To address this knowledge gap, we applied long-term time-lapse live-cell imaging to track the cellular and nuclear dynamics of PGCCs during the development and evolution of patient-derived high-grade serous carcinoma (HGSC) organoids.Ī The workflow for labeling patient-derived HGSC cells with fluorescence markers, cell purification, organoid culture, and imaging-based studies. ĭespite our current understanding of cancer polyploidy, the role of PGCCs in malignant tumor development in a 3-dimensional (3D) tissue microenvironment has not been studied. Single PGCCs were shown to be capable of initiating tumor growth and metastasis and recapitulating properties of early embryogenesis. PGCCs have also been shown to express embryonic stemness markers. PGCCs were shown to give rise to viable daughter cells following stresses induced by irradiation, chemotherapy, a hypoxia-mimetic agent cobalt chloride (CoCl 2), cellular or viral oncogene-induced senescence, and gene mutation in leukemia cells. However, we and others have demonstrated that PGCCs are viable and capable of generating mitotically active daughter cells via amitotic mechanisms. However, the role of PGCCs in the development of malignant tumor histogenesis and evolution is largely unknown.įor a long time, PGCCs were considered non-dividing senescent cells because of their inability to execute mitosis. Increased genomic content invariably leads to the formation of PGCCs. The cancer genomic atlas projects show cancers have multiple structural defects, including polyploid genome, chromothripsis, and extrachromosomal DNA. Polyploid genomes exist in 37 to 50% of high-grade cancers. It is well known that polyploidy plays a crucial role in tumorigenesis and development. Giant cell size in cancer is commonly associated with increased genomic contents or polyploidy via whole genomic duplication or multiplication. Abnormal nuclear morphology was shown to correlate with high-level malignancy and poor prognosis in cancer patients. These nuclear abnormalities represent the most critical histologic criterion for making a cancer diagnosis. The abnormal nuclear features include nuclear pleomorphism, high nuclear to cytoplasmic (N/C) ratio, polyploid mitosis, and mononucleated or multinucleated giant cells, i.e., polyploid giant cancer cells (PGCCs). Pathologists have long observed that cancer cells exhibit abnormal nuclear morphology with increased cell size and genome copy number, commonly referred to as nuclear atypia. Our data support that PGCCs may represent a central regulator in malignant histogenesis, intratumoral heterogeneity, immune escape, and macroevolution via the de-repression of suppressed pre-embryogenic program in somatic cells. The formation of PGCCs via multiple modes of nuclear replication in the absence of cytokinesis leads to an increase in the nuclear-to-cytoplasmic (N/C) ratio and intracellular cell reproduction, which is remarkably similar to the mode of nuclear division during pre-embryogenesis. PGCCs can undergo several rounds of entosis to form complex tissue structures, termed fecundity structures. The fecundity cells can be decellularized to facilitate nuclear fusion and synchronized with other nuclei for subsequent nuclear replication. At the cellular level, the development of PGCCs was associated with forming transient intracellular cells, termed fecundity cells. PGCCs underwent restitution multipolar endomitosis, nuclear fragmentation, and micronuclei formation to increase nuclear contents and heterogeneity. Single cells underwent traditional mitosis to generate tissue with uniform nuclear size, while others formed PGCCs via asymmetric mitosis, endoreplication, multipolar endomitosis, nuclear fusion, and karyokinesis without cytokinesis. To understand how malignant tumors develop, we tracked cell membrane, nuclear membrane, spindle, and cell cycle dynamics in polyploid giant cancer cells (PGCCs) during the formation of high-grade serous carcinoma organoids using long-term time-lapse imaging.
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