Perivascular macrophages orchestrate the expansion of pericyte-like mesenchymal cells to create a proangiogenic niche in cancer.

SummaryUnderstanding how epithelial progenitors within exocrine glands establish specific cell lineages and form complex functional secretory units is vital for organ regeneration. Here we identify the transcription factor Sox10 as essential for both the maintenance and differentiation of epithelial KIT+FGFR2b+ progenitors into secretory units, containing acinar, myoepithelial, and intercalated duct cells. The KIT/FGFR2b-Sox10 axis marks the earliest multi-potent and tissue-specific progenitors of exocrine glands. Genetic deletion of epithelial Sox10 leads to loss of secretory units, which reduces organ size and function, but the ductal tree is retained. Intriguingly, the remaining duct progenitors do not compensate for loss of Sox10 and lack plasticity to properly form secretory units. However, overexpression of Sox10 in these ductal progenitors enhances their plasticity toward KIT+ progenitors and induces differentiation into secretory units. Therefore, Sox10 controls plasticity and multi-potency of epithelial KIT+ cells in secretory organs, such as mammary, lacrimal, and salivary glands.

Background Patient-derived xenograft (PDX) models have significantly enhanced cancer research, and often serve as a robust model. However, enhanced growth rate and altered pathological phenotype with serial passages have repeatedly been shown in adenoid cystic carcinoma (ACC) PDX tumors, which is a major concern. Methods We evaluated the fidelity of ACCs in their natural habitat by performing ACC orthotopic xenotransplantation (PDOX) in salivary glands. Findings Our PDOX model enabled solid tumors to integrate within the local epithelial, stromal and neuronal environment. Over serial passages, PDOX tumors maintained their stereotypic MYB-NFIB translocation, and FGFR2 and ATM point mutations. Tumor growth rate and histopathology were retained, including ACCs hallmark presentations of cribriform, tubular, solid areas and innervation. We also demonstrate that the PDOX model retains its capacity as a tool for drug testing. Interpretation Unlike the precedent PDX model, our data shows that the PDOX is a superior model for future cancer biology and therapy research. Fund This work was supported by the National Institutes of Health (NIH)/National Institute of Dental and Craniofacial Research (NIDCR) grants DE022557, DE027034, and DE027551.