Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, has an extremely high mortality rate, with a 5-year survival rate less than 7%. Deeper understanding of the disease is urgently needed to elucidate disease mechanism that can lead to better clinical solutions.

Our lab aims to dissect the progression of PDAC from mechanobiology perspective: the interplay between tumor cells and their physical environment can provide us biological insights on novel drug targets.

PDAC is highly metastatic, what is the impact of migration on cellular phenotypes?

During metastasis, cancer cells need to migrate and squeeze through many constrictions, imposed by extracellular matrix, crowded cell environment, endothelial cells layer and capillaries. Recently, we showed that constricted migration damages the nucleus and DNA, leading to genomic aberrations (Irianto et al. 2017). However, mechanisms behind this genomic changes are still unknown. Does it play a role in PDAC genomic heterogeneity?

Nuclear blebbing post-constricted migration.A549 expressing GFP-lamin A, migrating through 3 um Transwell membrane. (Red = pre-migration, Green = post-migration)
Nuclear protein segregation within constriction.Micropipette aspiration of U2OS with GFP-53BP1.

Desmoplasia causes significant pancreatic stiffening in PDAC progression.

Microenvironment stiffness dictates cell adhesions and contractility, which is upstream of many mechanotransduction pathways. What is the role of microenvironment stiffening in PDAC progression? Here we will use both 2D and 3D cultures of both patient derived cells and multiple lines to answer the question.

Organoid culture of patient derived PDAC cells and other PDAC cell lines.

Genomic heterogeneity

Genome instability and mutation is an enabling characteristics of cancer, and such genomic aberrations can either inactivate tumor suppressor genes or activate oncogenes. Genomic heterogeneity in PDAC has been reported by multiple studies, but again mechanisms is unknown. Can we tease out potential mechanisms from the mutation signatures? Here, we will utilize the genomic algorithms to analyze our whole genome sequencing data together with the publicly available PDAC genomic data.

Florida State UniversityCollege of Medicine
Department of Biomedical Sciences
© Irianto Lab, 2018
by Jerome Irianto