New research from Memorial Sloan Kettering Cancer Center (MSK) and the Sloan Kettering Institute — a hub for basic science and translational research within MSK — found a potential target against neuroendocrine transformation in lung and prostate cancers; discovered new clues about why donor T cells attack certain tissues in graft-versus-host disease; shed light on why T cells let go of their prey; and used CRISPR interference and dynamic cell-state transitions to discover enhancers that affect early human development.
Targeting exportin 1 may help prevent neuroendocrine transformation in lung and prostate cancers
Over time, some lung and prostate cancers gain resistance to treatment by transforming from adenocarcinomas to neuroendocrine tumors, which are more aggressive. New research from the lab of Charles Rudin, MD, PhD, led by lab Co-Director Álvaro Quintanal-Villalonga, PhD, looked at the role of the protein exportin 1 in these cancers, which transports other proteins from the cell nucleus to the cytoplasm. The research showed exportin 1 expression was elevated at early stages of neuroendocrine transformation and that its inhibition with the drug selinexor suppressed the transformation in mouse models, extending the response to targeted therapies. The findings suggest that inhibiting exportin 1 could present a therapeutic opportunity to help prevent or treat neuroendocrine transformation in lung and prostate cancers. Read more in Science Translational Medicine.
New clues about why donor T cells attack certain tissues in graft-versus-host disease
Graft-versus-host disease (GVHD) is a potentially fatal complication of stem cell and bone marrow transplants (BMTs) that use donor cells. BMTs may be used to treat blood cancers and some inherited blood disorders. GVHD occurs when T cells from the donor attack healthy tissues in the transplant recipient. It can affect many organs, especially the skin, liver, and gastrointestinal (GI) tract. Although T cells in the blood have been well studied, until now, little has been known about the makeup of the T cells that cause GVHD in the diseased tissues themselves. Now investigators from MSK have found clues about why donor T cells attack specific tissues.
Bone marrow transplant specialist Jonathan Peled, MD, PhD, and leukemia specialist Susan De Wolf, MD, led the research in Dr. Peled’s Memorial Hospital research lab and in collaboration with the labs of Marcel van den Brink, MD, PhD; Benjamin Greenbaum, PhD; and Christine Iacobuzio-Donahue, MD, PhD. The team collected tissues from seven patients who had died of or with GVHD, as well as samples from lab mice with GVHD and three control patients who did not have GVHD, then analyzed the T cells found in these tissues. They noted different patterns in the makeup of the T cells, based on where they clustered in the body. For example, T cells found in the esophagus and colon, both parts of the GI tract, were more similar to each other than T cells found in the skin and liver. By understanding more about the features of these harmful T cells, the researchers may eventually find new ways to prevent or treat GVHD. Read more in Science Translational Medicine.
Why T cells let go of their prey
Cytotoxic T cells are immune cells that fight pathogens and cancer cells by forming a specialized attachment to them — a cytotoxic immune synapse — and injecting molecules that kill the cell. As the target cell dies, the immune synapse dissolves, leaving the T cell free to search out new prey. Now, research from the immunology lab of Morgan Huse, PhD, of the Sloan Kettering Institute, has answered a key biological question: What causes T cells to detach from the dying target cells? The team, led by postdoctoral fellow Elisa Sanchez, PhD, used time-lapse imaging and a series of genetic and pharmacological experiments to show that the contraction of the dying cell’s cytoskeleton triggers the release — enabling the T cell to continue its patrol. Further research is underway to understand the biomechanical feedback mechanisms that enable T cells to know when to let go. Read more in Nature Immunology, including a related research briefing.
Using CRISPR interference and dynamic cell-state transitions to discover enhancers that affect early human development
Enhancers are regulatory DNA sequences that change the way genes are expressed. Mapping enhancers to genes is essential for understanding cell type-specific gene expression that is relevant to normal development, tissue regeneration, and disease. But because most disease-relevant enhancers have effects that may be weak or only temporary, they’ve been difficult to study. Researchers have sought better models for finding and studying enhancers in both normal and diseased cells. Now a team of investigators from MSK’s Sloan Kettering Institute and Johns Hopkins University reports that dynamic cell-state transitions can be leveraged to improve the sensitivity of enhancer discovery.
Developmental biologist Danwei Huangfu, PhD, and graduate student Renhe Luo led the team at MSK; biomedical engineer Michael Beer, PhD, MA, was the senior author from Johns Hopkins. They focused on enhancers required for the differentiation of the definitive endoderm, the layer of embryonic cells crucial for the formation of many internal organs. By applying CRISPR interference in human embryonic stem cells, they targeted potential enhancers surrounding 10 core transcription factors, covering a total span of 40 million base pairs. They were able to identify multiple enhancers (between four and nine per locus) flanking each transcription factor gene. The comprehensive discovery of enhancers led to the development of improved enhancer-prediction methods. This work highlighted the importance of leveraging cell-state transitions — either normal or pathological — for finding enhancers across various biological contexts. Read more in Nature Genetics.