Projects

Our laboratory employs an interdisciplinary approach combining cell biology, biochemistry, as well as mouse and computational models to dissect the contributions of chromosomal instability (CIN) toward three key processes in human cancer: therapeutic resistance, immune evasion, and metastasis.

Major areas of investigation in the lab include: 

The role of CIN in cancer metastasis

We recently uncovered an important link between CIN and tumor metastasis: errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream NF-κB signaling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumor models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumor cells co-opt chronic activation of innate immune pathways to spread to distant organs.This work brings to light novel therapeutic strategies in otherwise aggressive metastasis-prone cancers. We are currently exploring the therapeutic utility of targeting CIN-activated pathways in the treatment of cancer metastasis. 

CIN and the tumor microenvironment 

The ability of CIN to promote chronic inflammatory signaling highlights the intimate crosstalk between the cancer genome and the tumor microenvironment. How chromosomally unstable tumor cells not only survive, but thrive and metastasize, amidst chronic inflammation remains a mystery. We are interested in dissecting tumor-intrinsic and extrinsic mechanisms that enable cancer cells to tolerate and co-opt chronic inflammatory signaling to acquire metastatic and drug-resistant traits. Such an understanding would pave the way for strategies that aim to exploit CIN-induced inflammation as a therapeutic vulnerability. 

The cellular biology of cytosolic DNA

Ongoing errors in chromosome segregation present cancer cells with a unique challenge, namely the presence of genomic double-stranded DNA in the cytoplasm, where it does not naturally belong. Beyond the ensuing inflammatory signaling, how cancer cells process cytosolic DNA is not understood. Using biochemical and cellular tools, including super-resolution microscopy, we are interested in interrogating key pathways involved in the generation and processing of cytosolic DNA and their impact on genomic instability and cellular metabolism.