The Gibbons lab studies both the cell-intrinsic mechanisms and interactions of tumor cells with their microenvironment that drive lung cancer progression and metastasis. Recently the group demonstrated that for cancer cells to escape the primary lung tumor and colonize distant organs, they need to suppress the immune system, a process that is mediated in part by suppression and exhaustion of T cell activity coordinated by the protein PD-L1. Translational work suggests that immunotherapy may have anti-metastatic effects and has driven the development of new clinical trials for early-stage lung cancer. This work has also uncovered new players in the area of primary and acquired resistance to immune checkpoint inhibitors and spurred exploration of interesting immune combination strategies in pre-clinical trials. Dr. Gibbons is part of the Lung Cancer Moon Shot and coordinates a team evaluating the immune profiles of mouse lung cancer models upon treatment with immune checkpoint combinations to determine immune activation, T-cell infiltration, and T-cell exhaustion. The functional genomics efforts in this project seek to uncover new therapeutic targets that would be appropriate for translation into early clinical trials.
Lung cancer is driven by bidirectional reciprocity between cancer cells and the tumor microenvironment (TME) that constantly interacts with the cancer cells. This interaction is not truly captured when cancer growth is restricted to in vitro cultures. In an effort to closely mimic in vivo lung cancer growth, the Gibbons laboratory uses 3D tissue culture models and an ex vivo system which is more representative of the physiological 3D cellular environment. They use this system for mechanistic and therapeutic interrogation of lung cancer phenotype in the face of different extracellular matrices, variable biophysical properties, and altered soluble factors. As part of this work the Gibbons lab has long-standing collaborations with the Miller lab at Rice University.
The epithelial-to-mesenchymal transition (EMT) is a proposed model of cancer progression and metastasis in NSCLC, but the precise mechanisms controlling EMT or the downstream effects of a mesenchymal shift are incompletely understood. The Gibbons lab has demonstrated roles for multiple microRNAs (e.g. miR-200 family and miR-96~182 cluster) that are regulated by the ZEB1 transcriptional repressor and act in coordination to produce the complementary expression changes needed to drive invasion and metastasis. This project is delineating the EMT-associated alterations in cell signaling pathways that allow for tumor cell survival and spread, thereby identifying new potential molecular targets and treatment strategies.
The group is also exploring new molecular mechanisms underlying cancer cell invasion and metastasis. The lab has identified novel metastasis driver genes from a functional in vivo screen of genomic alterations found in the lung cancer TCGA and is using cell and animal models to elucidate the biochemical and signaling pathways regulated by the novel drivers. The overarching goal is to identify new genes that could be developed as therapeutic targets in the prevention or treatment of metastatic lung cancers.