̽��ֱ�� of Cambridge - Walid Khaled

‘Exhausted’ immune cells in healthy women could be target for breast cancer prevention

jg533 — Thu, 28 Mar 2024 10:03:44 +0000

Everyone has BRCA1 and BRCA2 genes, but mutations in these genes - which can be inherited - increase the risk of breast and ovarian cancer.

̽��ֱ��study found that the immune cells in breast tissue of healthy women carrying BRCA1 or BRCA2 gene mutations show signs of malfunction known as ‘exhaustion’. This suggests that the immune cells can’t clear out damaged breast cells, which can eventually develop into breast cancer.

This is the first time that ‘exhausted’ immune cells have been reported in non-cancerous breast tissues at such scale - normally these cells are only found in late-stage tumours.

̽��ֱ��results raise the possibility of using existing immunotherapy drugs as early intervention to prevent breast cancer developing, in carriers of BRCA1 and BRCA2 gene mutations.

̽��ֱ��researchers have received a ‘Biology to Prevention Award’ from Cancer Research UK to trial this preventative approach in mice. If effective, this will pave the way to a pilot clinical trial in women carrying BRCA gene mutations.

“Our results suggest that in carriers of BRCA mutations, the immune system is failing to kill off damaged breast cells - which in turn seem to be working to keep these immune cells at bay,” said Professor Walid Khaled in the ̽��ֱ�� of Cambridge’s Department of Pharmacology and Wellcome-MRC Cambridge Stem Cell Institute, senior author of the report.

He added: “We’re very excited about this discovery, because it opens up potential for a preventative treatment other than surgery for carriers of BRCA breast cancer gene mutations.

“Drugs already exist that can overcome this block in immune cell function, but so far, they’ve only been approved for late-stage disease. No-one has really considered using them in a preventative way before.”

̽��ֱ��results are published today in the journal Nature Genetics.

Risk-reducing surgery, in which the breasts are removed, is offered to those at increased risk of breast cancer. This can be a difficult decision for young women to make and can have a significant effect on body image and sexual relationships.

“ ̽��ֱ��best way to prevent breast cancer is to really understand how it develops in the first place. Then we can identify these early changes and intervene,” said Khaled.

He added: “Late-stage breast cancer tends to be very unpredictable and hard to manage. As we make better and better drugs, the tumours just seem to find a way around it.”

Using samples of healthy breast tissue collected from 55 women across a range of ages, the researchers catalogued over 800,000 cells - including all the different types of breast cell.

̽��ֱ��resulting Human Breast Cell Atlas is now available as a resource for other researchers to use and add to. It contains huge amounts of information on other risk factors for breast cancer including Body Mass Index (BMI), menopausal status, contraceptive use and alcohol consumption.

“We've found that there are multiple breast cell types that change with pregnancy, and with age, and it’s the combination of these effects - and others - that drives the overall risk of breast cancer,” said Austin Reed, a PhD student in the ̽��ֱ�� of Cambridge’s Department of Pharmacology and joint first author of the report.

He added: “As we collect more of this type of information from samples around the world, we can learn more about how breast cancer develops and the impact of different risk factors - with the aim of improving treatment.”

One of the biggest challenges in treating breast cancer is that it is not just one disease, but many. Many different genetic variations can lead to breast cancer, and genetic risk interacts with other risk factors in complicated ways.

For example, it is known that the likelihood of breast cancer increases with age, but this risk is greatly reduced by pregnancy early in life. And age-associated risk is greatly increased in carriers of the breast cancer genes BRCA1 and BRCA2.

̽��ֱ��new study aimed to understand how some of these risk factors interact, by characterising the different cell types in the human breast under many different physiological states.

̽��ֱ��researchers used a technique called ‘single cell RNA-sequencing’ to characterise the many different breast cell types and states. Almost all cells in the body have the same set of genes, but only a subset of these are switched on in each cell – and these determine the cell’s identity and function. Single cell RNA-sequencing reveals which genes are switched on in individual cells.

