Application of Cancer Cell Reprogramming Technology to Human Cancer Research

Pan, Xiu-Yang; Tsai, Ming‐Ho; Wuputra, Kenly; Ku, Chia‐Chen; Lin, Wen‐Hsin; Lin, Ying‐Chu; Kishikawa, Shotaro; Noguchi, Michiya; Saito, Shoji; Lin, Chang-Sheng; Yokoyama, Kazunari K.

doi:10.21873/anticanres.11703

Cited by 15 publications

(11 citation statements)

References 63 publications

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“…In this study, we report what we have learned about both the failure and the requirements for successful creation of normal epiblast-emulating cells (i.e., hiPSCs) from ATCs (the first from this virulently malignant cancer), suggesting that cancer-derived hiPSCs may, indeed, provide a tool for better understanding and targeting the earliest origins and progression of tissue-specific cancers ( Camara et al., 2016 ; Pan et al., 2017 )—an assay we have termed reprogram enablement. Furthermore, ICM-like cells derived from neoplastic cells, although ostensibly normal, do maintain—in a quiescent manner poised to be experimentally “unleashed”—the oncogenic potential of the starting cancer cells, enhancing this tool's utility.…”

Section: Discussionmentioning

confidence: 99%

“Reprogram Enablement” as an Assay for Identifying Early Oncogenic Pathways by Their Ability to Allow Neoplastic Cells to Reacquire an Epiblast State

et al. 2020

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Summary One approach to understanding how tissue-specific cancers emerge is to determine the requirements for “reprograming” such neoplastic cells back to their developmentally normal primordial pre-malignant epiblast-like pluripotent state and then scrutinizing their spontaneous reconversion to a neoplasm, perhaps rendering salient the earliest pivotal oncogenic pathway(s) (before other aberrations accumulate in the adult tumor). For the prototypical malignancy anaplastic thyroid carcinoma (ATC), we found that tonic RAS reduction was obligatory for reprogramming cancer cells to a normal epiblast-emulating cells, confirmed by changes in their transcriptomic and epigenetic profiles, loss of neoplastic behavior, and ability to derive normal somatic cells from their “epiblast organoids.” Without such suppression, ATCs re-emerged from the clones. Hence, for ATC, RAS inhibition was its “reprogram enablement” (RE) factor. Each cancer likely has its own RE factor; identifying it may illuminate pre-malignant risk markers, better classifications, therapeutic targets, and tissue-specification of a previously pluripotent, now neoplastic, cell.

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Section: Discussionmentioning

confidence: 99%

“Reprogram Enablement” as an Assay for Identifying Early Oncogenic Pathways by Their Ability to Allow Neoplastic Cells to Reacquire an Epiblast State

et al. 2020

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“…Suitable reconditioning of microenvironments may reprogram phenotypically plastic metastatic tumor cells toward a more benign phenotype (14). The extent of downregulated tumor suppressor genes in tumor and stromal cells following oncogenic events, decisively determine the tumor phenotype (22,37). Adult skin epithelium when exposed to different mutational and non-mutational insults develops dynamic cellular behavior for returning to a homeostatic state (16,35).…”

Section: Multiscale Modeling Of Communication Processes In Tumor Systemsmentioning

confidence: 99%

Anakoinosis: Correcting Aberrant Homeostasis of Cancer Tissue—Going Beyond Apoptosis Induction

et al. 2019

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The current approach to systemic therapy for metastatic cancer is aimed predominantly at inducing apoptosis of cancer cells by blocking tumor-promoting signaling pathways or by eradicating cell compartments within the tumor. In contrast, a systems view of therapy primarily considers the communication protocols that exist at multiple levels within the tumor complex, and the role of key regulators of such systems. Such regulators may have far-reaching influence on tumor response to therapy and therefore patient survival. This implies that neoplasia may be considered as a cell non-autonomous disease. The multi-scale activity ranges from intra-tumor cell compartments, to the tumor, to the tumor-harboring organ to the organism. In contrast to molecularly targeted therapies, a systems approach that identifies the complex communications networks driving tumor growth offers the prospect of disrupting or "normalizing" such aberrant communicative behaviors and therefore attenuating tumor growth. Communicative reprogramming, a treatment strategy referred to as anakoinosis, requires novel therapeutic instruments, so-called master modifiers to deliver concerted tumor growth-attenuating action. The diversity of biological outcomes following pro-anakoinotic tumor therapy, such as differentiation, trans-differentiation, control of tumor-associated inflammation, etc. demonstrates that long-term tumor control may occur in multiple forms, inducing even continuous complete remission. Accordingly, pro-anakoinotic therapies dramatically extend the repertoire for achieving tumor control and may activate apoptosis pathways for controlling resistant metastatic tumor disease and hematologic neoplasia.

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“…These aspects make the efficiency of generating iPSCs from cancer cells low (Kim and Zaret, 2015). Despite the low efficiency, there are several examples of iPSCs generated from cancer cells (Pan et al., 2017), mainly from established cancer cell lines (Bernhardt et al., 2017) and much less common from primary tumors (Kim et al., 2013, Kotini et al., 2017). However, the generation of iPSCs from benign tumors or pre-malignant lesions has been less explored (Papapetrou, 2016).…”

Section: Introductionmentioning

confidence: 99%

Reprogramming Captures the Genetic and Tumorigenic Properties of Neurofibromatosis Type 1 Plexiform Neurofibromas

et al. 2019

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SummaryNeurofibromatosis type 1 (NF1) is a tumor predisposition genetic disease caused by mutations in the NF1 tumor suppressor gene. Plexiform neurofibromas (PNFs) are benign Schwann cell (SC) tumors of the peripheral nerve sheath that develop through NF1 inactivation and can progress toward a malignant soft tissue sarcoma. There is a lack of non-perishable model systems to investigate PNF development. We reprogrammed PNF-derived NF1(−/−) cells, descendants from the tumor originating cell. These NF1(−/−)-induced pluripotent stem cells (iPSCs) captured the genomic status of PNFs and were able to differentiate toward neural crest stem cells and further to SCs. iPSC-derived NF1(−/−) SCs exhibited a continuous high proliferation rate, poor myelination ability, and a tendency to form 3D spheres that expressed the same markers as their PNF-derived primary SC counterparts. They represent a valuable model to study and treat PNFs. PNF-derived iPSC lines were banked for making them available.

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Application of Cancer Cell Reprogramming Technology to Human Cancer Research

Cited by 15 publications

References 63 publications

“Reprogram Enablement” as an Assay for Identifying Early Oncogenic Pathways by Their Ability to Allow Neoplastic Cells to Reacquire an Epiblast State

“Reprogram Enablement” as an Assay for Identifying Early Oncogenic Pathways by Their Ability to Allow Neoplastic Cells to Reacquire an Epiblast State

Anakoinosis: Correcting Aberrant Homeostasis of Cancer Tissue—Going Beyond Apoptosis Induction

Reprogramming Captures the Genetic and Tumorigenic Properties of Neurofibromatosis Type 1 Plexiform Neurofibromas

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