Investigator
University Of Otago
Deciphering Biophysical Modulation in Ovarian Cancer Cells
It has been long known that the oncogenic extracellular environment plays an indispensable role in developing and nurturing cancer cell progression and in resistance to standard treatments. However, by how much the biophysical components of tumour extracellular environment contribute to these processes is uncertain. In particular, the topographic environment is scarcely explored. The biophysical modulation of cell behaviour is primarily facilitated through mechanotransduction-associated mechanisms, including focal adhesion and Rho/ROCK signalling. Dysregulation of these pathways is commonly observed in ovarian cancer and, therefore, biophysical modulation of these mechanisms may be of great importance to ovarian cancer development and progression. In this work, aspects of the biophysical environment were explored using a bioimprinting technique. The study showed that topography-mediated substrate sensing delayed cell attachment, however, cell-cell interactions overrode the effect of topography in some cell lines, such as OVCAR-5. Also, 3D topographical cues were shown to modulate the inhibition of focal adhesion and Rho signalling, which resulted in higher MAPK activity in cells on the bioimprints. It was revealed that c-Src is vital to the biophysical modulation of cell proliferation and inhibition of c-Src could downregulate biophysically modulated MAPK activity. This study provides evidence that the biophysical extracellular environment affects key intracellular mechanisms associated with tumourigenicity in ovarian cancer cells.
Collagen I dysregulation is pivotal for ovarian cancer progression
As a principal matrisomal protein, collagen is involved in the regulation of the structural framework of extracellular matrix (ECM) and therefore is potentially crucial in determining the biophysical character of the ECM. It has been suggested that collagen architecture plays a role in ovarian cancer development, progression and therapeutic responses which led us to examine the collagen morphology in normal and cancerous ovarian tissue. Also, the behaviour of ovarian cancer cells cultured in four qualitatively different collagen gels was investigated. The results here provide evidence that collagen I morphology in the cancerous ovary is distinct from that in the normal ovary. Tumour-associated collagen I showed streams or channels of thick elongated collagen I fibrils. Moreover, fibril alignment was significantly more prevalent in endometrioid and clear cell cancers than other ovarian cancer subtypes. In this work, for the first-time collagen I architecture profiling (CAP) was introduced using histochemical staining, which distinguished between the collagen I morphologies of ovarian cancer subtypes. Immunohistochemical examination of ovarian normal and cancerous tissues also supported the notion that focal adhesion and Rho signalling are upregulated in ovarian cancers, especially in the high-grade serous tumours, as indicated by higher expression of p-FAK and p190RhoGEF. The results also support the concept that collagen I architecture, which might be collagen I concentration-dependent, influences proliferation in ovarian cancer cells. The study provides evidence that modification of collagen I architecture integrity is associated with ovarian cancer development and therapeutic responses.
