Researchers at Baylor College of Medicine and staff at other institutions have found that POT1, a gene known to be associated with risk of glioma, the most common type of malignant brain tumor, mediates its effects on a gender-specific basis. The researchers found that female mice with glioma that lacked the gene survived less than males. This led them to study human glioma cells, where they found that low POT1 expression correlated with decreased survival in women.
The study, published in the journal Cancer Research, also shows that compared to male tumors, female tumors had decreased expression of immune signatures and increased expression of cell replication markers, suggesting that the immune response and tumor cell proliferation may be involved in promoting the tumor seemed growth.
This study began as a collaboration between Dr. Benjamin Deneen in Baylor and the laboratory of Dr. Melissa Bondy, previously at Baylor and now at Stanford University. Bondy and her group investigate familial or inherited forms of glioma from an epidemiological point of view. Her studies have linked mutations in the POT1 gene to the risk of developing glioma.
In the current study, the researchers examined whether Pot1 mutations influence glioma development in a mouse model of the state developed in the Deneen laboratory.
“We started our study by switching off the Pot1 gene in our mouse model and examining whether this affects the development and growth of glioma tumors,” said lead author Dr. Ali Jalali, Assistant Professor of Neurosurgery at Baylor.
Jalali and his colleagues worked with male and female mice and pooled the data from both groups in their first analyzes.
“This analysis showed that the lack of Pot1 did not appear to affect tumor growth,” said Jalali. “But then a team member looked at the male and female responses separately. Unexpectedly, we found that in the absence of Pot1, gliomas grew faster in female mice. Women also had shorter survival times than men. “
The team then investigated whether the level of POT1 expression in glioma tumors was related to gender-dependent survival in patients. “We found that a decrease in POT1 expression in human gliomas also had sex-related effects on tumor growth,” said Jalali.
Next, the researchers looked at what might mediate the sex-related effects of POT1 deficiency by comparing the genes expressed by glioma tumors with or without POT1. They performed these analyzes in both human glioma samples and gliomas from the animal model.
“We observed that in the absence of POT1 there was a sex-specific effect on the expression of genes involved in the immune response in both mice and humans,” said Jalali. “Some of these genes are known to help activate immune cells such as T cells and macrophages, which have been shown to play a role in cancer growth. We also took a closer look at the tumors and found that female mice lacking the Pot1 gene had less infiltration of immune cells into the tumors compared to male mice. This suggested the possibility that a sex-dependent change in immune response contributed to the observed sex-specific differences in tumor aggressiveness caused by the loss of Pot1. “
In addition, Jalali and his colleagues compared the proliferation ability of glioma cells with and without Pot1 and found that female glioma cells without Pot1 proliferate more than male glioma cells. They also saw consistent gender-dependent effects on telomeres length, the tips of the chromosomes, and on markers of DNA damage.
“Taken together, our results not only show that mutations in the Pot1 gene promote glioma development in a sex-dependent manner, but also support that the mutations could promote glioma development by increasing the tumor’s ability to proliferate, transforming immune infiltration into tumors, and probably others as well unexplored effects, ”said Deneen, corresponding author of the work and professor and Dr. Russell J. and Marian K. Blattner, Department of Neurosurgery at Baylor. “It is important that POT1 effects are gender-dependent in our animal model as well as in human glioma. We are interested in understanding how POT1 leads to these gender-dependent effects in glioma, and possibly other cancers, and whether other genes that are also linked to glioma work in this way. “
“This has been a great collaboration,” said Bondy, co-author of the study. “It’s exciting that we were able to translate what we found in epidemiological studies on human families into an animal model. We have shown in animal models that Pot1 has a functional role that influences glioma growth. Understanding how POT1 mutations promote the development of gliomas in a sex-dependent manner would provide important new insights into how the disease can be managed and managed. “
Other contributors to this work are Kwanha Yu, Vivek B. Beechar, Navish Bosquez Huerta, Anthony Grichuk, Deepika Mehra, Brittney Lozzi, Kathleen Kong, Kenneth Scott, Ganesh Rao, and Matthew Bainbridge. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Texas Children’s Hospital, Rady’s Children’s Hospital in San Diego, and Stanford University.
This study was supported by NIH grants (K08-NS110976, R01-CA217105, R01-NS094615, DK56338, CA125123, ES030285, R50-CA252125), the National Cancer Institute (Cancer Therapeutic Discovery) (U01-CA217842), and the American Cancer Society (Rob) supports postdoctoral fellowship from Rutherford Glioblastoma Research (PF-15-220-01-TBG). The project also received support from CPRIT (RP150578, RP170719), the Dan L. Duncan Comprehensive Cancer Center, and the John S. Dunn Gulf Coast Chemical Genomics Consortium.