No abstract

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in wildtype and transformed murine astrocytes, as well as patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned during early development by gonadal sex. These data provide a rationale for the further study of sex differences in radiation response and how senescence might be enhanced for radiation sensitization. The determination that p21 and gonadal sex are required for sex differences in radiation response will serve as a foundation for these future mechanistic studies.

Sex differences in incidence and outcome are consistently observed in cancer, including in the most common malignant brain tumor – glioblastoma (GBM). Women are less likely to develop GBM and have a survival advantage compared to men. Previous research from our lab identified the proteins Rb, p16, and p21 as key mediators of female protection against cellular transformation. Strikingly, these proteins are all primary components of the senescence response, a potent cell-intrinsic anti-cancer mechanism that results in permanent cell cycle arrest, preventing proliferation of damaged cells. We hypothesized that sex differences in GBM incidence and outcome are mediated by differences in senescence induction after DNA damage in male and female cells. Using both wildtype astrocytes and a GBM model, we found that females have a lower threshold for senescence induction in response to oxidative stress, telomere shortening, and treatment with chemotherapy or radiation. Following irradiation, female GBM model cells had higher levels of p21 expression, and p21 levels correlated with the percentage of senescent cells. Knocking out p21 eliminated sex differences in the senescence response following irradiation. Achieving a better understanding of mechanisms of senescence and how they differ in male and female cells could advance development of senescence-directed therapies and potentially improve treatment for brain tumors.

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in both wildtype and transformed murine astrocytes and patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned by gonadal sex. These data suggest that sex differences in p21 induced senescence contribute to the female survival advantage in GBM.

We present here the complete genomes of two Streptomyces bacteriophages, Satis and JustBecause. Both phages were isolated directly from soil samples collected in St. Louis, MO, and present with an unusual prolate head morphology and large genome lengths of over 180 kb.