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Researchers uncover ‘on/off switch’ for breast cancer metastasis
The research could help clinicians better predict patient response to existing medicines
Researchers from Stanford University have discovered an “on/off switch” for breast cancer metastasis, in a move that could redefine treatment.
Despite their promise, immunotherapies fail to treat many cancers, including over 80 per cent of some of the most advanced breast cancers and many of those patients who do respond still experience metastases eventually.
Researchers from Stanford University and the Arc Institute has revealed a better way to predict and improve patient responses.
A team led by Lingyin Li, associate professor of biochemistry at Stanford and Arc Core investigator, found that a protein called ENPP1 acts as an “on/off switch” that controls breast cancer’s ability to both resist immunotherapy and metastasise.
The study, published in December in the Proceedings of the National Academy of Sciences, showed that ENPP1 is produced by cancer cells and by healthy cells in and around the tumour, and that high patient ENPP1 levels are linked to immunotherapy resistance and subsequent metastases.
The research could lead to new, more effective immunotherapies and help clinicians better predict patient response to existing medicines.
“Our study should offer hope for everyone,” said Li, who is also an institute scholar at Sarafan ChEM-H.
Thawing cold tumours
Immunotherapies, like pembrolizumab (Keytruda), work by blocking an immune-dampening interaction between a cancer cell and a T cell, a kind of immune cell. For this to be effective, though, T cells need to permeate the tumour. So-called “hot” tumours, like those in melanoma and a subset of lung cancer, are treatable through immunotherapies, but many others, like breast and pancreatic cancers, are “cold,” devoid of T cell infiltration.
In her quest to turn cold tumours hot, Li started with cGAMP, a molecule that cells produce when their DNA is damaged, which happens when a cell becomes cancerous. If left intact, cGAMP activates an immune response through what is known as the STING pathway, which can help make a tumour hot.
Li previously discovered that cGAMP is exported outside the cells but often, before it can trigger a response, a protein called ENPP1 chews up these molecular “danger” signals. ENPP1, she proposed, helped keep cold tumours cold.
High levels of ENPP1 correlate with poor prognosis in many cancers, but the protein can perform many actions in the body, so Li set out to determine if its cGAMP-chewing ability is behind its clinical significance.
An on/off switch
Li began collaborating with two professors at the University of California, San Francisco: Hani Goodarzi, also an incoming Arc Institute Core investigator, and Laura Van’t Veer, a clinician who leads the I-SPY 2 trial, a groundbreaking breast cancer trial.
ENPP1 levels naturally vary across individuals, so the team looked at data from patients in the I-SPY 2 trial to see how responses to pembrolizumab varied with ENPP1 levels at the time of diagnosis.
Patients with high ENPP1 levels had low response to pembrolizumab and high chance of metastases. Those with low ENPP1 levels had a high response to pembrolizumab and no metastases. ENPP1 predicted both response to immunotherapy and likelihood of relapse.
Two things were suddenly clear: that ENPP1 was critical in metastases, not just in primary tumours and that they should be looking at ENPP1 in healthy cells, not only in cancer cells.
Songnan Wang, an MD-PhD student in biochemistry, Arc researcher and first author on the paper, said: “Using the finest molecular scalpels developed in our lab, I was excited to dig deeper and figure out exactly how ENPP1 has such a dramatic influence on clinical outcomes.”
In a series of mouse studies, Wang proved that removing ENPP1 entirely or eliminating only its cGAMP-chewing ability in normal and cancer cells yielded exactly the same result: decreased tumour growth and decreased metastases. And the team proved that it resulted directly from suppressing the STING pathway. They found an on/off switch.
Ovarian cancer cells quickly activate survival responses after PARP inhibitor treatment, and a lung cancer drug could help block this, research suggests.
PARP inhibitors are a common treatment for ovarian cancer, particularly in tumours with faulty DNA repair. They stop cancer cells fixing DNA damage, which leads to cell death, but many tumours later stop responding.
Researchers identified a way cancer cells may survive PARP inhibitor treatment from the outset, pointing to a potential way to block that response. A Mayo Clinic team found ovarian cancer cells rapidly switch on a pro-survival programme after exposure to PARP inhibitors. A key driver is FRA1, a transcription factor (a protein that turns genes on and off) that helps cancer cells adapt and avoid death.
The team then tested whether brigatinib, a drug approved for certain lung cancers, could block this response and boost the effect of PARP inhibitors. Brigatinib was chosen because it inhibits multiple signalling pathways involved in cancer cell survival.
In laboratory studies, combining brigatinib with a PARP inhibitor was more effective than either treatment alone. Notably, the effect was seen in cancer cells but not normal cells, suggesting a more targeted approach.
Brigatinib also appeared to act in an unexpected way. Rather than working through the usual DNA repair routes, it shut down two signalling molecules, FAK and EPHA2, that aggressive ovarian cancer cells rely on. FAK and EPHA2 are proteins that relay survival signals inside cells. Blocking both at once weakened the cells’ ability to adapt and resist treatment, making them more vulnerable to PARP inhibitors.
Tumours with higher levels of FAK and EPHA2 responded better to the drug combination. Other data link high levels of these molecules to more aggressive disease, pointing to potential benefit in harder-to-treat cases.
