Personalized Medicine–Based Approach to Model Patterns of Chemoresistance and Tumor Recurrence Using Ovarian Cancer Stem Cell Spheroids

Abstract

Chemoresistant ovarian cancers grow in suspension within the ascites fluid. To screen the effect of chemotherapeutics and biologics on resistant ovarian cancers with a personalized basis, we developed a 3D hanging drop spheroid platform. We initiated spheroids with primary aldehyde dehydrogenase-positive (ALDH) CD133 ovarian cancer stem cells (OvCSC) from different patient samples and demonstrated that stem cell progeny from harvested spheroids was similar to the primary tumor. OvCSC spheroids were utilized to initiate tumors in immunodeficient mice. Drug responses to cisplatin and ALDH-targeting compound or JAK2 inhibitor determined whether the OvCSC population within the spheroids could be targeted. Cells that escaped therapy were isolated and used to initiate new spheroids and model tumor reemergence in a personalized manner. OvCSC spheroids from different patients exhibited varying and personalized responses to chemotherapeutics. Xenografts were established from OvCSC spheroids, even with a single spheroid. Distinct responses to therapy were observed in distinct primary tumor xenografts similar to those observed in spheroids. Spheroids resistant to cisplatin/ALDH inhibitor therapy had persistent, albeit lower ALDH expression and complete loss of CD133 expression, whereas those resistant to cisplatin/JAK2 inhibitor therapy were enriched for ALDH cells. Our 3D hanging drop suspension platform can be used to propagate primary OvCSCs that represent individual patient tumors effectively by differentiating and initiating tumors in mice. Therefore, our platform can be used to study cancer stem cell biology and model tumor reemergence to identify new targeted therapeutics from an effective personalized medicine standpoint..

Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

“…With this combinatory approach, it will be possible to gain a more complete picture of the cancer microenvironment and ascertain potential avenues of treatment. Additionally, non-cell factors such as chemotaxis, 130 3D culture 94,[131][132][133][134][135][136] , and hypoxia 137 should be considered for future investigations, in conjunction with mechanical cues to create a microenvironment that can more fully recapitulate in vivo conditions. The study of ovarian cancer mechanotransduction promises to improve patient treatment through future investigations that utilize designs pertinent to the specific microenvironment.…”

Cancer Stem Cells in the Personalized Therapy of Colorectal Cancer

“…Distinct responses to therapy were observed in distinct primary tumor xenografts similar to those observed in spheroids. Spheroids resistant to Cisplatin/ALDH inhibitor therapy had persistent, albeit lower ALDH expression and complete loss of CD133 expression while those resistant to cisplatin/JAK2 inhibitor therapy were enriched for ALDH+ cells [54].…”

“…measures to change biomarker expression lead to the corresponding change in treatment response. In other words, a strong association between biomarker and treatment outcome should result from a similar direct treatment effect on both, biomarker level and endpoint of therapy [54].…”

Organoid of ovarian cancer: genomic analysis and drug screening

“…The results showed that globular stem cells sustain their resistance to cisplatin/ALDH inhibitor, although the expression of ALDH is low, and that of CD133 is completely lost. However, spheres resistant to cisplatin/JAK2 inhibitors have enriched ALDH+91 cells [35]. In the above-mentioned studies, the culture of spheroids originated from the ascites in the late stage of cancer.…”