Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are notoriously challenging for treatment. Hyperactive nuclear factor κB (NF-κB) is a common culprit in both cancers. Previously, we discovered that protein arginine methyltransferase 5 (PRMT5) methylated and activated NF-κB. Here, we show that PRMT5 is highly expressed in PDAC and CRC. Overexpression of PRMT5 promoted cancer progression, while shRNA knockdown showed an opposite effect. Using an innovative AlphaLISA high throughput screen, we discovered a lead compound, PR5-LL-CM01, which exhibited robust tumor inhibition effects in both cancers. An in silico structure prediction suggested that PR5-LL-CM01 inhibits PRMT5 by binding with its active pocket. Importantly, PR5-LL-CM01 showed higher anti-tumor efficacy than the commercial PRMT5 inhibitor, EPZ015666, in both PDAC and CRC. This study clearly highlights the significant potential of PRMT5 as a therapeutic target in PDAC and CRC, and establishes PR5-LL-CM01 as a promising basis for new drug development in the future.

While photodynamic therapy (PDT) can induce acute inflammation in the irradiated tumor site, a sustained systemic, adaptive immune response is desirable, as it may control the growth of nonirradiated distant disease. Previously, we developed porphyrin lipoprotein (PLP), a ∼20 nm nanoparticle photosensitizer, and observed that it not only efficiently eradicated irradiated primary VX2 buccal carcinomas in rabbits, but also induced regression of nonirradiated metastases in a draining lymph node. We hypothesized that PLP-mediated PDT can induce an abscopal effect and we sought to investigate the immune mechanism underlying such a response in a highly aggressive, dual subcutaneous AE17-OVA+ mesothelioma model in C57BL/6 mice. Four cycles of PLP-mediated PDT was sufficient to delay the growth of a distal, nonirradiated tumor four-fold relative to controls. Serum cytokine analysis revealed high interleukin-6 levels, showing a 30-fold increase relative to phosphate-buffered solution (PBS) treated mice. Flow cytometry revealed an increase in CD4+ T cells and effector memory CD8+ T cells in non-irradiated tumors. Notably, PDT in combination with PD-1 antibody therapy prolonged survival compared to monotherapy and PBS. PLP-mediated PDT shows promise in generating a systemic immune response that can complement other treatments, improving prognoses for patients with metastatic cancers.

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Aim: Factors that make species resilient to climate change can be difficult to study with empirical data because conditions cannot be experimentally controlled. We used trait-based evolutionary ecological agent-based modelling to understand how dispersal, selection, extirpation, and other factors contribute to resilience under three climate change scenarios to test the extent to which high dispersal rate contributes to persistence of species and the extent to which they occupy large geographic ranges on an evolutionary time-scale involving speciation, dispersal, gene flow, and extinction. Location: Hesperia (an imaginary continent with controlled environmental heterogeneity).Major taxa studied: Modelled mammalian herbivore clade with 16 terminal species, each of which is a metapopulation with a variable number of local populations. Methods:We used NetLogo to model trait-based biotic responses to climate change in an environmentally heterogeneous continent in an evolving clade, the species of which are each represented by local populations that disperse and interbreed; they also are subject to selection, genetic drift, and local extirpation. We simulated mammalian herbivores, whose success depends on tooth crown height, vegetation type, precipitation and grit. Results:We found that high dispersal probability usually allowed species to successfully track their ancestral habitat as the continent's geography was altered by climate change. However, tracking was insufficient to allow species' traits to adapt to novel habitats that arose through the climate change process. High dispersal rates combined with moderate plasticity (lower extirpation risk) facilitated occupation of novel habitats, as did weak selective regimes. Main conclusions:The interaction between dispersal, probability of local extirpation, and selection intensity were jointly required to understand the likelihood of species survival and how widespread they would be. Diversity and geographic occupancy were maximized when parameters facilitated evolutionary adaptation to novel habitats. High rates of dispersal were sufficient for habitat tracking but insufficient by themselves to allow occupation of newly emerged environments.

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