Arun Kanakkanthara, an oncology investigator at Mayo Clinic and a senior author of the study, said: “This work shows that drug resistance does not always emerge slowly over time; cancer cells can activate survival programmes very early after treatment begins.”
John Weroha, a medical oncologist at Mayo Clinic and a senior author of the study, said: “From a clinical perspective, resistance remains one of the biggest challenges in treating ovarian cancer. By combining mechanistic insights from Dr Kanakkanthara’s laboratory with my clinical experience, this preclinical work supports the strategy of targeting resistance early, before it has a chance to take hold. This strategy could improve patient outcomes.”
Nighttime temperatures during pregnancy may be linked to a higher chance of an autism diagnosis in children, a recent study suggests.
The research tracked nearly 295,000 mother-child pairs in Southern California from 2001 to 2014 and linked warmer overnight temperatures with higher risk in early and late pregnancy.
Children of mothers exposed to higher than typical nighttime temperatures during weeks one to 10 of pregnancy had a 15 per cent higher risk of an autism diagnosis.
Exposure during weeks 30 to 37 was linked to a 13 per cent higher risk.
Lead author David Luglio, a post-doctoral fellow at Tulane University, said: “A key takeaway is that we identified specific windows when a mother and her developing child can be most affected by exposures to higher nighttime temperatures.
“This is critical and hopefully can help mothers prepare accordingly.”
The study is described as the first to examine how temperature may affect fetal neurodevelopment, the process by which a baby’s brain and nervous system form during pregnancy.
Extreme temperatures linked to increased risk were classified as above the 90th percentile, meaning 3.6°F hotter than average, and the 99th percentile, 5.6°F above average.
The association held even after researchers accounted for factors such as neighbourhood conditions, vegetation and fine-particle air pollution.
The study could not account for other factors such as access to air conditioning. Researchers did not find the same association with daytime temperatures, potentially because people spend more time away from home during the day.
“Heat waves are becoming more frequent, and people may only think of the dangers of daytime heat exposure,” said Mostafijur Rahman, assistant professor of environmental health sciences at Tulane University.
“These results indicate a strong association between high nighttime temperatures during pregnancy and autism risk in children and show that we need to think about exposure to heat around the clock.”
The study did not examine how higher temperatures at night might affect prenatal development, though Luglio said it is possible that warmer nights disrupt sleep for pregnant mothers.
Previous research has suggested insufficient sleep during pregnancy may be linked to a higher risk of neurocognitive delays in children.
“Extreme heat exposure during pregnancy has been linked to a range of adverse health outcomes, including prenatal neurodevelopment delays and complications with an embryo’s development of a central nervous system,” Luglio said.
“The goal of our study was to specifically explore the link between prenatal heat exposure and autism diagnoses for the first time.”
Kindbody has launched a fertility platform integrating AI with clinical care and patient support for employers and health plans.
The platform will enter a pilot with select Kindbody employer clients in 2026, covering over three million lives, ahead of wider availability in 2027.
Building on the company’s clinical model, the platform aims to improve outcomes and cost efficiency across family-building journeys. It connects Kindbody-owned clinics, partner clinics and an integrated clinical app.
The app offers virtual care across conception, pregnancy and reproductive health, extending through the menopause transition.
Launch features include updates in medication management, third-party reproduction, adoption, pregnancy, men’s health and global programme design.
David Stern, chief executive of Kindbody, said: “With our next-generation fertility platform, Kindbody is redefining what comprehensive, intelligent and affordable family-building care looks like for employers, health plans and patients.
“By unifying best-in-class clinical care, AI-driven intelligence and whole-person support, we are making it easier and more cost-effective for more people to build the families they envision.”
Kindbody has expanded access via its national network of IVF centres, including IVIRMA, Inception Fertility and Ivy Fertility.
A new Fertility Medication Portal is designed to streamline authorisations so medicines can be dispensed on time, giving patients visibility from prescription to coverage, pharmacy fulfilment and delivery tracking.
Through KindMan, men’s health education, digital resources and integrated clinical care are expanding, including hormone management programmes.
Services cover andropause (age-related testosterone decline), erectile dysfunction, low testosterone and other male reproductive conditions.
Specialist fertility care includes semen analysis, diagnostic testing, male hormone panels, genetic testing, surgical sperm extraction and sperm cryopreservation.
Launching in the second quarter, a pregnancy support app will act as a digital companion for expecting and new parents, with resources, interactive tools and clinical assessments to identify social drivers of health and mental health needs during pregnancy and beyond.
Kindbody’s physician-led menopause programme provides consultations with board-certified obstetricians and gynaecologists to diagnose, treat and manage menopausal symptoms, including hormone replacement therapy where appropriate, with support from nutritionists, mental health therapists and pelvic floor specialists.
AI and analytics will be embedded across the care journey. An AI care navigator will guide employees from benefit activation through intake, triage and scheduling.
Tools will track benefits and treatment plans, showing coverage and expected out-of-pocket costs at each step.
AI-supported scribing will assist clinicians with documentation, and a predictor tool will estimate a patient’s likelihood of having a baby across different treatment paths.
In 2027, Kindbody plans a savings model for eligible large employers that it says will guarantee lower total fertility spend while improving clinical efficiency and patient experience.
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