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 2024-2024 Gerry fellow is Ines Godet.

Mentor: Joan Massagué

Project Title: Uncovering the impact of current therapies on LUAD dormant metastasis

Despite recent therapeutic advances, LUAD remains a leading cause of mortality worldwide, with most deaths attributed to metastasis. Metastasis is mediated by disseminated metastasis initiating cells (MICs) that resist multiple physical, metabolic, immune, and therapeutic barriers, and can persist in a latent state in distant sites for months to years. Eventually, MICs drive metastatic relapse, which is clinically uncurable. Adjuvant therapy seeks to prevent cancer relapse by eliminating residual MICs during the latency period. However, efforts to improve adjuvant treatments are hindered by an insufficient understanding of the molecular mechanisms supporting the long-term viability of dormant MICs. Therefore, overt metastasis could potentially be prevented by leveraging an improved understanding of residual MICs to clear them prior to metastatic outbreak. Based on our findings, I hypothesize that MICs are early-stage progenitors with the ability to enter a quiescent state that confers protection against immune surveillance and against therapies targeting growth pathways. My preliminary results confirm that the metastatic dormant ability is associated with the SOX2+ progenitor state. Furthermore, SOX2+ MICs entering a slow-cycling state in response to dormancy signals remain sensitive to killing by targeted KRAS inhibitors but contain a subpopulation that survives and resumes growth upon the removal of KRAS inhibition and dormancy signals. To expand on these findings, I will integrate models of metastatic dormancy both in vitro and in vivo, with strategies to trace and fate-map SOX2+ progenitor cells. Moreover, I will characterize the effect of current targeted and immune checkpoint inhibitors in dormant MICs. In this project I aim to define (1) the dependence of MICs on oncogenic signaling, the (2) effect of targeted therapy and immunotherapy on latent MICs, and (3) strategies to overcome potential resistance mechanisms in MICs. My ultimate goal is to delineate strategies to clear latent MICs and prevent LUAD recurrence.

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 2022-2025 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

Unlocking phenotypic plasticity and nonmutational epigenetic reprogramming are emerging hallmarks of cancer. The regulation of phenotypic switches between cell states is a fundamental biological process, yet the molecular mechanisms of such cell fate plasticity remain poorly understood. Using our pioneering single-cell profiling of synchronously resected samples from patients undergoing cancer surgery, we identified distinct lineage trajectories that are selectively favored during the progression from normal epithelium to primary tumor and metastasis within the same patients. Our bioinformatic analysis revealed that an intestinal stem cell state serves as pivotal hub bridging colon-restricted lineages to non-colon lineages during cancer progression. Through gene-module analysis, we identified that the expression of the RNA-binding protein ZFP36L2 is closely associated with a stress associated intestinal stem cell state in both the normal intestinal crypt and in primary and metastatic tumors. In neurons and immune cells, RNA-binding proteins ZFP36, ZFP36L1, and ZFP36L2 bind to AU-rich elements in the 3’UTRs of target mRNAs to mediate RNA degradation or translation regulation. ZFP36L1/2 are essential for the self-renewal of early burst-forming unit erythroid progenitors and for maintaining quiescence in lymphocytes and muscle progenitors. Leveraging patient-derived multiomic data, organoids, and intestinal regeneration/CRC mouse models, we now demonstrate that ZFP36L2 plays a crucial role in stress-induced cellular dedifferentiation during injury repair and tumor progression. Loss of ZFP36L2 function impairs progenitor regeneration and metastatic seeding – both of which require dedifferentiation into an intestinal stem cell state, while promoting proliferation and transdifferentiation. We find that ZFP36L2 forms RNA-dependent, phase-separated biomolecular condensates that are dynamically regulated during organoid regeneration and can respond to external stresses or stimuli. Mechanistically, ZFP36L2 can directly bind and regulate the decay of mRNAs containing the UAUUUA motif in their 3’UTR. Using IP-MS to delineate ZFP36L2-containing protein complexes, we unexpectedly found that ZFP36L2 also interacts with transcription factors and chromatin remodeler complexes, playing a key role in regulating the epigenetic landscape and chromatin accessibility. Using high-resolution live imaging, we also observed dynamic nuclear-cytoplasmic shuttling of ZFP36L2 condensates. Moving forward, we will focus on mechanistic dissection and explore the potential of targeting ZFP36L2, in combination with other therapies, as a treatment strategy to combat metastasis.