Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive forms of cancer driven by the crosstalk between cancer cells and the fibrotic tumour stroma. The cytoskeleton, the primary architectural framework of the cell, serves as the biomechanical mediator in this crosstalk by undergoing rapid structural and functional reorganisation in response to a variety of signals from the tumour stroma. In turn, the structure and dynamics of the cytoskeleton modulate intracellular transport and mechanosignalling. Understanding how biophysical cues regulate the cytoskeletal machinery is therefore paramount to design therapies to reprogram the interaction between cancer cells and their microenvironment.
Here, I explore the pharmacological regulation of cytoskeletal contractility in PDAC cells by retinoids, vitamin A derivatives shown to induce mechanical quiescence in pancreatic stellate cells. I find that targeting the retinoid acid receptor β (RAR-β) results in transcriptional repression of Myosin light chain 2, a key regulator of actomyosin contractility. This results in reduced traction force generation, invasive potential, and impaired cytoskeletal reinforcement in response to mechanical stimuli. Given their clinical success in other cancers, I propose that retinoids may be repositioned to disrupt the mechanical communication between PDAC cells and the extracellular matrix (ECM).
In the second part of this work, I use a self-assembling polypeptide platform to study the response of PDAC cells to the hallmarks of the tumour stroma: stiffness and acidosis. I report that these factors cooperate to upregulate HIF-1A through the nuclear sequestration of pVHL, an enzyme responsible for its degradation. I propose that extracellular acidosis impairs the transport of pVHL by disrupting microtubule stability through a mechanism mediated by the Rho effector diaphanous-related formin (mDia). Given the pivotal role of HIF-1A in cancer cell survival, metabolism and ECM deposition, this work highlights the cytoskeleton as a mediator in the crossroads between acidosis, mechanosignalling and cancer.