Decoding RNA functions in tumor metastasis
We discovered the first metastasis-regulating miRNA, miR-10b (Nature 2007), identified miR-9 as an epithelial-mesenchymal transition (EMT)-inducing miRNA that promotes metastasis by targeting E-cadherin (Nature Cell Biology 2010), and reported the first systemic delivery of miRNA inhibitors (“antagomiR-10b”) as an anti-metastatic therapeutic (Nature Biotechnology 2010), illuminating a new treatment direction. Indeed, studies from other groups showed that combining miR-10b inhibitors with low-dose doxorubicin achieved durable regression of pre-existing lymph node metastases and distant metastases in preclinical models of metastatic breast cancer (Cancer Research 2015; Scientific Reports 2017). Since the inaugural study on miR-10b, its role as a metastasis promoter has been extensively validated. To date, more than 100 studies have been completed on miR-10b and metastasis across ~20 cancer types. At MD Anderson Cancer Center, our lab generated miR-10b knockout mice and found that genetic deletion of miR-10b suppressed oncogene-induced mammary tumorigenesis, EMT, and metastasis and reactivated tumor-suppressive pathways (Cancer Research 2016). Our group also showed that miR-100 simultaneously induces EMT and inhibits tumorigenesis, migration and invasion by targeting distinct genes, indicating that EMT is not always associated with increased tumorigenicity, motility and invasiveness (PLoS Genetics 2014). Recently, through targeted inactivation, restoration (genetic rescue) and overexpression of MALAT1 in genetically engineered mouse models, our lab demonstrated that the lncRNA MALAT1 suppresses breast cancer metastasis through binding and inactivation of TEAD (Nature Genetics 2018). This paradigm-shifting study redefined lncRNA regulation of metastasis and provided a framework for the rigorous characterization of non-coding and coding gene products. In ongoing work, our lab discovered that MALAT1 regulates bone homeostasis and bone metastasis.
Discovery of novel metastasis driver genes
Despite decades of cancer drug development, the survival rate of patients with metastatic disease remains dismal. Understanding and targeting the molecular underpinnings of metastasis remain one of the most pressing challenges in cancer treatment. Recently, our laboratory developed an in vivo positive selection system by using a next-generation forward genetics approach, and our pilot screen identified several genes that promoted bone metastasis. Building on this new system and our long-standing expertise in metastasis, we will screen for metastasis driver genes at multiple target organs and in multiple cancer types, and then we will ascribe functions to coding and non-coding gene products in metastasis by using rigorous gain-of-function, loss-of-function and genetic rescue approaches. The successful completion of this project will advance our understanding of metastasis and reveal novel and valid targets for anti-metastatic therapies.
Identifying molecular determinants of cancer therapy resistance
Our early work showed that treatment with mTOR inhibitors leads to activation of ERK through a feedback response in cancer patients; this could explain the limited benefit of rapamycin and its derivatives in treating certain tumor types and has a significant impact on cancer therapies (Journal of Clinical Investigation 2008). Our lab discovered that the EMT inducer ZEB1 dictates tumor radioresistance. We identified ZEB1 as a player in the DNA damage response pathway linking ATM to CHK1 (Nature Cell Biology 2014), and demonstrated the therapeutic utility of nanoparticle-encapsulated miR-205 (a ZEB1-targeting miRNA) mimics as tumor radiosensitizers (Nature Communications 2014). Recently, our lab revealed a non-canonical function of the miRNA biogenesis factor DGCR8 in DNA double-strand break repair and radiotherapy resistance (Nature Communications 2021). In a tour-de-force study, by using genetically engineered mouse models, transposon-mediated oncogene-induced liver cancer models and patient-derived xenograft models, our lab found that loss of LIFR promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis, which can be targeted by an LCN2-neutralizing antibody (Nature Communications 2021). We also found that glucocorticoid receptor (GR) acts as a transcriptional activator of PD-L1 and a transcriptional repressor of MHC-I in pancreatic cancer cells, and that GR depletion or inhibition promotes the infiltration and activity of cytotoxic T cells, leading to enhanced immune surveillance and sensitization of pancreatic tumors to immune checkpoint inhibitors (Nature Communications 2021). In ongoing work, we continue to study the mechanisms of immunotherapy resistance in liver cancer and pancreatic cancer.