, Director, Institute for Life Course & Aging, University of Toronto, Factor-Inwentash Faculty of Social Work, University of Toronto. “Public health strategies that strengthen social support, address pain and sleep problems, and promote meaningful engagement could substantially improve well-being among older adults.”

The authors emphasize that many of the identified factors are modifiable, suggesting opportunities for targeted interventions, including social programming, pain management, sleep treatment, and community-based supports to help more older Canadians achieve complete mental health.

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