Papers of the Month
By Megan Avakian
Promising new target for oral cancer treatment
NIEHS-funded researchers identified how the aryl hydrocarbon receptor (AhR), an environmental chemical receptor, suppresses the body’s immune response to oral cancer. They also discovered that removing AhR from cancer cells stops tumor growth. Results identify a new target for treatments that help the immune system fight cancer.
The researchers used gene-editing techniques to delete AhR from mouse oral cancer cells and then transplanted the altered cancer cells into normal mice. They measured tumor growth and compared changes in gene expression and immune response between AhR-negative and unaltered tumor cells.
While unaltered tumor cells showed robust growth in mice, mice with the AhR-negative cells were completely tumor free within two weeks. This lack of tumor growth was accompanied by an increase in immune cells and a decrease in multiple immune checkpoint proteins. Immune checkpoints can block immune cells from killing tumor cells. Furthermore, when mice previously injected with AhR-negative cells were given the unaltered tumor cells 100 days later, they had a strong immune response and zero tumor growth, suggesting a long-term antitumor immune response.
According to the authors, study results highlight the role of AhR in reducing tumor immune response and point to AhR as a promising target for cancer immunotherapy.
Citation: Kenison JE, Wang Z, Yang K, Snyder M, Quintana FJ, Sherr DH. 2021. The aryl hydrocarbon receptor suppresses immunity to oral squamous cell carcinoma through immune checkpoint regulation. Proc Natl Acad Sci U S A 118(19):e2012692118.
New insights into how COVID-19 may damage the heart
A new study by NIEHS-funded researchers provides insight into how SARS-CoV-2, the virus that causes COVID-19, damages heart cells. The findings may inform treatment strategies to protect heart health in COVID-19 patients.
Using stem cells, the researchers created three types of human heart cells — cardiomyocytes, cardiac fibroblasts, and endothelial cells — and exposed them to small amounts of the SARS-CoV-2 virus for 48 hours. The virus was only able to infect and replicate in cardiomyocytes, the heart muscle cells. Unlike the other cell types, cardiomyocytes had ACE2 receptors on their surface, which serve as the cellular entry point for the virus.
Following infection, the researchers used sequencing techniques to assess changes in protein and gene expression and high-magnification imaging to identify cell structural changes. Infected cardiomyocytes showed structural defects, as the heart muscle fibers were sliced into small fragments. Typically organized as long filaments, these muscle fibers control the contraction of heart cells to produce the heartbeat. The cells also had decreased expression of genes important in contracting the heart muscles, and many were missing nuclear DNA. Without this DNA, cells can no longer function. Heart tissue samples from deceased COVID-19 patients mirrored the structural and genetic changes observed in cell models.
According to the researchers, the results provide insight into how COVID-19 harms the heart and may guide the development of therapies to prevent heart damage in COVID-19 patients.
Citation: Perez-Bermejo JA, Kang S, Rockwood SJ, Simoneau CR, Joy DA, Silva AC, Ramadoss GN, Flanigan WR, Fozouni P, Li H, Chen PY, Nakamura K, Whitman JD, Hanson PJ, McManus BM, Ott M, Conklin BR, McDevitt TC. 2021. SARS-CoV-2 infection of human iPSC-derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19. Sci Transl Med 13(590):eabf7872.
Widely used herbicide linked to preterm birth
Exposure to glyphosate — the most heavily used herbicide in the world — was associated with preterm birth, according to a new NIEHS-funded study. It is the first study to assess the link between exposure to a glyphosate breakdown product called aminomethylphosphonic acid (AMPA) and birth outcomes. People are exposed to glyphosate through diet, drinking water, and occupational and residential use of the herbicide.
The study included 247 pregnant women in northern Puerto Rico. The researchers assessed exposure to glyphosate and AMPA in previously collected urine samples. They measured exposure at participants’ first and third study visits — around 18 and 26 weeks of pregnancy, respectively — and examined associations with preterm births. Preterm birth, which occurs when a baby is born before 37 weeks of pregnancy, increases the risk for poor health in infancy and later life.
The odds of preterm birth were significantly elevated among women with higher urinary concentrations of glyphosate and AMPA at the third visit. There was no association between exposure to glyphosate or AMPA and preterm birth at the first visit or the average of the two visits. Given the widespread use of glyphosate and potential for long-term adverse health effects in preterm infants, the authors call for additional studies to investigate this link.
Citation: Silver MK, Fernandez J, Tang J, McDade A, Sabino J, Rosario Z, Vélez Vega C, Alshawabkeh A, Cordero JF, Meeker JD. 2021. Prenatal exposure to glyphosate and its environmental degradate, aminomethylphosphonic acid (AMPA), and preterm birth: A nested case-control study in the PROTECT cohort (Puerto Rico). Environ Health Perspect 129(5):57011.
Mechanistic insight points to treatment for arsenic-induced skin cancer
NIEHS-funded researchers shed light on how low-level arsenic exposure leads to skin cancer. Such exposure is known to cause skin lesions that can progress into cancer.
The researchers investigated the role of the FTO protein in arsenic-induced skin tumors. The study included a combination of cells, mice, and samples from humans with arsenic-related skin lesions. They exposed the human skin cell line, called keratinocytes, and mice to low-level arsenic. Using gene editing techniques, they deleted FTO in mice and keratinocytes. They used sequencing methods to measure a type of RNA modification called N6-methyladenosine (m6A), which alters gene expression. FTO reverses this modification by removing a compound called a methyl group from m6A. This demethylation process can increase expression of genes that promote cancer.
In human samples and keratinocytes exposed to arsenic, FTO expression increased while m6A methylation decreased. Deleting FTO from arsenic-exposed keratinocytes and mice suppressed tumor formation. Arsenic-exposed mice given drugs to block FTO activity had increased m6A methylation and reduced tumor growth.
To determine how arsenic increased FTO, the researchers examined markers of autophagy, the process of degrading proteins built up in the cell. Compared to controls, arsenic-related tumor cells had reduced autophagy and decreased expression of autophagy-related genes, resulting in FTO accumulation in the cell.
Taken together, these results help define the role of FTO and the m6A RNA modification in arsenic-related skin cancer. The authors suggest targeting FTO may provide a promising therapeutic approach to reduce skin cancer risk in arsenic-exposed individuals.
Citation: Cui YH, Yang S, Wei J, Shea CR, Zhong W, Wang F, Shah P, Kibriya MG, Cui X, Ahsan H, He C, He YY. 2021. Autophagy of the m6A mRNA demethylase FTO is impaired by low-level arsenic exposure to promote tumorigenesis. Nat Commun 12(1):2183.