Proc. SPIE 11076, Advances in Microscopic Imaging II, 1107611 (22 July 2019)

Invited paper, SPIE/OSA European Conferences on Biomedical Optics (ECBO) 2019:, SPIE/OSA European Conferences on Biomedical Optics (ECBO) 2019, 23-27 June 2019, Munich, Germany; Paper 11076-38 (2019).

One of the greatest challenges for early cancer detection is how to effectively manage patients who are at risk for developing invasive cancer. As most at-risk patients will not develop cancer, frequent and invasive surveillance of at risk patients carries financial, physical, and emotional burdens. But clinicians lack tools to accurately predict which patients will likely progress into malignancy. With our increased understanding of molecular changes in cancer development, it is now established that disrupted epigenome that can alter nuclear architecture occurs in all stages of cancer development including in normal precursor cells. Therefore, assessment of nanoscale nuclear architecture represents a promising strategy for identifying pre-cancerous changes. Here we present the development of three dimensional nuclear architecture mapping (3D-nanoNAM) to assess the depth-resolved properties of phase objects with slowly varying refractive index without a strong interface, based on a variant form of Fourier-domain optical coherence tomography (FD-OCT). By computing the Fourier phase of the FD-OCT signal resulting from the light back-scattered by cell nuclei, 3D-nanoNAM quantifies, with nanoscale sensitivity, the depth-resolved alterations in mean nuclear optical density, and localized heterogeneity in optical density of the cell nuclei. We demonstrate that 3D-nanoNAM distinguishes high-risk patients with inflammatory bowel disease (IBD) colitis from those at low-risk via/through imaging tissue sections that appear histologically normal according to pathologists. As 3D-nanoNAM uses clinically prepared formalin-fixed, paraffin-embedded tissue sections, it can be integrated into the clinical workflow.

Molecular Cell; 75(1): 117-130 (2019).

I contributed to the data and statistical analysis performed in the study.

Telomeres are essential for genome stability. Oxidative stress caused by excess reactive oxygen species (ROS) accelerates telomere shortening. Although telomeres are hypersensitive to ROS-mediated 8-oxoguanine (8-oxoG) formation, the biological effect of this common lesion at telomeres is poorly understood because ROS have pleiotropic effects. Here we developed a chemoptogenetic tool that selectively produces 8-oxoG only at telomeres. Acute telomeric 8-oxoG formation increased telomere fragility in cells lacking OGG1, the enzyme that removes 8-oxoG, but did not compromise cell survival. However, chronic telomeric 8-oxoG induction over time shortens telomeres and impairs cell growth. Accumulation of telomeric 8-oxoG in chronically exposed OGG1-deficient cells triggers replication stress, as evidenced by mitotic DNA synthesis at telomeres, and significantly increases telomere losses. These losses generate chromosome fusions, leading to chromatin bridges and micronucleus formation upon cell division. By confining base damage to the telomeres, we show that telomeric 8-oxoG accumulation directly drives telomere crisis.‍

R01CA232593 (April 01, 2019 - March 31, 2024)

We received an R01 grant award from the National Cancer Institute (NCI) at the National Institutes of Health (NIH) on studying and quantifying subtle, nanoscale alternations in nuclear architecture of epithelial cells of colorectal cancer precursors and predict their risk of developing into cancer.

Cancer Res; 79 (13 Supplement): 1642 (2019). [AACR Annual Meeting 2019, March 29-April 3 2019, Atlanta, Georgia]

Poster presentation on our preliminary results showing that epithelial- and stromal-domain expression and co-expression diversity of the biomarkers captured by highly multiplexed imaging predict risk of CRC recurrence and allow us to infer epithelial and stromal-domain protein networks specific to the risk-of-recurrence from the underlying signaling networks.

Cell Reports; 24(4): 873-882 (2018).

As a part of this work, we developed a nuclei segmentation method for stochastic optical reconstruction microscopy that avoids segmentation getting stuck in local minima due to numerous and distinct chromatin clusters within the nuclei reconstructed using localization microscopy.