Force of nature: mechanical regulation of cancer plasticity

The Rosalind and Morris Goodman Cancer Institute Frontiers in Cancer Research Lecture Series is pleased to welcome Miranda V. Hunter, Ph.D, Postdoctoal Fellow, Memorial Sloan Kettering Cancer Center.

The seminar will take place on Monday, April 7, 2025 at 2:00pm in the GCI Karp Room 501.

Abstract:
I am a cell biologist studying how cancer cells survive and thrive in challenging environments. My research aims to define how tumor cells sense, respond, and adapt to different mechanical environments, and how these mechanisms enable tumor progression. To this end, I will discuss my work applying spatial transcriptomics, mechanical perturbations, and quantitative microscopy to a zebrafish model of melanoma. This approach revealed that cells at the tumor border are reprogrammed to drive tumor invasion, adopting a novel “interface” cell state. I found that in vivo, actively invading interface cells are exposed to significant compressive stress as they escape the primary tumor and colonize neighboring tissues. By mechanically manipulating melanoma cells and profiling their epigenetic, transcriptional, and morphometric states, I showed that mechanical force triggers establishment of the interface identity and drives melanoma invasion. Tumor cell compression induces rapid remodeling of cytoskeletal and nuclear architecture, reinforcing the cell against mechanical stress. Compression-induced nuclear stiffening promotes upregulation of the chromatin modifier HMGB2, leading to changes in chromatin architecture and gene expression that cause the melanoma cell to become more invasive and drug resistant. My work demonstrates that mechanical force has significant influence on the transcriptional, epigenetic, and phenotypic states of the tumor cell, and provides a mechanism to the longstanding question of how the cellular microenvironment triggers changes in cancer behavior.

Bio:
Miranda completed her BSc in Anatomy and Cell Biology at McGill in 2012. She then moved to the University of Toronto for a PhD in Cell and Systems Biology with Rodrigo Fernandez-Gonzalez, studying how cell polarity directs embryonic wound repair in Drosophila. She joined the lab of Richard White at Sloan Kettering in 2018, where she has been using a zebrafish model of melanoma to study the influence of the cellular and mechanical microenvironments on cancer invasion and plasticity. Her work has been funded by fellowships from NSERC, CIHR, CRS, and most recently a K99 award from the National Cancer Institute.