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Turner, M. C.

Publications and source records attributed to Turner, M. C..

2 recordsLinked to original sources

Shifts in vernalization and phenology at the rear edge hold insight into adaptation of 1 temperate plants to future milder winters

O_LITemperate plants often regulate reproduction through winter cues, such as vernalization, that may decrease under climate change. Studies of rear-edge populations, glacial relicts that persist in environments that have warmed since last glaciation, can provide insight into adaptive potential to milder winters. C_LIO_LIWe studied how rear-edge populations have adapted to shorter winters and compared them to the rest of the range in the herb Campanula americana. Using citizen science, climate data and experimental climate manipulation, we characterize variation in vernalization requirements and reproductive phenology across the range and their potential climatic drivers. C_LIO_LIRear-edge populations experienced little to no vernalization in nature. In climate manipulation experiments, these populations also had a reduced vernalization requirement, weaker response to changes in vernalization length, and flowered later compared to the rest of the range. C_LIO_LIOur results suggest shifts in phenology and its underlying regulation at the rear edge to compensate for unreliable vernalization cues. Thus, future milder winters may be less detrimental to these populations than more northern ones. Furthermore, our results showcase strong adaptive shifts at the rear edge of temperate plants ranges, highlighting the importance of these areas in studies of predicted future climates. C_LI

evolutionary biology↗

Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment

Background & AimsPancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma, which contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown. MethodsWe used a dual recombinase mouse model to delete Hif1 or Hif2 in -smooth muscle actin (SMA)-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF-Hif2 expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, a HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. ResultsCAF-specific deletion of HIF2, but not HIF1, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = 0.0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. ConclusionsTogether, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.

cancer biology↗