Papers of the Month
Extramural
By Sara Amolegbe
Gulf Killifish survived polluted waters with genes from another fish
NIEHS grantees found that Gulf Killifish in the Houston Ship Channel rapidly evolved to adapt to lethal levels of aromatic hydrocarbon pollutants. The findings suggest that the Gulf Killifish acquired the resistance genes from breeding with the closely related Atlantic Killifish.
The researchers sampled fish from 12 sites spanning the pollution gradient, spawned them separately in the laboratory, and exposed their embryos to a range of concentrations of pollutants. They found that fish from the most polluted sites were the most resistant to harmful effects, and that resistance was retained through at least two generations in a clean environment. To understand the genetic basis of this resistance, they sequenced the genomes of hundreds of Gulf Killifish from very polluted, moderately polluted, and clean water. Fish with higher resistance had lower activation of the aryl hydrocarbon receptor (AHR), a protein that is involved in cardiac toxicity by aromatic hydrocarbons.
The scientists were surprised to find that the adaptive DNA regulating AHR signaling came from an Atlantic Coast species of killifish, which has been known to rapidly evolve resistance to high levels of pollution. The authors suggest that their transport to the Gulf was likely an accident initiated by humans. Non-native species can put populations at risk for negative ecological consequences, but according to the authors, this study shows that in some rare cases, interbreeding between distinct genetic populations can provide variation necessary for adaptation following extreme environmental change.
Citation: Oziolor EM, Reid NM, Yair S, Lee KM, VerPloeg SG, Bruns PC, Shaw JR, Whitehead A, Matson CW. 2019. Adaptive introgression enables evolutionary rescue from extreme environmental pollution. Science 364(6439):455-457.
Fewer new asthma cases with improved air quality
Air quality improvements in the Los Angeles region is linked to roughly 20% fewer new asthma cases in children, according to an NIEHS-funded study. The authors say the study provides evidence of a robust and consistent association between nitrogen dioxide levels in the community and development of asthma in childhood.
Air quality improvements in Los Angeles cut nitrogen dioxide pollution by 22% and fine particulate matter (PM) by 36% between 1993 and 2006. To assess new-onset cases of asthma before, during, and after this period, scientists used data from 4,140 children in nine California communities between 1993 and 2014. They identified physician-diagnosed cases of asthma from annual questionnaires completed by parents or guardians and collected community-level air pollution data for nitrogen dioxide, PM2.5, PM10, and ozone.
Using statistical methods, they examined the four air pollutants separately and found that reductions in nitrogen dioxide and PM2.5 were associated with fewer new-onset asthma cases. They estimated that nitrogen dioxide reductions achieved in the Los Angeles region between 1993 and 2006 led to a 20% lower rate of asthma. The researchers also found that decreased community-level PM2.5 was linked to a 19% lower rate, but more research is needed to confirm this association.
Citation: Garcia E, Berhane KT, Islam T, McConnell R, Urman R, Chen Z, Gilliland FD. 2019. Association of changes in air quality with incident asthma in children in California, 1993-2014. JAMA 321(19):1906-1915.
Compound suppresses DNA pathway, makes tumors more susceptible to chemo
NIEHS grantees have discovered that a small molecule compound can block a DNA pathway that helps tumors withstand damage from chemotherapy drugs. The compound targets translesion synthesis, a damage tolerance process that allows specialized enzymes that copy DNA to replicate past damaged DNA. Some tumors can withstand damage from chemotherapy drugs by relying on translesion synthesis, which allows them to survive, but it can also introduce new mutations that allow cancer cells to become resistant to future treatment.
Researchers screened 10,000 small molecule compounds looking for a molecule to block or inhibit Rev1, a key protein involved in translesion synthesis. They found that a molecule called JH-RE-06 appeared to block Rev1 from interacting with other key proteins in the translesion synthesis pathway. The researchers used X-ray crystallography to visualize the interactions between Rev1 and JH-RE-06 and found that JH-RE-06 pairs up with Rev1 and locks it into a chemical structure where it can no longer help cancer cells survive.
The researchers then tested the molecule in human cancer cell lines. They showed that it enhanced the ability of several different types of chemotherapy to kill cells, while also suppressing their ability to mutate in the presence of DNA-damaging drugs. In a mouse model of human melanoma, they found that not only did the tumors stop growing in mice treated with a combination of the chemotherapy drug cisplatin and JH-RE-06, those mice also survived longer.
Citation: Wojtaszek JL, Chatterjee N, Najeeb J, Ramos A, Lee M, Bian K, Xue JY, Fenton BA, Park H, Li D, Hemann MT, Hong J, Walker GC, Zhou P. 2019. A small molecule targeting mutagenic translesion synthesis improves chemotherapy. Cell; doi: 10.1016/j.cell.2019.05.028 [Online 6 June 2019].
Big data helps identify better ways to research breast cancer
By analyzing large volumes of data, NIEHS grantees found substantial differences between lab-created breast cancer cell lines and actual advanced, or metastatic, breast cancer tumor samples. By identifying key genomic differences and similarities between cell lines and tumor samples, the study also introduced a framework for selecting relevant cell lines for modeling metastatic breast cancer.
Current models used in the lab frequently involve culturing cells on flat dishes, or cell lines, to predict tumor growth. The differences between cell lines and tumor samples have raised questions about whether the cell lines accurately capture what is going on in a tumor. To answer this question, the researchers performed an integrative analysis of data taken from genomic databases to comprehensively compare multiple types of molecular features between breast cancer cell lines and metastatic breast cancer samples.
The researchers found substantial differences between lab-created breast cancer cell lines and metastatic breast cancer tumor samples. Surprisingly, MDA-MB-231, a cancer cell line used in nearly all metastatic breast cancer research, showed little genomic similarities to patient tumor samples. The organoid model, a new technology that uses 3D tissue cultures, was found to most closely mirror patient samples. According to the authors, identifying differences in the models used to assess cancer metastasis, or spreading within the body, can help scientists develop more sophisticated research models and better interpret model results.
Citation: Liu K, Newbury PA, Glicksberg BS, Zeng WZD, Paithankar S, Andrechek ER, Chen B. 2019. Evaluating cell lines as models for metastatic breast cancer through integrative analysis of genomic data. Nat Commun 10(1):2138.
(Sara Amolegbe is a research and communication specialist for MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)
