The Daniel Higginson Lab

The Daniel Higginson Lab: Research Overview

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I am a radiation oncologist who specializes in the use of highly precise, high-dose radiotherapy to treat tumors in the spine, brain, and other organs. I use advanced imaging and radiosurgery technology to precisely target cancers while sparing normal tissue. With these technologies, we can give repeated courses of radiation to tumors next to the spinal cord. I am part of a multidisciplinary team of neurosurgeons, radiation oncologists, and interventional radiologists that provides seamless personalized care.

I am also a physician-scientist and the principal investigator of a research group dedicated to understanding how DNA double-strand break repair (DSBR) pathways are used after radiation. DSBR is more efficient in normal cells than in cancer cells, so how well radiotherapy works depends on whether it causes DNA double-strand breaks. There are two well-characterized DSBR pathways — homologous recombination (HR) and nonhomologous end joining — and emerging evidence supports the importance of a third pathway, known as microhomology-mediated end joining (MMEJ). Understanding MMEJ is significant to radiation treatments designed to target HR deficiency in cancer, such as those caused by BRCA1 or BRCA2 mutations.

Homologous recombination (HR) and nonhomologous end- joining (NHEJ) are considered the two primary double- strand break repair (DSBR) pathways that are used in response to therapeutic radiation therapy. However, whole- genome sequencing of radiation-induced cancers has found prevalent small deletions involving short stretches of microhomology surrounding arounda break sites. In addition, the genomes of HR-deficient cancers also contain an enrichment ofmany such deletions, which are created through a pathway known as microhomology-mediated end- joining (MMEJ).  MMEJ is poorly characterized, with as only one factor, polymerase theta, identified as unique to MMEJ has been identified (polymerase theta).

My group uses genome- editing and sequencing techniques to characterize the genome scars left behind by NHEJ and MMEJ.  We study the relative usage of MMEJ in different cellular contexts, with a focus on the mechanisms ofhow the pathway is regulatedion of the pathway.  The overall goal of our work is to improve our understanding of MMEJ in therapeutic radiation treatment and as a backup pathway in HR- deficient cancers.