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Bioinformatics, Computational and Systems Biology

Bioinformatics, Computational and Systems Biology - Poster Session D

Poster A4 - MICAL2 expression promotes invasion and metastasis by cell autonomous and non-cell autonomous mechanisms in Pancreatic Cells

Friday, October 25, 2024
3:30 PM – 4:30 PM EST
Location: Exhibit Hall E, F & G

Introduction:  Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer due to its propensity for early metastasis. MICAL (microtubule-associated monooxygenase) proteins are one of the highly expressed genes in PDAC) that induce actin depolymerization, but despite this knowledge, the holistic impact of MICAL2 on cytoskeleton states of cells remains a major question. Here, we have taken a multi-scale modeling approach to connect cytoskeletal gene expression programs exhibited by pancreatic cancer cells to connect biochemical signaling networks and extracellular matrix conditions that regulate the cellular mechanical state. This in turn is used to predict cell migration behavior.

Materials and

Methods:  We have developed a hybrid computational model to understand the biochemical and mechanical pathways associated with MICAL2 activity and its impact on cell mechanics such as cell-substrate adhesion, cell stiffness and cell migration. The model integrates MICAL2-driven changes in actin oxidation and polymerization dynamics, its effect on the ratios of cytoskeletal and nuclear concentrations of g- and f-actin, consequent MRTF-SRF-driven gene transcription, and downstream effects on cytoskeletal biochemical interactions and dynamics. The activity of key cytoskeletal elements then informs cytoskeletal mechanics which is in turn used to predict cell-environment interactions and cell migration.

Results, Conclusions, and Discussions: The model forms the basis for understanding the mechanisms via which MICAL2 overexpression affects cellular mechanical properties, cell migration and invasion in tissues, and emergent phenomena such as collective cell migration and durotaxis. The model also helps us separate the cytoskeletal and nuclear effects of MICAL2 signaling and understand transcriptional activity is required MICAL2 related cell migration and invasion. Our preliminary results using our modeling framework indicate that while MICAL2 activity confined to cytoskeletal signaling does increase cell migration, activation of SRF transcriptional factor significantly adds to the cytoskeletal changes and increased migration of cells in 3D environments.

MICAL2-dependent modulation of the cytoskeletal actin structure alters the mechanical properties of cells to promote a highly metastatic phenotype characterized by weak adhesion to other cells and ECM and decreased cell stiffness. Our model allows us to determine how the expression of MICAL2 impacts pancreatic cancer cell migration across soft and stiff substrates. Metastasis-related emergent behaviors reveal hidden collective cell migration dynamics and durotaxis in 3D environments. Eventually, an understanding of MICAL2-dependent modulation may facilitate the prediction of metastatic potential and the identification of targeted treatments.

Acknowledgements (Optional):