There is growing appreciation of the importance of the mechanical properties of the tumor microenvironment on disease progression. However, the role of extracellular matrix (ECM) stiffness and cellular mechanotransduction in epithelial ovarian cancer (EOC) is largely unknown. Here, we investigated the effect of substrate rigidity on various aspects of SKOV3 human EOC cell morphology and migration. Young’s modulus values of normal mouse peritoneum, a principal target tissue for EOC metastasis, were determined by atomic force microscopy (AFM) and hydrogels were fabricated to mimic these values. We find that cell spreading, focal adhesion formation, myosin light chain phosphorylation, and cellular traction forces all increase on stiffer matrices. Substrate rigidity also positively regulates random cell migration and, importantly, directional increases in matrix tension promote SKOV3 cell durotaxis. Matrix rigidity also promotes nuclear translocation of YAP1, an oncogenic transcription factor associated with aggressive metastatic EOC. Furthermore, disaggregation of multicellular EOC spheroids, a behavior associated with dissemination and metastasis, is enhanced by matrix stiffness through a mechanotransduction pathway involving ROCK, actomyosin contractility, and FAK. Finally, this pattern of mechanosensitivity is maintained in highly metastatic SKOV3ip.1 cells. These results establish that the mechanical properties of the tumor microenvironment may play a role in EOC metastasis.

There is growing appreciation of the importance of the mechanical properties of the tumor microenvironment on disease progression. However, the role of extracellular matrix (ECM) stiffness and cellular mechanotransduction in epithelial ovarian cancer (EOC) is largely unknown. Here, we investigated the effect of substrate rigidity on various aspects of SKOV3 human EOC cell morphology and migration. Young's modulus values of normal mouse peritoneum, a principal target tissue for EOC metastasis, were determined by atomic force microscopy (AFM) and hydrogels were fabricated to mimic these values. We find that cell spreading, focal adhesion formation, myosin light chain phosphorylation, and cellular traction forces all increase on stiffer matrices. Substrate rigidity also positively regulates random cell migration and, importantly, directional increases in matrix tension promote SKOV3 cell durotaxis. Matrix rigidity also promotes nuclear translocation of YAP1, an oncogenic transcription factor associated with aggressive metastatic EOC. Furthermore, disaggregation of multicellular EOC spheroids, a behavior associated with dissemination and metastasis, is enhanced by matrix stiffness through a mechanotransduction pathway involving ROCK, actomyosin contractility, and FAK. Finally, this pattern of mechanosensitivity is maintained in highly metastatic SKOV3ip.1 cells. These results establish that the mechanical properties of the tumor microenvironment may play a role in EOC metastasis.peer-reviewed)

The advent of multi-gene panels has changed the landscape of cancer genetic testing. Multi-gene panel testing utilizing nextgeneration sequencing is now widely ordered by genetics specialists as it allows for more efficient testing when there are multiple genes associated with similar cancer types. This expanded testing has led to the detection of pathogenic variants/likely pathogenic variants (PVs/LPVs) in genes previously unavailable for clinical testing, including the moderate penetrance breast cancer genes,

Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) have distinct genetic etiologies but overlapping phenotypes. Genetic testing may be required for accurate diagnosis, which is critical for determining prognosis, screening recommendations, and treatment options. Our study aimed to compare the efficacy of germline-only versus paired (germline and tumor) genetic testing for clarifying the diagnosis in patients with features of NF2 and SWN. We performed a retrospective chart review of patients referred for NF2/SWN genetic testing at Massachusetts General Hospital from 2015 to 2020. Logistic regression analysis was performed to assess factors associated with diagnostic clarity. Overall, paired testing had 8.5 times greater odds of providing diagnostic clarity than germline-only testing (p < 0.01). Among patients who underwent paired testing, those who had analysis of two or more tumors had the greatest likelihood of gaining diagnostic clarity, with odds 13 times greater than patients who underwent germline-only testing (p < 0.01). Paired testing with analysis of one tumor significantly increased the odds of diagnostic clarity over germline-only testing by a factor of 6.5 (p < 0.01). These results have implications for genetic testing strategies and counseling patients about genetic testing utility. They also support the routine use of testing in individuals with suspected NF2 or SWN and improved insurance coverage for paired testing within this population.