“Breast cancer occurs around the world, but social inequalities mean not everyone has access to treatment. Prevention is the most cost-effective approach. It not only tackles inequality, which mostly affects low-income countries, but also improves disease outcome in high-income countries,” said Dr Sara Pensa, Senior Research Associate in the ̽��ֱ�� of Cambridge’s Department of Pharmacology and joint first author of the study.

Breast tissue samples were provided by the Breast Cancer Now tissue bank.

̽��ֱ��research was primarily funded by the Medical Research Council and Cancer Research UK.

Reference: Reed, A.D. et al: ‘A human breast cell atlas enables mapping of homeostatic cellular shifts in the adult breast.’ Nature Genetics, March 2024. DOI: 10.1038/s41588-024-01688-9

Researchers at the ̽��ֱ�� of Cambridge have created the world’s largest catalogue of human breast cells, which has revealed early cell changes in healthy carriers of BRCA1 and BRCA2 gene mutations.

We’re very excited about this discovery, because it opens up potential for a preventative treatment other than surgery for carriers of BRCA breast cancer gene mutations.

Walid Khaled

Angiola Harry on Unsplash

Woman holds pink breast cancer awareness ribbon. Credit angiola-harry-unsplash

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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£3 million UKRI funding to support research into better health, ageing, and wellbeing

cjb250 — Mon, 12 Feb 2024 10:20:56 +0000

UKRI funding of £3 million is awarded today to support a new research cluster, as part of the MRC National Mouse Genetics Network (MRC NMGN), focused on improving existing models of ageing with the aim of improving lifelong health and wellbeing. ̽��ֱ��cluster is led by scientists at the Universities of Cambridge and Newcastle.

̽��ֱ��MRC NMGN focuses on age-related biological changes in model organisms, particularly the mouse, to try and improve our understanding and diagnosis of the most challenging disease area of our time - and generate therapeutic avenues.

This award brings the UKRI’s total investment in the MRC NMGN to £25 million.

̽��ֱ��need to improve how people age has become a major requirement of modern societies. Regular increases in life expectancy result in older populations, making healthy ageing essential for a better quality of life and a reduced burden on health and social services.

Understanding the biological mechanisms underlying the ageing process is paramount for tackling the challenges brought about by our older populations.

̽��ֱ��new tools generated as a result of this research will be made available to the scientific community to improve understanding of the ageing process, and to provide a resource for preclinical testing and intervention.

Professor Walid Khaled from Cambridge’s Wellcome-MRC Cambridge Stem Cell Institute and Department of Pharmacology, and Co-lead of the new MRC National Mouse Genetics Network Ageing Cluster, said: “I am very pleased to be co-leading this project from Cambridge and I am looking forward to working with the rest of the team from around the UK. ‘Prevention is better than cure’ and so our project will generate a reference map that we will use in the future to assess interventions that could prevent ageing related health decline.”

Professor Anne Ferguson-Smith, Pro-Vice-Chancellor (Research & International Partnerships) and Arthur Balfour Professor of Genetics at Cambridge, said: "Collaboration is central to our research activities in Cambridge. ̽��ֱ��new Ageing Cluster is a fine example of multiple institutions working together to add value and bring exciting new insight and expertise to advance the critically important field of healthy ageing. I am proud to be part of this important initiative which can deliver new routes to improved health span."

Professor David Burn, Pro Vice Chancellor, Faculty of Medical Sciences at Newcastle ̽��ֱ��, added: "I am delighted that Newcastle ̽��ֱ�� is an important part of the UKRI Mouse Genetics Network Ageing Cluster. This cluster offers researchers the opportunity to develop new animal models so that we may better understand ageing. This, in turn, will allow us to translate this research into extending healthy lifespan in humans in the future.”

̽��ֱ�� ̽��ֱ�� is bringing together its world leading expertise to tackle the topic of extending the healthy lifespan. Scientists in the School of Biological Sciences are addressing some of the biggest questions in human biology, including: What if we could identify those at risk of developing chronic age-related conditions before they present in the clinic? What if we could intervene before any symptoms arise and prevent disease onset?

