Waddell, C. | bioRxiv Science

bioRxiv2021

The heterogeneity of the DNA damage response landscape determines patient outcomes in ovarian cancer

Defective DNA damage response (DDR) pathways allow cancer cells to accrue genomic aberrations and evade normal cellular growth checkpoints. Defective DDR also determines response to chemotherapy. However, the interaction and overlap between the two double strand repair pathways and the three single strand repair pathways is complex, and has remained poorly understood. Here we show that, in ovarian cancer, a disease hallmarked by chromosomal instability, explant cultures show a range of DDR abrogation patterns. Defective homologous recombination (HR) and non-homologous end joining (NHEJ) are near mutually exclusive with HR deficient (HRD) cells showing increased abrogation of the single strand repair pathways compared to NHEJ defective cells. When combined with global markers of DNA damage, including mitochondrial membrane functionality and reactive oxygen species burden, the pattern of DDR abrogation allows the construction of DDR signatures which are predictive of both ex vivo cytotoxicity, and more importantly, patient outcome. SignificanceHolistic assessment of the DDR is possible, shows improved ability to predict response to chemotherapy over single pathway assessment, and is applicable to a variety of ovarian cancer types. Such an assessment has clinical utility in settings of therapeutic dilemma such as retreatment for relapse.

cell biology↗

bioRxiv2018

Population extinctions driven by climate change, population size, and time since observation may make rare species databases inaccurate

Loss of biological diversity through population extinctions is a global phenomenon that threatens many ecosystems. Managers often rely on databases of rare species locations to plan land use actions and conserve at-risk taxa, so it is crucial that the information they contain is accurate and dependable. However, climate change, small population sizes, and long gaps between surveys may be leading to undetected extinctions of many populations. We used repeated survey records for a rare but widespread orchid, Cypripedium fasciculatum (clustered ladys slipper), to model population extinction risk based on elevation, population size, and time between observations. Population size was negatively associated with extinction, while elevation and time between observations interacted such that low elevation populations were most vulnerable to extinction, but only over larger time spans. We interpret population losses at low elevations as a potential signal of climate change impacts. We used this model to estimate the probability of persistence of populations across California and Oregon, and found that 31%-56% of the 2415 populations reported in databases from this region are likely extinct. Managers should be aware that the number of populations of rare species in their databases is potentially an overestimate, and consider resurveying these populations to document their presence and condition, with priority given to older reports of small populations, especially those at low elevations or in other areas with high climate vulnerability.

ecology↗