Naomi Duggan

Although at the root of cancer are mutations that activate oncogenes and inactivate tumor suppressor genes, as well as changes in gene copy number resulting from genomic instability, there has been increased recognition that the tumor microenvironment, particularly the mechanics of the extracellular matrix (ECM), plays a key role in restraining or promoting tumor progression[1, 2]. Many studies have demonstrated the increase in ECM stiffness leads the activation of cancer­associated fibroblasts (CAF), characterized by a higher α-smooth muscle actin and larger cellular tractions. As a consequence, the intricate interplay between fibroblasts and cancer cells influences cancer cell proliferation, breaching the basement membrane during invasion, and eventually metastasis. Importantly, matrix properties have essential roles in orchestrating this crosstalk, where CAF mediates the formation of matrix fiber tracks that cancer cells use to migrate away from the tumor; however, it’s still unclear due to lack of matrix models[3]. Here, we will use highly biomimetic polyisocyanides (PIC) hydrogels with fibrous structure and nonlinear mechanics, closely mimicking the ECM in nearly all aspects[4, 5]. Our prior works have shown that PIC can respond to cellular tractions and form unique fiber tracks[6, 7]. Therefore, it emerges as an ideal matrix model to study the crosstalk between fibroblasts and cancer cells, yet fully tunable compared with natural ECM. By using advanced microscopy, we aim to visualize how the matrix mediates the force cues generated by the adjacent fibroblasts to regulate cancer cells organization and invasion. In addition, the downstream mechanotransduction pathways will be characterized to study how cancer cells process the transmitted signals, such as, typically, YAP and TAZ transcription factors, focal adhesion kinase (FAK), and Rho activity, which have cross talks with the cytoskeleton and are highly sensitive to mechanical stimuli. Lastly, this research offers the opportunity to work in a multicultural and multidisciplinary environment, providing an avenue for acquiring expertise in 3D cell culture, mechanobiology, advanced microscopy, and biomaterials. The collaborative and conducive working environment within Prof. Rocha's lab adds to the overall positive experience of being part of this research endeavor.