Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study GBM's natural evolutionary trajectory by using rare multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES transition potentially via activation of the HIF1A–FOSL2 axis. High-NES tumor cells could recruit and polarize bone marrow–derived macrophages through activation of the FOSL2–ANXA1–FPR1/3 axis. These polarized macrophages can efficiently suppress T-cell activity and accelerate NES transition in tumor cells. Moreover, the polarized macrophages could upregulate CCL2 to induce tumor cell migration. Significance: GBM progression could be induced by hypoxia via the HIF1A–FOSL2 axis. Tumor-derived ANXA1 is associated with recruitment and polarization of bone marrow–derived macrophages to suppress the immunoenvironment. The polarized macrophages promote tumor cell NES transition and migration. This article is highlighted in the In This Issue feature, p. 2711

Diabetes is a global epidemic and affects millions of individuals in the United States. Devising novel treatments for diabetes continues to be a great medical challenge. Postnatal beta cell growth or compensation is largely attributed to beta cell proliferation, which declines continuously with age. To boost beta cell proliferation to regenerate an adequate functional mass, there is a need to understand the signaling pathways that regulate beta cell proliferation for creating practical strategies to promote the process. Transforming growth factor β (TGFβ) belongs to a signaling superfamily that governs pancreatic development and the regeneration of beta cells after pancreatic diseases. TGFβ exerts its functions by activation of downstream Smad proteins and through its crosstalk with other pathways. Accumulating data demonstrate that the TGFβ receptor signaling pathway also participates in the control of beta cell proliferation. This review details the role of the TGFβ receptor signaling pathway in beta cell proliferation physiologically and in the pathogenesis of diabetes.

The Cre/loxP system has been used extensively in mouse models with a limitation of one lineage at a time. Differences in function and other properties among populations of adult β-cells is termed β-cell heterogeneity, which was recently associated with diabetic phenotypes. Nevertheless, the presence of a developmentally derived β-cell heterogeneity is unclear. Here, we have developed a novel dual lineage-tracing technology, using a combination of two recombinase systems, Dre/RoxP and Cre/LoxP, to independently trace green fluorescent Pdx1-lineage cells and red fluorescent Ptf1a-lineage cells in the developing and adult mouse pancreas. We detected a few Pdx1⁺/Ptf1a⁻ lineage cells in addition to the vast majority of Pdx1⁺/Ptf1a⁺ lineage cells in the pancreas. Moreover, Pdx1⁺/Ptf1a⁺ lineage β-cells had fewer Ki-67⁺ proliferating β-cells, and expressed higher mRNA levels of insulin, Glut2, Pdx1, MafA and Nkx6.1, but lower CCND1 and CDK4 levels, compared with Pdx1⁺/Ptf1a⁻ lineage β-cells. Furthermore, more TSQ-high, SSC-high cells were detected in the Pdx1⁺Ptf1a⁺ lineage population than in the Pdx1⁺Ptf1a⁻ lineage population. Together, these data suggest that differential activation of Ptf1a in the developing pancreas may correlate with this β-cell heterogeneity.

Supplementary Table from Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma