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 2021-2023 Gerry fellow is Arianna Baggiolini.
Mentor: Lorenz Studer
Project: Melanoma brain metastases and modeling using human pluripotent stem cell (hPSC)-derived brain organoids
The brain microenvironment poses a unique selective pressure on the metastatic melanoma cells that infiltrate through the blood-brain barrier. The brain is in fact characterized by exclusive immune and metabolic constraints and it is composed of unique cell types as neurons, astrocytes and microglia. Increasing evidence suggests that the brain microenvironment plays an important role in the pathogenesis of brain metastasis. Microglia are the fast responder to melanoma invasion into the brain and may acquire a reactive state that can be either phagocytic and protective, or pro-metastatic. Similarly, astrocytes may acquire a pro-metastatic reactive state that supports metastatic cells. Finally, neurons have also been shown to be able to interact with cancer cells through the formation of pseudo-synapses.
We hypothesize that 1) the instruction of the niche and the following aberrant activation of non-neuronal cell types (microglia and astrocytes) are major pathological events that support metastatic melanoma cell survival in the brain microenvironment; 2) the integration of the melanoma cells in the neuronal network has as a prometastatic effect and that 3) the identification of factors that modulate cellular cross-talk between melanoma cells and microglia, astrocytes and neurons will provide promising avenues for treatment of melanoma brain metastases.
The study of melanoma micro-metastases in the brain microenvironment is challenging, in particular in the human context, because of the difficult access to brain cells. This study uses human pluripotent stem cell (hPSC) technologies to generate a comprehensive, humanized platform for disease modeling that incorporates the complexity of the neuroinflammatory axis and recapitulates the human brain microenvironment. Our study will highlight the molecular drivers determined by the unique selective pressure of the brain microenvironment and the mechanisms underlying adaptation, cellular cross-talk and niche remodeling.
GMTEC’s 2019-2021 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.
Shulamit Katzman Endowed Postdoctoral Research Fellow
The Shulamit Katzman Endowed Postdoctoral Research fellowship is awarded to an individual studying the mechanics of metastasis. This highly competitive recognition is set up through a generous gift from the Katzman family specifically for this purpose.
GMTEC’s 2021-2023 Shulamit Katzman Endowed Postdoctoral Research Fellow is Kaloyan Tsanov.
Mentor: Scott Lowe
Project: Organ-specific Effects of Smad4 in Metastatic Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related mortality in the US by 2030. The majority of these deaths are due to metastasis, yet few determinants of PDAC’s high metastatic potential have been identified. Inactivation of SMAD4 – a core mediator of TGFβ signaling – occurs in about half of PDAC cases and has been associated with higher metastatic proclivity. How loss of SMAD4 facilitates metastasis and whether it is required for tumor maintenance after successful colonization remains unclear.
To address these questions, I have generated a novel mouse model that allows for precise spatiotemporal control of endogenous Smad4 expression throughout PDAC development. Smad4 depletion in the pre-malignant pancreas led to the emergence of metastatic PDAC, while its subsequent restoration in advanced tumors had surprisingly different outcomes based on the tumor’s organ of residence. Integrative transcriptomic and epigenomic analysis revealed organ-specific changes in the activity of key transcription factors, pointing to a potential mechanistic basis for the observed phenotypes. The overall objective of this project is to gain deeper understanding of the molecular and cellular mechanisms that mediate Smad4’s organspecific functions.
To this end, I propose a combinatorial approach that leverages our new mouse model, functional genetics tools, and single cell analytics to define critical transcription factors and cell populations. By using Smad4 as a lens into PDAC metastasis, these studies promise to illuminate how genetic and epigenetic factors interact to shape malignant behavior in an organ-specific manner, which may uncover broader principles and inform the clinical management of metastatic disease.