Project description:Certain embryonic genes, such as carcinoembryonic antigens (CEA) and oncofetal antigens, become re-expressed in malignant transformation and we hypothesized that a similar phenomenon features tumor endothelial cells as well. Therefore, we performed a systematic search for mouse embryo-specific gene expression at days E11 and E18 in comparison to adult mouse and queried for overexpression of these genes in sorted murine tumor endothelial cells.
Project description:Mice were vaccinated with iBoost technology against a tumor vascular target, prior to B16F10 or CT26 tumor inoculation. Tumors from control and target vaccinated mice were excised and subject to RNAseq
Project description:Tumor-associated breast vasculature was laser-cappture microdissected from IDC breast cancer cases. The goal of the study was to characterize the heterogeneity of breast tumor-associated vasculature and identify gene expression signatures predictive of clinical outcome. common reference design, 32 samples
Project description:Tumor vasculature are structurally chaotic and functionally inefficient. Restoring aberrant tumor blood vessels, or “normalize” the tumor vasculature can alleviate hypoxia and enhance intra-tumoral drug delivery. However, identifying tumor vascular normalizing drugs are currently hampered by an absence of efficient screening platform. We aimed to develop a robust method to visualize, digitalize and evaluate the structural and functional changes of tumor vasculature in batch: zebrafish functional xenograft vasculature platform (zFXVP). As proof of principle, we applied zFXVP to a small compound library which has been implicated in affecting the morphology of tumor vasculature. zFXVP identified PF-502 as a durable tumor vascular normalization agent. Further molecular analysis using RNA-Seq, pharmaceutical inhibition and gene knockout indicate PF-502 can induce endothelial cell cycle arrest and simplify redundant tumor vasculature by blocking PI3K/mTOR signaling and stabilize the vessel lumen and stimulate the blood function by activating Notch1 signaling with mediating S3 cleavage. Last, in mouse tumor xenograft model, PF-502 reproduced a potent vascular normalizing effect at a sub MTD (maximum tolerated dose) and showed its ability to improve intra-tumoral drug delivery and synergize chemotherapy, which confirms the reliability of zFXVP and implicates the potential application of PF-502 in clinical practice as an adjuvant vascular normalization drug.
Project description:Tumor-associated breast vasculature was laser-cappture microdissected from IDC breast cancer cases. The goal of the study was to characterize the heterogeneity of breast tumor-associated vasculature and identify gene expression signatures predictive of clinical outcome.
Project description:Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer-resistant protein (BCRP), in drug-resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies.