Platelet microRNAs inhibit primary tumor growth via broad modulation of tumor cell mRNA expression in ectopic pancreatic cancer in mice

We investigated the contributions of platelet microRNAs (miRNAs) to the rate of growth and regulation of gene expression in primary ectopic tumors using mouse models. We previously identified an inhibitory role for platelets in solid tumor growth, mediated by tumor infiltration of platelet microvesicles (microparticles) which are enriched in platelet-derived miRNAs. To investigate the specific roles of platelet miRNAs in tumor growth models, we implanted pancreatic ductal adenocarcinoma cells as a bolus into mice with megakaryocyte-/platelet-specific depletion of mature miRNAs. We observed an ~50% increase in the rate of growth of ectopic primary tumors in these mice compared to controls including at early stages, associated with reduced apoptosis in the tumors, in particular in tumor cells associated with platelet microvesicles—which were depleted of platelet-enriched miRNAs—demonstrating a specific role for platelet miRNAs in modulation of primary tumor growth. Differential expression RNA sequencing of tumor cells isolated from advanced primary tumors revealed a broad cohort of mRNAs modulated in the tumor cells as a function of host platelet miRNAs. Altered genes comprised 548 up-regulated transcripts and 43 down-regulated transcripts, mostly mRNAs altogether spanning a variety of growth signaling pathways–notably pathways related to epithelial-mesenchymal transition—in tumor cells from platelet miRNA-deleted mice compared with those from control mice. Tumors in platelet miRNA-depleted mice showed more sarcomatoid growth and more advanced tumor grade, indicating roles for host platelet miRNAs in tumor plasticity. We further validated increased protein expression of selected genes associated with increased cognate mRNAs in the tumors due to platelet miRNA depletion in the host animals, providing proof of principle of widespread effects of platelet miRNAs on tumor cell functional gene expression in primary tumors in vivo. Together, these data demonstrate that platelet-derived miRNAs modulate solid tumor growth in vivo by broad-spectrum restructuring of the tumor cell transcriptome.

RETSAT Mutation Selected for Hypoxia Adaptation Inhibits Tumor Growth

Hypoxia occurs not only in natural environments including high altitude, underground burrows and deep sea, but also in human pathological conditions, such as hypoxic solid tumors. It has been well documented that hypoxia related signaling pathway is associated with a poor clinical outcome. Our group has recently identified multiple novel genes critical for solid tumor growth comparing the genome-wide convergent/parallel sequence evolution of highland mammals. Among them, a single mutation on the retinol saturase gene (RETSAT) containing amino acid switch from glutamine (Q) to arginine (R) at the position 247 was identified. Here, we demonstrate that RETSAT is mostly downregulated in multiple types of human cancers, whose lower expression correlates with worse clinical outcome. We show that higher expression of RETSAT is positively associated with immune infiltration in different human cancers. Furthermore, we identify that the promoter region of RETSAT is highly methylated, which leads to its decreased expressions in tumor tissues comparing to normal tissues. Furthermore, we show that RETSAT knockdown promotes, while its overexpression inhibits, the cell proliferation ability of mouse embryonic fibroblasts (MEFs) and B16 in vitro. In addition, the mice carrying homozygous Q247R mutation (RETSATR/R) is more resistant to xenograft tumor formation, as well as DMBA/TPA induced cutaneous keratinocyte carcinoma formation, compared to littermate wild-type (RETSATQ/Q) mice. Mechanistic study uncovers that the oncogenic factor, the prolyl isomerase (PPIase) Pin1 and its related downstream signaling pathway, were both markedly repressed in the mutant mice compared to the wild-type mice. In summary, these results suggest that interdisciplinary study between evolution and tumor biology can facilitate identification of novel molecular events essential for hypoxic solid tumor growth in the future.

Small-sized copolymeric nanoparticles for tumor penetration and intracellular drug release

Small-sized copolymeric nanoparticles have been developed for deep tumor penetration and nuclear drug delivery, which exhibit excellent solid tumor growth suppression.