Research

Overview

Our research focuses on how RNA regulation shapes breast cancer metastasis and anti-tumor immunity. We investigate how RNA processing and RNA surveillance control tumor cell plasticity, metastatic progression, and interactions with the immune system. Our work spans three interconnected areas: RNA regulation during epithelial-mesenchymal transition (EMT), cryptic splicing and tumor immunity, and the biology of circulating tumor cells. By combining mechanistic RNA biology with functional genomics, computational approaches, and patient-derived models, we seek to uncover new mechanisms of cancer progression and identify tumor-specific therapeutic targets, including neoantigens generated by aberrant RNA processing, that can be leveraged for cancer immunotherapy.

RNA Regulation during EMT

Cancer cells undergo extensive molecular rewiring to metastasize. A central component of this process is epithelial-to-mesenchymal transition (EMT), in which epithelial cells lose cell-cell adhesion and acquire migratory and invasive properties. Our work has established RNA regulation, particularly alternative splicing, as an important mechanism controlling EMT and breast cancer metastasis.

Through the study of CD44 alternative splicing, our work showed for the first time that alternative isoform switching plays an essential role in driving EMT. Subsequently, we identified RNA-binding proteins (RBPs), including hnRNPM and AKAP8, as key regulators of the splicing programs that control epithelial and mesenchymal cell states.

We continue to investigate how RBPs and post-transcriptional RNA regulatory pathways shape gene expression, protein production, cell identity, and cellular plasticity. By integrating computational and experimental approaches, we study how RNA processing, stability, and expression contribute to metastasis. We are also investigating how transposable elements influence RNA regulation, EMT, and cancer progression, with the goal of identifying new vulnerabilities and therapeutic opportunities in metastatic breast cancer.

Cryptic Splicing, dsRNA, and Tumor Immunity

Triple-negative breast cancer (TNBC) remains a major clinical challenge because of its aggressive behavior, limited targeted therapies, and poor prognosis. Dysregulation of RNA splicing is an emerging mechanism of tumor progression, immune remodeling, and metastatic adaptation. Tumor-specific splicing events arising from RBP dysfunction can generate non-canonical peptides that could be leveraged for targeted immunotherapy, yet the RBP programs that drive these processes remain incompletely defined.

Our recent work has uncovered a link between RNA surveillance, cryptic splicing, and anti-tumor immunity. We found that the RNA-binding protein hnRNPM safeguards transcriptome integrity by suppressing cryptic splicing within long interspersed nuclear elements (LINEs). Loss of hnRNPM leads to the accumulation of double-stranded RNA (dsRNA) and activation of interferon signaling. hnRNPM-deficient patient tumors also show increased interferon signaling and immune-cell infiltration, suggesting that aberrant RNA processing can influence the tumor immune microenvironment.

We are now investigating how RBP dysregulation and cryptic splicing generate immunostimulatory RNAs and tumor-specific neoantigens, and how these mechanisms can be harnessed to enhance anti-tumor immunity. Our goal is to uncover new mechanisms of tumor-immune regulation that can be leveraged to develop more effective immunotherapies for metastatic breast cancer.

Circulating Tumor Cells and Metastasis

Most cancer-associated deaths result from distant metastases rather than primary tumors. Circulating tumor cells (CTCs) are tumor cells that enter the bloodstream and can seed metastatic lesions in distant organs. Survival in the circulation exposes CTCs to mechanical stress, loss of extracellular matrix attachment, oxidative stress, and immune attack, requiring tumor cells to adapt to a highly challenging environment.

Our work revealed that TNBC cells form highly metastatic CTC clusters through an extracellular matrix-based mechanism involving hyaluronan (HA) and its receptor CD44. HA promotes interactions between tumor cells and the extracellular matrix that are reinforced by desmosomes, allowing CTCs to form stable clusters despite the loss of epithelial junctions during EMT. These clusters can also recruit non-tumor cells, including immune cells, potentially enhancing their survival and metastatic capacity.

We also use single-cell RNA sequencing to investigate the molecular diversity of CTCs and have identified new cell-surface markers for detecting live CTCs. These markers improve detection of heterogeneous CTC populations, especially aggressive CTCs that have lost conventional epithelial markers. We are using these approaches to understand how tumor cells adapt to the circulation, define mechanisms that promote metastatic progression, and develop CTC-based strategies for monitoring metastatic disease.

See the Publications page for our recent papers, the Funding page for current grant support, and Join Us if you're interested in contributing to this work.