UKRI’s strategy for 2022-2027 aims to harness the full power of the UK’s research and innovation system to tackle major national and global challenges. A total of £75m has been allocated to the theme of Securing better health, ageing and wellbeing, which aims to improve population health, tackle the health inequalities affecting people and communities, and advance interventions that keep us healthier for longer.

̽��ֱ�� ̽��ֱ�� of Cambridge has received UKRI funding for research on age-related biological changes in model organisms as part of a national collaboration.

‘Prevention is better than cure’ and so our project will generate a reference map that we will use in the future to assess interventions that could prevent ageing related health decline

Walid Khaled

Lauren Christy Pitcher ( ̽��ֱ�� Biomedical Services)

White mouse

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Live cells discovered in human breast milk could aid breast cancer research

Anonymous — Fri, 28 Jan 2022 10:00:04 +0000

̽��ֱ��study was led by researchers from the Wellcome-MRC Cambridge Stem Cell Institute (CSCI) and the Department of Pharmacology at the ̽��ֱ�� of Cambridge.

Breast tissue is dynamic, changing over time during puberty, pregnancy, breastfeeding and aging. ̽��ֱ��paper, published today in the journal Nature Communications, focuses on the changes that take place during lactation by investigating cells found in human milk.

This research, led by Dr Alecia-Jane Twigger of CSCI, found that the cells in milk, once thought to be dead or dying, are in fact very much alive. These living cells provide researchers with the chance to study not only the changes that occur in mammary tissues during lactation, but also insight into a potential early indicator of future breast cancer development.

“I believe that by studying human milk cells, we will be able to answer some of the most fundamental questions around mammary gland function such as: how is milk produced? Why do some women struggle to make milk? and what strategies can be employed to improve breastfeeding outcomes for women?” said Dr Alecia-Jane Twigger at the Wellcome-MRC Cambridge Stem Cell Institute, who led the study.

̽��ֱ��researchers collected voluntary breast milk samples from lactating women, as well as samples of non-lactating breast tissue donated from women who elected to have aesthetic breast reduction surgery. Using single-cell RNA sequencing analysis, the team conducted a novel comparison of the composition of the mammary cells taken using these two methods, identifying the distinctions between lactating and non-lactating human mammary glands.

While accessing breast tissue for study relies on donors already undergoing surgery, breast milk samples are much simpler to acquire. Breast milk donors are engaged via midwives or women’s networks (an undertaking made more challenging by the pandemic) and agree to share their samples over time. Typical daily production for lactating women is between 750-800ml, and the sample size for Twigger’s research is on average a mere 50ml, an amount which can contain hundreds of thousands of cells for study.

By collecting these samples donated by breastfeeding women – samples now known to contain living and viable cells – researchers have the opportunity to capture dynamic cells in a non-invasive way. This greater ease of access to breast cells can open the door to more studies on women’s health in the future.

“ ̽��ֱ��first time Alecia told me that she found live cells in milk I was surprised and excited about the possibilities. We hope this finding will enable future studies into the early steps of breast cancer,” said Dr Walid Khaled, at the Wellcome-MRC Cambridge Stem Cell Institute and ̽��ֱ�� of Cambridge's Department of Pharmacology, who was also involved in the study.

This paper and its findings are part of the Human Breast Cell Atlas project funded by the MRC.

This research was funded by the MRC, BBSRC and Wellcome-MRC Cambridge Stem Cell Institute.

Reference: Twigger, A, et al.: ‘Transcriptional changes in the mammary gland during lactation revealed by single cell sequencing of cells from human milk.’ Nature Communications, Jan 2022. DOI: 10.1038/s41467-021-27895-0

Researchers have explored the cellular changes that occur in human mammary tissue in lactating and non-lactating women, offering insight into the relationship between pregnancy, lactation and breast cancer.

