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 2022-2024 Gerry fellow, Jun Ho Lee

Jun Ho Lee

GMTEC’s 2022-2024 Gerry fellow is Jun Ho Lee.

Mentor: Joan Massagué

Project: Characterizing contextual mediator of TGFβ-induced fibrogenic EMTs in metastasis

The cytokine TGF-β is a central regulator of tissue homeostasis and regeneration though multiple coordinated effects on epithelial, immune, and mesenchymal stromal systems. Malfunctions of TGF-β signaling cause fibrosis, immune dysfunction, and cancer. As part of its multifunctional program, TGF-β induces epithelial mesenchymal transitions (EMTs). Carcinoma cells undergo TGF-β dependent EMT and adopt a highly plastic phenotype that facilitates tumor growth and metastasis. TGF-β-induced EMTs in epithelial progenitor cells are accompanied by expression of fibrogenic factors that activate fibroblasts to produce and remodel the extracellular matrix. This not only occurs during wound healing and in fibrotic diseases but also in primary and metastatic tumors, suggesting that EMT and fibrogenesis are parts of an orchestrated program. The Massagué lab recently discovered that the transcription factor RAS-Responsive Element-Binding Protein 1 (RREB1), activated by RAS-MAPK signaling, synergizes with SMADs to coordinately transactivate the EMT transcription factor Snai1 and fibrogenic genes in carcinoma progenitors. This finding raised important questions, which are the focus of my postdoctoral research project: Does TGF-β-driven metastasis result from induction of EMT, of intra-tumoral fibrosis, or of both? Why do these SMAD target genes require RREB1 for activation while others do not? Finally, what biochemical functions does RREB1 bring to its collaboration with SMADs in the transcriptional activation of these genes?

We are using a combination of genetically engineered mouse models (GEMM), transplanted metastasis models, biochemical and molecular approaches to address these questions. Using proteomics approaches coupled with a CRISPR-based genetic screen, we identified a set of RREB1-interacting transcriptional regulators that are essential for the TGF-β fibrogenic EMT program in pancreatic cancer and lung adenocarcinoma cells. Based on the analysis of these RREB1 cofactors to date, we are testing the hypothesis that 1) pre-bound RREB1 to the regulatory loci of KRAS-dependent metastatic TGF-β mediates a prerequisite event for the recruitment of the cofactors and 2) these genes leverage the subsequent biochemical action of the cofactors. We are using integrative transcriptomic and epigenetic profiling to elucidate the basis for the collaboration between the TGF-β and RAS pathways. Our goal is to delineate the contextual role of TGF-β in metastasis by identifying the transcriptional requirement and determinant of these responses. Beyond advancing our understanding of TGF-β signaling, this work will illuminate the cooption of regenerative processes during cancer progression and metastasis.

GMTEC’s 2021-2023 Gerry fellow, Arianna Baggiolini

Arianna Baggiolini

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.

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 2022-2024 Shulamit Katzman Endowed Postdoctoral Research Fellow, Qingwen Jiang

Qingwen Jiang

GMTEC’s 2022-2024 Shulamit Katzman Endowed Postdoctoral Research Fellow is Qingwen Jiang.

Mentor: Karuna Ganesh

Project: Delineating a novel ZFP36L1/2-REST axis as a master regulator of metastatic plasticity

The regulation of phenotypic switch from a quiescent, self-renewing stem-like state to a proliferative, differentiated state is a fundamental biological process, yet the molecular mechanisms of such cell fate plasticity remain poorly understood. We have shown that in both intestinal regeneration and colorectal cancer (CRC) metastasis, quiescent regenerative progenitors transiently downregulate the mRNA levels of the transcriptional silencer REST/NSRF,in turn derepressing the expression of L1CAM and other genes required for tissue regeneration. Proliferation, restoration of epithelial structures and macrometastatic outgrowth, on the other hand, require high REST level. In neurons, RNA binding proteins ZFP36L1/2, have been shown to bind to the AU rich elements in the 3’UTR of REST and target REST mRNA for degradation. ZFP36L1/2 are required for self-renewal of early burst forming unit erythroid progenitors, and for maintenance of quiescence in lymphocytes and muscle progenitors. While ZFP36L1/2 mutations are uncommon in primary tumors, the Pan Cancer Analysis of Whole Genomes recently identified recurrent metastasis-specific deletions and truncations in ZFP36L1/2, nominating these proteins as novel metastasis-specific putative tumor suppressors in colorectal cancer. Using cBioportal, we identified ZFP36L2 truncations/deletions in 5-9% of the CRC tumors, the majority of which occur as a recurrent ZFP36L2 G144Afs*43 frameshift mutations, retaining the conserved Tis11D_N domain of unknown function while deleting the RNA binding CCCH zinc fingers. To our best knowledge, the functional significance of this novel metastasis-specific mutation hasn’t been studied. These observations support the hypothesis that ZFP36L2 is a master regulator of cell fate plasticity in intestinal epithelial progenitors, the loss of ZFP36L1/2 function impairs progenitor self-renewal and metastatic seeding, but in turn promotes proliferation. Leveraging cBioPortal data as well as genetic and biochemical approaches using patient-derived organoids and intestinal regeneration/CRC mouse models, we hope to better understand the functional consequences of ZFP36L2/REST axis in regulating cell fate plasticity.