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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.
An early PET scan after one cycle of chemotherapy may help predict how aggressive breast cancer responds to treatment, a study suggests.
Research led by The Institute of Cancer Research, London and King’s College London suggests that an early scan taken after one cycle of chemotherapy could help predict how well a patient’s cancer will respond to treatment.
The study focused on patients with triple-negative breast cancer (TNBC), an aggressive form of the disease in which cancer cells lack receptors for the hormones oestrogen and progesterone, as well as the HER2 protein.
Patients with TNBC are usually treated with chemotherapy prior to surgery. While many respond well, residual disease at surgery, typically around six months later, is associated with a significantly poorer prognosis. Identifying people sooner who are unlikely to respond remains a major clinical challenge.
The research explored whether using PET imaging shortly after treatment begins, rather than relying only on MRI scans later in the treatment process, could provide earlier insight into how a patient’s cancer is responding. Twenty-two patients were recruited, with fourteen undergoing FDG-PET scans before treatment and after the first cycle of chemotherapy.
The findings, published in Clinical Cancer Research, showed that changes seen on PET scans after just one cycle of chemotherapy were strongly associated with subsequent response, including whether there was no detectable cancer, known as a complete response, by the end of treatment. Importantly, early PET response showed stronger associations with treatment outcomes than standard mid-treatment MRI scans in this study.
Being able to identify patients who are not responding well at an early stage could allow clinicians to adjust treatment sooner or consider alternative approaches. These findings may also support future strategies to better tailor treatment intensity to individual patients.
The study also compared two types of PET tracers, FDG and FLT, to determine which was most suitable. While both met the study’s technical criteria, FDG-PET was selected for further evaluation due to its better image quality, greater consistency and wider use in clinical practice.
The research also explored how imaging changes after just one cycle of chemotherapy relate to the body’s immune response to treatment. Biopsies taken before and after the first cycle of chemotherapy showed that an increase in immune cells within the tumour was strongly associated with both early PET changes and improved treatment outcomes.
The researchers emphasise that these findings now need to be validated in larger studies. Future work will aim to confirm these results in broader patient groups and explore more accessible imaging approaches, such as ultrasound, alongside PET and MRI.
Sheeba Irshad, professor of cancer immunology at King’s College London and lead of the Breast Cancer Now KCL Research Unit, said:
“In patients who had PET scans both before treatment and after the first cycle, we found that this early scan could predict whether they were likely to achieve a complete response by the end of treatment. These findings highlight the potential of early imaging to guide treatment decisions, and now need to be validated in larger, modern clinical trials.”
Andrew Tutt, professor of breast oncology at The Institute of Cancer Research, London, said:
“Research that helps us determine early who is already benefitting from standard neoadjuvant chemotherapy and who might benefit from clinical trials to find better treatments is vital. This study shows that FDG-PET may have great value in this regard. We hope to be able to design studies that further investigate and validate these findings.”
The study was supported by funding from King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, Breast Cancer Now, Cancer Research UK, and Guy’s and St Thomas’ Charity.
We are excited unveil the three finalists competing for one of the Femtech World Awards’ most coveted honours: the Startup of the Year Award, sponsored by Future Fertility.
This award celebrates an early-stage company making a bold impact in women’s health through innovation, vision and execution.
The winner will be announced at our virtual ceremony on 19 June, with the decision made by a representative from category sponsor Future Fertility.
Congratulations to the shortlist and thank you to everyone who entered or nominated.
Startup of the Year Shortlist
Hello Inside is the first women’s health AI company to turn daily metabolic signals into outcomes women feel and healthcare systems reimburse.
Women’s health has long been under-researched, and current AI benchmarks fail on women’s health questions roughly sixty percent of the time.
Hello Inside built the architecture to close that gap.
Across four years and 12,000+ validated metabolic profiles, three in four women improve at least one symptom within ninety days.
They lose four kilograms in three months, moving from overweight into the healthy range. In a clinical study with Alisa Vitti’s Flo Living, 91.9 per cent reduced PMS burden within sixty days.
OvartiX is doing something that has never been done before: building a drug discovery engine purpose-built for women’s health.
Its lead programme, OVX001, targets medically induced menopause – a condition affecting young female cancer patients who undergo chemotherapy or radiotherapy.
These women are cured of cancer but enter menopause overnight.
There is currently no approved drug to prevent it. OVX001 is designed to change that, preserving 80–95 per cent of ovarian follicles during treatment without compromising anti-tumour efficacy.
Behind the science is the OmiXX platform: the first ML-driven drug discovery tool built specifically for female physiology, using proprietary ovarian cellular models and human multi-omics data.
U-Ploid is an early-stage biotechnology company tackling one of the most fundamental challenges in fertility care: the sharp, age-related decline in egg quality that limits outcomes across IVF and egg freezing.
While much of the field focuses on improving assessment and selection, U-Ploid is developing a first-in-class therapeutic approach designed to improve egg quality itself by addressing the biological causes of age-related chromosomal errors.
Supported by strong preclinical evidence and now advancing into human studies, U-Ploid combines scientific rigour, regulatory discipline and long-term vision to help redefine what is possible in fertility care.
Gestational diabetes is a strong risk factor for future type 2 diabetes, even in women with normal pre-pregnancy weight, according to a study at the University of Gothenburg.
The researchers call for earlier testing and better follow-up.
“Our results show that gestational diabetes functions as a kind of stress test for the body’s ability to manage blood sugar, and identifies women with a greatly increased risk of future type 2 diabetes”, said Jon Edqvist, PhD and affiliated to research at the University of Gothenburg, and operating room nurse at Sahlgrenska University Hospital.
Gestational diabetes is a special type of diabetes that can affect pregnant women.
The condition is defined as elevated blood sugar levels, without previously known diabetes. Treatment involves self-monitoring of blood sugar, advice on lifestyle habits and, if necessary, medication.
Identifying gestational diabetes is important because the disease increases the risk of complications such as preeclampsia, the need for a cesarean section and high birth weight for the baby.
Those who have had gestational diabetes are also at higher risk of later developing type 2 diabetes.
In the current study, published in eClinicalMedicine, researchers now show that gestational diabetes is a strong indicator of future risk of developing type 2 diabetes, even in women with normal weight before pregnancy.
Elevated risk even with normal weight
The study is based on data from the Medical Birth Registry on just over 1.15 million first-time mothers in Sweden, who gave birth between 1987 and 2019. 16,870 women with confirmed gestational diabetes were compared with age-matched women without the diagnosis. The median follow-up period was nine years.
The results show that women with a BMI of 35 and above, i.e. severe obesity, had an almost tenfold increased risk of developing gestational diabetes compared to women with normal weight.
The risk of subsequent type 2 diabetes also increased with higher BMI, but it was significantly increased even with normal weight, which the researchers describe as particularly worrying.
More follow-up and more studies
The researchers behind the study welcome the recently updated recommendations on gestational diabetes in Sweden, where a higher proportion of pregnant women at increased risk are expected to be offered testing earlier in pregnancy, and if necessary, interventions.
“Diagnostics and care of gestational diabetes have looked very different in different parts of the country,” said Annika Rosengren, professor at the University of Gothenburg.
“There is a need for both improved follow-up after gestational diabetes, and more studies that investigate how such follow-up affects future health and prognosis”
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