We hope this finding will enable future studies into the early steps of breast cancer

Walid Khaled

Jamie Grill/ ̽��ֱ��Image Bank

Breast milk in bottles

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Changes can be detected in BRCA1 breast cells before they turn cancerous

jg533 — Tue, 09 Mar 2021 09:17:18 +0000

̽��ֱ��study, funded by Cancer Research UK, showed that before becoming cancerous, breast cells with the BRCA1 gene mutation undergo changes similar to those normally seen in late pregnancy.

Although this is early research, in the future doctors could screen women with BRCA1 mutations to monitor changes to their breast cells, which could help inform who might benefit from preventative surgery, and to give reassurance to those who can wait.

BRCA1 mutations significantly increase the risk of developing breast cancer at a younger age. Many women who discover they carry the faulty gene choose to have a preventative mastectomy. This involves surgically removing some or all of the healthy breast tissue, which can reduce but not eradicate the risk of developing breast cancer.

Not all women who have BRCA1 mutations will go on to develop cancer so for some, this life-changing surgery may be unnecessary, or could at least be delayed until early warning signs are spotted.

Researchers led by Karsten Bach and Dr Sara Pensa at the ̽��ֱ�� of Cambridge wanted to develop a method to detect the early changes occurring in BRCA1-affected breast cells indicating that they are progressing towards breast cancer.

̽��ֱ��team analysed the mammary tissue of 15 mice at various ages carrying the BRCA1 mutation to look for changes in the tissue that were happening before the mice developed tumours.

̽��ֱ��researchers found that having a BRCA1 mutation triggered certain pathways to be switched on in a type of stem cell called a luminal progenitor breast cell that are only activated during pregnancy. These messages tell the progenitor cell to turn into alveolar cells, which make up the chambers in the breast where milk-production takes place during late pregnancy.

Karsten Bach, co-author on the study and PhD student at the Department of Pharmacology and Cancer Research UK Cambridge Institute, said: “We thought we’d been given the wrong mice at first. Then we realised that having the BRCA1 mutation seemed to cause the cells in their breast tissue to behave as if the mouse was pregnant.

“ ̽��ֱ��changes we saw happened very early on before any tumours were detected, so we reasoned that markers of these cellular changes could be used to monitor people who we know are at increased risk for breast cancer.”

Next the team analysed breast cells from 12 women who had a BRCA1 mutation and had undergone a preventative mastectomy.

Surprisingly, the team found that only 4 out of the 12 women had detectable levels of these markers of early stages of tumour initiation. This suggests that the majority of women may have been at lower risk of already being on the path towards tumour development when they had the surgery.

Dr Sara Pensa co-author and Senior Research Associate at the Department of Pharmacology and Wellcome-MRC Stem Cell Institute, said: “One of the mysteries surrounding BRCA gene mutations is how they increase a woman's risk of cancer so dramatically in the breast tissue, as opposed to say the kidneys or lung. It seems that certain pathways in breast cells that are usually switched on by hormones during pregnancy are triggered by BRCA1 mutations and cause the cells to grow out of control.”

Although this is early work and larger clinical trials will be needed, the researchers hope to build on their findings and develop a blood test to detect the early changes occurring in BRCA1 breast cells.

Researchers say in the future, doctors could screen at-risk women with BRCA1 mutations, and help them have informed conversations with women about their risk, guide decisions about preventative surgery, and to give reassurance to those considered not to need surgery at that time.

Michelle Mitchell, chief executive for Cancer Research UK, said: “ ̽��ֱ��discovery of BRCA mutations gave much needed answers to families with a strong history of breast cancer. However, for women that carry the BRCA mutation that are yet to develop breast cancer, they face an incredibly difficult dilemma.

“This is fascinating research, and we look forward to seeing the next steps, which could mean in the future, doctors could detect if women carrying these mutations have breast cells that are behaving differently. This could make a world of difference, as they may not need preventative surgery until later in life, or even at all.”

Reference

Bach K. & Pensa S. et al.'Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors.' Nature Communications, March 2021.

Original press release by Cancer Research UK (CRUK).

Researchers may have found the earliest changes that occur in seemingly healthy breast tissue long before any tumours appear, according to a new study published today in the journal Nature Communications.

