# Examining Mitochondria Dysfunction and Oxidative Stress in Senescence

> **NIH NIH K00** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $86,378

## Abstract

PROJECT SUMMARY/ABSTRACT
Cancer metastasis is responsible for 90% of cancer-related mortality world-wide.[1] A widely-held hypothesis is
that during cancer progression, heterogeneous subclonal populations emerge that not only drive tumor growth,
but also enable cancer cells to metastasize to distant organs.[2] Current dogma suggests that heterogeneity
stems from the ability of cancer cells to continuously alter their genome in a process known as genomic
instability.[3] However, sequencing efforts have revealed that the genetics of metastases generally reflect that
of the primary tumor.[4-6] This suggests that other mechanisms may drive cancer metastasis, such as
chromosomal instability (CIN).
CIN is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. CIN
generates copy number alterations encompassing entire chromosomes (numerical CIN) and subchromosomal
rearrangements (structural CIN) that promote tumor heterogeneity and accelerate tumor evolution. Thus, CIN is
a powerful mechanism to rapidly shape the phenotypic landscape of tumor cell populations. However, whether
CIN is a causal driver or is a mere bystander in cancer metastasis has been a matter of conjecture for
decades.
Until recently, addressing the role of CIN in metastasis has been an experimental technical challenge.
Capitalizing on my recent ability to genetically manipulate chromosome segregation error rates, I propose to
investigate the cell-autonomous and non-cell autonomous mechanisms of CIN in metastasis. The
proposed doctoral training work (Aim 1) will investigate the fundamental relationship between CIN and the
behavior of metastatic cancers. To date, my work revealed that in addition to fueling karyotypic heterogeneity,
CIN drives metastasis through tumor-cell autonomous activation of that the cGAS-STING cytosolic DNA sensing
pathway (Aim 1).[7] Over the next two years, I will determine whether targeting CIN-driven or CIN-
dependent pathway such as cGAS-STING, can be used as a therapeutic strategy to limit metastatic
spread and prolong patient survival.
For my postdoctoral research (Aim 2), I plan to study how innate and adaptive immune cell populations
within the tumor microenvironment respond to CIN using a novel mouse model of lung cancer. In
summary, my research provides a novel paradigm for how CIN contributes to innate immunity signaling in cancer
metastasis. My post-doctoral research will establish new models of CIN that provide insight into tumor-stromal
interactions, and illuminate potential therapeutic targets. In addition, I have also proposed a comprehensive
training plan that will prepare me for my transition to a post-doctoral research position.

## Key facts

- **NIH application ID:** 10327441
- **Project number:** 4K00CA234950-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Bryan D Ngo
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $86,378
- **Award type:** 4N
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10327441

## Citation

> US National Institutes of Health, RePORTER application 10327441, Examining Mitochondria Dysfunction and Oxidative Stress in Senescence (4K00CA234950-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10327441. Licensed CC0.

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