Page 34 - Hormel Institute Annual Report 2021-22

Edward H. Hinchcliffe, PhD
“Understanding the mechanisms of cell
division is key to understanding cancer.”
Edward H. Hinchcliffe
34 | THE HORMEL INSTITUTE Cellular Dynamics
ASSISTANT DIRECTOR FOR EDUCATION / PROFESSOR
// UNIVERSITY OF MINNESOTA
My lab seeks to understand the cellular basis for tumorigenesis, in particular pediatric diffuse midline gliomas. We
study cell division, the process where cells sepa- rate duplicated chromosomes into two daughter cells - called mitosis. Mistakes in mitosis lead to uneven chromosome segregations, which is a hallmark of cancer progression. We use live-cell microscopy to study cell cycle checkpoint control mechanisms, CRISPR-Cas9 genetic manipulation of cancer driver mutations, and do translational studies using cGAS-STING agonists.
Current research projects
We are studying oncogenic mutations in core histone proteins that drive pediatric brain tumors. We find these are linked to chromosome insta- bility and loss of cell cycle checkpoint control.
We are also studying whether the inflammation response to chromosome missegregation and micronucleation are targets for anti-cancer thera- py. The cGAS-STING pathway is part of the innate immune response that detects double stranded DNA in the cytoplasm. dsDNA can be the result of genomic DNA leaking from the nucleus. In the case of chromosome missegregation, a small micronucleus – adjacent to the main nucleus, forms around the lagging chromosome(s). These
micronuclei are defective, and “leak” – exposing the chromatin
to the cytoplasm. The exposed dsDNA recruit cyclic GMP-AMP Synthase (cGAS) and activates Stimulator of Interferon Genes (the STING protein) turning on the IRF3 transcription factor and expression of pro-inflammatory genes, such as type I interferons like INFß. The
cGAS-STING pathway induces both an immune signaling response and triggers senescence of neighboring cells. Thus, leaky micronuclei may block the proliferation of chromosomally un- stable tumor cells, while also initiating regional tumor immune editing.
Multiple centrosomes in cancer cell