It seems that certain pathways in breast cells that are usually switched on by hormones during pregnancy are triggered by BRCA1 mutations and cause the cells to grow out of control.

Sara Pensa

slgckgc on Flickr

Mammogram image

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Secrets of naked mole-rat cancer resistance unearthed

jg533 — Wed, 01 Jul 2020 15:00:00 +0000

Understanding how these remarkable animals are almost completely immune to cancer could improve our understanding of the early stages of the disease in people and lead to new ways to prevent or better treat it.

Until now, it was thought that naked mole-rats almost never got cancer because their healthy cells were resistant to being converted into cancer cells. However, researchers at the ̽��ֱ�� of Cambridge have shown for the first time that genes known to cause cancer in cells of other rodents can also lead naked mole-rat cells to become cancerous. ̽��ֱ��results are published today in the journal Nature.

This finding suggests that what sets naked mole-rats apart is the microenvironment - the complex system of cells and molecules surrounding a cell, including the immune system. ̽��ֱ��researchers believe interactions with this microenvironment are what stops the initial stages of cancer from developing into tumours, rather than a cancer resistance mechanism within healthy cells as previously thought.

Dr Walid Khaled, one of the senior authors of the study from the ̽��ֱ�� of Cambridge's Department of Pharmacology, said: “ ̽��ֱ��results were a surprise to us and have completely transformed our understanding of cancer resistance in naked mole-rats. If we can understand what’s special about these animals’ immune systems and how they protect them from cancer, we may be able to develop interventions to prevent the disease in people.”

Naked mole-rats (Heterocephalus glaber) are burrowing rodents native to East Africa. They can live for up to 37 years and are highly cancer resistant, with only a few cases ever observed in captive animals. Other unusual traits that have made them of interest to science include being the only cold-blooded mammal, lacking pain sensitivity to chemical stimuli in their skin and being able to withstand very low levels of oxygen (hypoxia).

In the study, the researchers analysed 79 different cell lines, grown from five different tissues (intestine, kidney, pancreas, lung and skin) of 11 individual naked mole-rats. They infected cells with modified viruses to introduce cancer causing genes. These genes are known to cause cancer in mice and rat cells, but were not expected to be able to transform naked mole-rat cells into cancer cells.

Fazal Hadi, lead researcher of the study from the Cancer Research UK Cambridge Centre, said: “To our surprise, the infected naked mole-rat cells began to multiply and rapidly form colonies in the lab. We knew from this accelerated growth that they had become cancerous.”

̽��ֱ��team then injected these cells into mice, and within weeks, the mice formed tumours. This striking result indicates that the environment of the naked mole-rat’s body prevents the cancer from developing, contradicting previous studies that suggested that an inherent feature of naked mole-rat cells stopped them turning cancerous in the first place.

̽��ֱ��scientists will now continue to investigate the mechanisms by which naked mole-rats stop cancer cells from developing into tumours. One avenue of particular interest is the unique immune system of naked mole-rats, as our immune systems play a critical role in protecting us from cancer and this power has already been effectively exploited in modern immunotherapy treatments.

Dr Ewan St. John Smith, one of the senior authors of the study from the ̽��ֱ�� of Cambridge's Department of Pharmacology said: “All our work with naked mole-rats, from studying their hypoxia resistance to pain insensitivity and cancer resistance, is aiming to leverage the extreme biology of this species to understand more about how our bodies work normally.”

This research was funded by Cancer Research UK.

Reference: Hadi, F. et al; 'Transformation of naked mole-rat cells,' Nature, July 2020. DOI: 10.1038/s41586-020-2410-x

Adapted from a press release by Cancer Research UK.

Naked mole-rats can live for an incredibly long time and have an exceptional resistance to cancer thanks to unique conditions in their bodies that stop cancer cells multiplying, according to new research.

If we can understand what’s special about these animals’ immune systems and how they protect them from cancer, we may be able to develop interventions to prevent the disease in people

Walid Khaled

Meghan Murphy, Smithsonian’s National Zoo, on Flickr

Naked mole rat

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