Abstract
Drug treatment against liver cancer has limited efficacy due to heterogeneous response among liver cancer subtypes. In addition, the functional biophysical phenotypes which arise from this heterogeneity and contribute to aggressive invasive behavior remain poorly understood. This study interrogated how heterogeneity in liver cancer subtypes contributes to differences in invasive phenotypes and drug response. Utilizing histological analysis, quantitative 2D invasion metrics, reconstituted 3D hydrogels, and bioinformatics, our study linked cytoskeletal dynamics to differential invasion profiles and drug resistance in liver cancer subtypes. We investigated cytoskeletal regulation in 2D and 3D culture environments using two liver cancer cell lines, SNU-475 and HepG2, chosen for their distinct cytoskeletal features and invasion profiles. For SNU-475 cells, a model for aggressive liver cancer, many cytoskeletal inhibitors abrogated 2D migration but only some suppressed 3D migration. For HepG2 cells, cytoskeletal inhibition did not significantly affect 3D migration but did affect proliferative capabilities and spheroid core growth. This study highlights cytoskeleton driven phenotypic variation, their consequences and coexistence within the same tumor, as well as efficacy of targeting biophysical phenotypes that may be masked in traditional screens against tumor growth.
Highlights
Drug treatment against liver cancer has limited efficacy due to heterogeneous response among liver cancer subtypes
Advances in genomics and pathology have made efforts to pinpoint the molecular mechanisms behind this heterogeneous drug resistance, the functional mechanical and biophysical phenotypes, like proliferation and invasion, which result from this heterogeneity remain poorly understood[4]
When compared to 2D culture environments, 3D environments produce tumor growth, invasion, and drug resistance profiles which more closely resemble those seen in patients and represent a clinically more relevant platform for drug testing20–22. 3D hydrogel systems such as those made of collagen capture the importance of fibrillar architecture and provide a more physiologically relevant setting for interrogating liver cancer cell dynamics
Summary
Drug treatment against liver cancer has limited efficacy due to heterogeneous response among liver cancer subtypes. This study interrogated how heterogeneity in liver cancer subtypes contributes to differences in invasive phenotypes and drug response. Components of the Rho family of small GTPases have become key drug targets for cancer therapeutics, cancer cells display heterogeneous cytoskeletal regulation and have differing responses to drug treatment[18]. Traditional drug discovery in cancer therapy has largely focused on the bulk killing of tumors, and previous studies of liver cancer have identified key somatic mutations that dictate heterogeneous drug response[19] Many of these studies focus mainly on static readouts such as live/dead assays and histological analysis and do not capture key dynamic functional behaviors which result from this heterogeneity. 3D hydrogel systems such as those made of collagen capture the importance of fibrillar architecture and provide a more physiologically relevant setting for interrogating liver cancer cell dynamics These differences attributed to cell-ECM interactions severely alter liver cancer cell response to drugs[14,21]. Assessments of 3D interactions with the ECM in conjunction with standard readouts of drug response in cancer are needed to understand how cytoskeletal inhibition differentially affects invasion dynamics of different liver cancer subtypes
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