Recent preprints and publications from IRM researchers. This month: a new technique for tracing cancer cells back to the source, another step toward producing patient blood stem cells outside of the body, and a search for coronavirus targets in the brain that leverages insights from other viral fights.

Which cancer cells go rogue?

Why do some cancerous cells metastasize to other parts of the body, often with grave consequences for health? In a preprint posted this month, researchers from the Lengner and Stanger labs use a new technique, macsGESTALT, to study the origin of metastatic pancreatic cancer cells. After stimulating tumor growth in mice with an injection of specially engineered pancreatic cells, the researchers collected information on tens-of-thousands of cells away from the injection site. Using sophisticated computational analysis, they were able to trace the “lineage” of these colonizing cells back to specific cells in the original tumor. So what makes a cell more likely to take up root somewhere else? According to the researchers, led by MD-PhD student Kamen Simeonov, metastatic cells overwhelmingly originate from a subgroup of highly aggressive tumor cells that progress mostly—but not fully—through a pathway known as epithelial–mesenchymal transition (EMT). They anticipate that the macsGESTALT technique will help other teams answer questions about cancer biology and the development of stem cells into functional tissues. (bioRxiv)

Finding a blood-making bottleneck

Hematopoietic stem cells (HSCs) give rise to the blood cells that carry oxygen throughout the body and fight infections. For patients of many hematological diseases, an HSC transplant restarts the blood production system after it is destroyed by chemotherapy. But there is a catch: successful transplants require matching donors, limiting the number of patients able to receive this therapy. To get around this limitation, scientists are developing methods to grow large numbers of compatible HSCs outside of the body. As a step toward this goal, researchers from Kai Tan and Nancy Speck’s laboratories profiled nearly 40,000 rare single cells from sites of HSC formation in embryonic mouse arteries over a three day window. Using a pair of methods to watch which genes get “turned on,” or expressed, during this crucial period, the researchers found a bottleneck along the pathway by which cells transition into HSCs. Cells exit this bottleneck—termed the “pre-hemogenic endothelial”, or “pre-HE,” stage—when RUNX1, a gene known to be critical for HSC development, is expressed. By pinpointing when RUNX1 becomes vital and characterizing different cell populations later in the three-day period, the team uncovered important conditions for growing HSCs in the laboratory. (Blood)

Probing for coronavirus weak spots in the brain

Although we know COVD-19 as a respiratory illness, its effects go well beyond the lungs. Patients can suffer from a variety of symptoms—including neurological issues such as dizziness and confusion—that suggest a propensity for SARS-CoV-2 to infect cells throughout the body. To search for potential viral targets in the brain, researchers from the Ming and Song labs took advantage of a system previously used to understand the behavior of Zika virus: organoids cultured from human-induced pluripotent stem cells (hiPSCs). Organoids use a combination of hiPSC-derived cell types to mimic the three-dimensional structure of actual human organs. After growing organoid models of the cerebral cortex, hippocampus, hypothalamus, and midbrain, the researchers exposed each “minibrains” to SARS-CoV-2. Their results suggest that choroid plexus epithelial cells, which line the blood/cerebral spinal fluid (CSF) barrier, are prone to high levels of infection, offering clues for further exploration of COVID-19’s impact on the brain. (bioRxiv, final manuscript in Cell Stem Cell)