New research from Memorial Sloan Kettering Cancer Center (MSK) finds improving intestinal metabolism may help treat chronic inflammation and prevent cancer; shows how breast cancer resistance is linked to APOBEC3 enzymes; investigates opportunities for restoring sensitivity to endocrine therapy; and finds acupuncture may help prostate cancer survivors wake up less often at night to urinate.
Improving intestinal metabolism could help treat chronic inflammation and prevent cancer, findings in mice suggest
The intestine, as one of the highly regenerative organs in the human body, is constantly renewing itself. In mammals, the lining of the intestine replaces itself with new cells every week or so to keep up with the wear and tear from digestion and waste elimination. To do this, intestinal stem cells must differentiate and produce a variety of cells that perform different functions — from absorbing nutrients to producing secretions that protect the body from harmful bacteria.
Now, scientists at MSK are showing for the first time in a living organism how cellular metabolism — which turns nutrients from the diet into energy — plays a key role in determining cell specification during this regeneration process. And their findings have important implications for regenerative medicine and cancer prevention.
Using genetically modified mouse models and organoids, the team — led by postdoctoral researcher Almudena Chaves-Perez, PhD, and medical oncologist Scott Millman, MD, PhD, both members of the lab of senior study author Scott Lowe, PhD — showed that certain metabolites are required for stem cells to differentiate properly.
“It has long been thought that these metabolites were primarily involved in energy production,” Dr. Chaves-Perez says. “And they are. But they also have a second life. What we’re starting to see is that they also play an active role in driving differentiation in stem cells. Some metabolites are like movie directors, actively shaping the storyline of stem cell differentiation.”
Without a key metabolite — called alpha-ketoglutarate — the cell lineage that protects against harmful bacteria can’t properly form, they found.
This finding is especially relevant for diseases like ulcerative colitis, where the formation of this lineage is impaired. In a mouse model of colitis, supplementing this key metabolite reversed the impairment in differentiation and helped the tissue to regenerate.
“We gave the mice alpha-ketoglutarate, and it was amazing to see how much their tissue was able to heal itself,” Dr. Chaves-Perez adds.
Over time, chronic inflammation caused by conditions like colitis can lead to the development of colorectal cancer.
The findings point to the potential to supplement certain metabolites in the diet to improve tissue regeneration and healing for conditions that involve chronic inflammation and impaired cell differentiation, as well as for age-related decline, Dr. Lowe says.
A previous study from the lab found alpha-ketoglutarate helps p53 — a guardian against cancer — do its job in pancreatic cancer, and that increasing the metabolite might help suppress tumor growth when p53’s function was impaired. So the pro-regenerative effects seen in the intestine may have implications for cancer as well, Dr. Lowe adds.
“The work suggests that metabolites not only support cellular bioenergetics and biosynthesis, but also actively dictate cell fate in vivo — in this case, to promote the regeneration of damaged tissue,” an accompanying News and Views commentary notes.
Read more in Nature.
Breast cancer resistance is linked to APOBEC3 enzymes
A study led by physician-scientist Sarat Chandarlapaty, MD, PhD, sheds light on breast cancer resistance to hormonal therapy and targeted therapy. The research team found that APOBEC3 enzymes play a key role in causing this resistance and in triggering and promoting breast cancer growth.
APOBEC3 enzymes were first known for their antiviral effects — they defend the body by disrupting the invaders’ genetic material. In 2022, MSK researchers found strong evidence in animal and cell culture studies that APOBEC3 enzymes play a role in causing cancer-related mutations.
In the new study, Dr. Chandarlapaty and colleagues analyzed 3,880 patient samples and identified mutational signatures linked to APOBEC3 enzymes. Patients with these signatures had shorter progression-free survival on hormonal and targeted therapies. They found that APOBEC3 activity promotes resistance by causing mutations such as loss of RB1, a tumor suppressor gene.
The research shows that APOBEC3-related mutations are a prominent cause of genomic instability in breast cancer, contributing specifically to resistance to hormonal and targeted therapies. Additionally, APOBEC3-related mutations were present in pretreatment samples, emphasizing their role in driving cancer development. The findings suggest APOBEC3 mutagenesis as a key factor in therapy resistance and a potential therapeutic target. Read more in Nature Genetics.
Restoring sensitivity to endocrine therapy
Women with estrogen receptor positive (ER+) breast cancer are usually treated with drugs that prevent estrogen from fueling the cancer’s growth. However, when ER+ cancer spreads, it often develops resistance to these hormonal therapies. To better understand this process, a team led by Dr. Chandarlapaty performed a genetic screening using CRISPR-Cas9 to reveal that a protein called NR2F2 plays a role in the resistance. NR2F2 changes how certain genes are controlled, resulting in repressed ER signaling, which makes hormonal therapies less effective.
Experiments with models using real patient tumor samples showed that blocking or removing NR2F2 made cancer cells more sensitive to endocrine therapy again. This suggests that drugs targeting NR2F2 could help make endocrine therapies more effective. Read more in Science Translational Medicine.
Acupuncture may help prostate cancer survivors wake up less often at night to urinate
Many men who have been treated for prostate cancer wake up frequently during the night to urinate. This condition, called nocturia, negatively impacts sleep and other aspects of a patient’s quality of life. In a new clinical trial, a team of doctors at MSK led by integrative medicine specialist Kevin Liou, MD, wanted to see if acupuncture could help with this condition. They conducted a pilot study that included 60 men who were experiencing nocturia after treatment for prostate cancer.
Those included in the trial had received a variety of treatments for their cancer, including surgery, external-beam radiation, brachytherapy (radioactive seeds), and/or hormone therapy. They enrolled in the trial an average of about eight years after finishing treatment for prostate cancer.
The men were randomly assigned to two groups. One group got acupuncture once a week for 10 weeks. The other group received the usual care for nocturia. The doctors checked how many times each man woke up to urinate before and after they completed the full course of treatment with either acupuncture or usual care.
They found that the men who got acupuncture woke up on average about one time less per night than those who didn’t get it, and the benefits lasted at least a month after the acupuncture treatments ended. There were no serious side effects from the treatments.
“Even though this was a small study, it suggests that acupuncture can help men who have received prostate cancer treatment by reducing the number of times they wake up at night to urinate,” Dr. Liou says. “More research is needed, but these findings are a promising start.” Read more in JAMA Oncology.