Chemotherapy-Induced Depletion of OCT4-Positive Cancer Stem Cells in a Mouse Model of Malignant Testicular Cancer

Pierpont, Timothy M.; Lyndaker, Amy M.; Anderson, Claire; Jin, Qiming; Moore, Elizabeth S.; Roden, Jamie; Braxton, Alicia M.; Bagepalli, Lina; Kataria, Nandita; Hu, Hilary Z.; Garness, Jason; Cook, Matthew S.; Capel, Blanche; Schlafer, Donald H.; Southard, Teresa; Weiss, Robert S.

doi:10.1016/j.celrep.2017.10.078

Cited by 47 publications

(63 citation statements)

References 44 publications

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“…[ 159 ] The second is testicular cancer, which lacks detectable YAP and TAZ expression, and is interestingly also the tumor type that is most sensitive to chemotherapy. [ 160,161 ]…”

Section: Introductionmentioning

confidence: 99%

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

2020

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The transcriptional co-activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD-family co-activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy. YAP-TEAD cooperates with the RAS-induced AP-1 (FOS/JUN) transcription factor to drive tumor growth and cooperates with MRTF-SRF to promote activation of cancer-associated fibroblasts, matrix stiffening, and metastasis. The key upstream repressor of YAP/TAZ activation is the Hippo (MST1/2-LATS1/2) pathway and the key upstream activators are mechanically induced Integrin-SRC and E-cadherin-AJUBA/TRIP6/LIMD1, growth factor induced PI3K-AKT, and inflammation-induced G-protein coupled receptor (GPCR) signals, all of which antagonize the Hippo pathway. In this review, strategies to target YAP/TAZ activity in cancer are discussed along with the prospects for synergy with established pillars of cancer therapy.

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“…[ 159 ] The second is testicular cancer, which lacks detectable YAP and TAZ expression, and is interestingly also the tumor type that is most sensitive to chemotherapy. [ 160,161 ]…”

Section: Introductionmentioning

confidence: 99%

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

2020

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“…OCT4 is crucial for stem cell pluripotency and plays an important role in embryonic development. Several reports note that OCT4 also contributes to tumorigenesis and impacts cancer in a context‐dependent manner . Here, we have tested eight OCT4 mutants and identified two (OCT4FL‐K128N and OCT4FL C198R) that enhance cellular reprogramming.…”

Section: Discussion and Outlookmentioning

confidence: 94%

Cancer‐associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17

et al. 2019

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The functional consequences of cancer‐associated missense mutations are unclear for the majority of proteins. We have previously demonstrated that the activity of SOX and Pit‐Oct‐Unc (POU) family factors during pluripotency reprogramming can be switched and enhanced with rationally placed point mutations. Here, we interrogated cancer mutation databases and identified recurrently mutated positions at critical structural interfaces of the DNA‐binding domains of paralogous SOX and POU family transcription factors. Using the conversion of mouse embryonic fibroblasts to induced pluripotent stem cells as functional readout, we identified several gain‐of‐function mutations that enhance pluripotency reprogramming by SOX2 and OCT4. Wild‐type SOX17 cannot support reprogramming but the recurrent missense mutation SOX17‐V118M is capable of inducing pluripotency. Furthermore, SOX17‐V118M promotes oncogenic transformation, enhances thermostability and elevates cellular protein levels of SOX17. We conclude that the mutational profile of SOX and POU family factors in cancer can guide the design of high‐performance reprogramming factors. Furthermore, we propose cellular reprogramming as a suitable assay to study the functional impact of cancer‐associated mutations.

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“…GCNIS‐derived, type II tumours can be divided into two main histologic types, seminomatous and non‐seminomatous TGCTs, with non‐seminomatous types further grouped into embryonal carcinoma, yolk sac tumour, teratoma and choriocarcinoma (Looijenga & Oosterhuis, ; Williamson et al ., ). TGCTs are not believed to derive from a mature germ cell but rather to arise from PGCs (Oosterhuis & Looijenga, ) and hence have their origin during embryogenesis (Pierpont et al ., ). A current tumour evolution model suggests that non‐GCNIS‐derived, type I GC tumours arise in the early stages of germ cell development during PGC migration and proliferation, whereas GCNIS‐derived tumours are preceded by GCNIS cells that originate from gonadal PGCs (Cheng et al ., ; Pierce et al ., ).…”

Section: Meiotic Factors In Testicular Germ Cell Tumours: Meiosis Ormentioning

confidence: 97%

Meiotic gene activation in somatic and germ cell tumours

Feichtinger

McFarlane

2019

Andrology

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Background Germ cell tumours are uniquely associated with the gametogenic tissues of males and females. A feature of these cancers is that they can express genes that are normally tightly restricted to meiotic cells. This aberrant gene expression has been used as an indicator that these cancer cells are attempting a programmed germ line event, meiotic entry. However, work in non‐germ cell cancers has also indicated that meiotic genes can become aberrantly activated in a wide range of cancer types and indeed provide functions that serve as oncogenic drivers. Here, we review the activation of meiotic factors in cancers and explore commonalities between meiotic gene activation in germ cell and non‐germ cell cancers. Objectives The objectives of this review are to highlight key questions relating to meiotic gene activation in germ cell tumours and to offer possible interpretations as to the biological relevance in this unique cancer type. Materials and Methods PubMed and the GEPIA database were searched for papers in English and for cancer gene expression data, respectively. Results We provide a brief overview of meiotic progression, with a focus on the unique mechanisms of reductional chromosome segregation in meiosis I. We then offer detailed insight into the role of meiotic chromosome regulators in non‐germ cell cancers and extend this to provide an overview of how this might relate to germ cell tumours. Conclusions We propose that meiotic gene activation in germ cell tumours might not indicate an unscheduled attempt to enter a full meiotic programme. Rather, it might simply reflect either aberrant activation of a subset of meiotic genes, with little or no biological relevance, or aberrant activation of a subset of meiotic genes as positive tumour evolutionary/oncogenic drivers. These postulates provide the provocation for further studies in this emerging field.

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Chemotherapy-Induced Depletion of OCT4-Positive Cancer Stem Cells in a Mouse Model of Malignant Testicular Cancer

Cited by 47 publications

References 44 publications

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

Cancer‐associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17

Meiotic gene activation in somatic and germ cell tumours

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