The Alan and Sandra Gerry Postdoctoral Research Fellowship Recipients
The Gerry fellowship is awarded to an individual who has demonstrated excellence among their peers and whose work has a focus in metastasis research. This fellowship is set up through a generous gift from the Gerry family specifically for this purpose.
GMTEC’s current Gerry fellow is Joseph Chan.
Mentor: Dana Pe’er
Project: Integrative Single-Cell Sequencing in Lung Cancer Patients with Combined Neuroendocrine Histology to Identify Molecular Drivers and Targets of Small Cell Transformation
The most common type of lung cancer is adenocarcinoma (LUAD), for which targeted therapies enjoy initial great response but invariably lead to metastatic relapse from drug resistance. One novel mechanism of resistance involves lineage plasticity whereby cancer cells switch identity from LUAD to a completely different lung cancer subtype called small cell lung cancer (SCLC). SCLC is a much more aggressive cancer with shorter survival than in LUAD, requiring different treatments. When SCLC transformation occurs, both LUAD and SCLC often coexist in the same tumor, making simultaneous treatment of the two cancer types complicated. Shared mutations between primary LUAD and SCLC metastases within the same patient suggest that these distinct tumor types share a common ancestor, but it remains unclear whether LUAD transforms directly into SCLC or whether a multipotent cancer stem cell gives rise to both histologies.
Our understanding of SCLC transformation is limited because previous studies have depended on sequencing the tumor in bulk, which only estimates the average signal for the entire tumor. Single cell sequencing however can isolate the signal from each cell within the tumor, which is ideal for tumors containing both LUAD and SCLC subpopulations. Differences between LUAD and transformed SCLC at this resolution can lend insight into what drives lineage plasticity. In this proposal, we will be first to integrate single-cell RNA, single-cell Assay for Transposase-Accessible Chromatin (ATAC), and bulk DNA sequencing to 1) identify important cell populations that represent ancestral or transitional states during SCLC transformation, 2) identify targets for new therapies that prevent the transformation between these cell populations, thereby blocking plasticity and subsequent metastasis. The resulting data is large-scale and high-dimensional, requiring the development of novel computational methods to identify novel transitional subpopulations, model the evolution between these subpopulations, and identify putative molecular drivers of plasticity. We will validate molecular markers using multiplexed ion beam imaging (MIBI) and perform functional validation through CRISPR-mediated knockout and drug inhibition in matched patient-derived xenografts of combined histology. Findings will have broad impact beyond lung cancer, as small cell transformation can occur in extrapulmonary malignancies and computational methods optimized for SCLC transformation will be generally applicable to questions involving lineage plasticity in any tumor.
GMTEC’s Metastasis Scholars Fellowship Recipients
Patricia M. R. Pereira 2020/2021 GMTEC Metastasis Scholar
Mentor: Jason Lewis
Project: Synergy between HER2-targeted immunotherapy and CAV1 modulation in HER2-driven metastatic gastric cancer
Trastuzumab is a humanized antibody prescribed for the treatment of gastric cancers (GC) characterized by high expression of human epidermal growth factor receptor 2 (HER2) protein and/or gene amplification. The drug’s effectiveness is limited, however, due to intrapatient heterogeneity and both inherent and acquired resistance mechanisms. These pitfalls have led to negative clinical trials with other HER2-targeted therapies including a trastuzumab-drug conjugate (ado-trastuzumab emtansine, TDM1) and anti-HER2 antibody combinations (trastuzumab plus pertuzumab). Since antibodies must bind to the extracellular domain of HER2, a depressed HER2 surface pool hinders binding and, consequently, decreases therapeutic efficacy and antibody-based diagnostic imaging.
We have recently demonstrated that HER2 is not always present at the cell surface for binding anti-HER2 antibodies, that caveolin-1 (CAV1) protein present in cholesterol-rich structures reduces HER2 availability at the cell membrane, and that CAV1 can be pharmacologically modulated with clinically-approved cholesterol-depleting drugs – statins. Modulation of CAV1 with lovastatin temporally enhances membrane HER2 availability in ways that increase the avidity of GC for anti-HER2 antibodies.
In the future, I aim to investigate the pathobiological role of CAV1 and its pharmacologic modulation to improve HER2-targeted molecular imaging and therapy of HER2-driven metastatic gastric cancer. These studies will support many future investigations, including the development of specific tumoral-CAV1 modulators, clinical translation of trastuzumab/CAV1 modulation combination therapy and the potential broader application to other membrane receptors and cancers.
Yudan Chi 2020/2021 GMTEC Metastasis Scholar
Mentor: Adrienne Boire
Project: Microenvironmental effects on cancer cells in Leptomeningeal Metastasis
Leptomeningeal metastasis (LM), or spread of cancer cells into the cerebrospinal fluid (CSF)-filled spaces surrounding the brain and spinal cord, is a bleak complication of cancer that is becoming more common. This distinct anatomic compartment enjoys a unique relationship with the systemic circulation. As a result, the CSF is hypoxic, contains minimal nutrients, and few conventional therapies penetrate into this space. As a result, treatments remain quite limited, and the outcomes of patients harboring LM remain dismal.
We ask how cancer cells overcome these constraints to live and grow within this harsh microenvironment. Microenvironmental heterogeneity is increasingly appreciated as a crucial factor for successful metastasis, potentially enabling cancer cells to thrive despite extreme microenvironments. To investigate this, we leveraged single-cell RNA sequencing (scRNA-seq) to study the microenvironmental landscape in human LM. This preliminary work provided evidence for a highly heterogeneous makeup of immune cell infiltrates, and genetic alterations within tumor cells and immune cells. In order to dissect mechanisms of molecular networks in the microenvironment of CSF, we will establish new LM syngeneic models and describe intra-tumor heterogeneity by scRNA-seq. In our preliminary results, we described that LCN2 is dramatically upregulated in cancer cells, which promotes cancer growth in the iron-deficient, hypoxic leptomeningeal space. We hypothesize that cancer cells employ specific LCN2/SLC22A17 systems to successfully outcompete other cells for iron and resist hypoxic stress. We will therefore focus subsequent work on analyzing gene expression and signaling pathways after iron exhaustion in vivo and in vitro. Ultimately, we will exploit downstream singling pathways to generate novel strategies to target cancer cell growth in the CSF, offering new treatment approaches for a dire clinical problem.