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.

Public Health Relevance

(PUBLIC HEALTH RELEVANCE) Despite advances in the treatment of cancer, the clinical manifestation of metastasis in vital organs is often the main culprit of cancer-related deaths. Once cancers spread to vital organs, treatment options are predominantly limited to palliation, and novel therapies for the treatment of patients with advanced disease have generally failed to improve patient overall survival. This proposal will uncover the mechanisms by which CIN contributes to metastasis, and determine whether targeting CIN-dependent pathways can be used as a therapeutic strategy to limit metastatic spread and significantly extend patient survival.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Mcguirl, Michele
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code