Mechanobiology of cancer and stem cells

Cancer has traditionally been regarded as a genetic disease in which mutations or changes in expression of specific genes drives uncontrolled cell growth.  Over the past two decades, it has become clear that many aspects of tumor progression are also strongly influenced by physical interactions between tumor cells and the tissue microenvironment.  For example, tumor cells undergo profound shape changes and absorb enormous mechanical stresses as they invade tissue.  These force-based interactions can drive both oncogenic signaling and genomic instability. For over a decade, we have been investigating mechanobiological regulation of cancer in the context of glioblastoma (GBM), the most common and malignant form of brain cancer. GBM has an average prognosis of less than 18 months after diagnosis and is characterized by dramatically altered brain biomechanics and diffuse infiltration of tumor cells through the brain. In 2009, we showed that changes in extracellular matrix (ECM) stiffness can strongly control GBM cell shape, migration, and proliferation (Ulrich et al., Cancer Research 2009).  Later, we extended these findings to primary, patient-derived GBM stem/initiating cells and showed that manipulation of force-sensing pathways could sensitize these cells to ECM mechanical signals that suppress motility and dramatically reduce invasion in vivo (Wong et al., Cancer Research 2015).   Our GBM studies have also given us the opportunity to investigate relatively unexplored aspects of cellular mechanobiology, such as how invasive cell motility is governed by non-integrin ECM receptors such as CD44 (Kim and Kumar, Molecular Cancer Research 2014) and cellular confinement (Pathak and Kumar, PNAS 2012).

In increasingly related work, we have been exploring how mechanical and other biophysical signals can be exploited to control the self-renewal and differentiation of “normal” neural stem cells (NSCs).  Much of our work has focused on hippocampal adult neural stem cells (NSCs), which generate neurons throughout life and are thought to play important roles in learning and memory.   We have discovered that ECM stiffness-based cues act through specific Rho GTPases to regulate NSC lineage commitment and maturation (Keng, DeJuan et al, Stem Cells 2011).  We have also discovered new connections between mechanotransductive signaling mediated by the Hippo pathway and canonical neurogenic

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signaling mediated through Wnt/β-catenin-based signaling (Rammenssee, Kang et al., Stem Cells 2016).  We have also explored analogous signaling events in pluripotent stem cells of therapeutic interest, including embryonic and induced pluripotent stem cells (Keung et al., Integrative Biology 2012).  In addition to uncovering new insights into stem cell biology, our findings are expected to prove useful in the design of systems for the expansion, differentiation, and delivery of stem cells.