Human Pluripotent Stem Cell-Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis.

Abstract:

:Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here, we generated a robust human cell model of LAM by reprogramming TSC2 mutation-bearing fibroblasts from a patient with both tuberous sclerosis complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSC), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/- mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributes to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM that can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM. Cancer Res; 77(20); 5491-502. ©2017 AACR.

journal_name

Cancer Res

journal_title

Cancer research

authors

Julian LM,Delaney SP,Wang Y,Goldberg AA,Doré C,Yockell-Lelièvre J,Tam RY,Giannikou K,McMurray F,Shoichet MS,Harper ME,Henske EP,Kwiatkowski DJ,Darling TN,Moss J,Kristof AS,Stanford WL

doi

10.1158/0008-5472.CAN-17-0925

subject

Has Abstract

pub_date

2017-10-15 00:00:00

pages

5491-5502

issue

20

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-17-0925

journal_volume

77

pub_type

杂志文章
  • Characterization of a unique nuclear estrogen-binding component in an estrogen-responsive mouse Leydig cell tumor.

    abstract::An estrogen-responsive mouse Leydig cell tumor line (Tumor 124958) has been shown to contain only a low-affinity binder for estradiol in the cytosol fraction. This differed from the putative estrogen receptor in terms of its hormone-binding specificity as well as affinity. In addition, the possibility that an estrogen...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Maeda Y,Sato B,Noma K,Kishimoto S,Koizumi K,Aono T,Matsumoto K

    更新日期:1983-09-01 00:00:00

  • EZH2 is essential for glioblastoma cancer stem cell maintenance.

    abstract::Overexpression of the polycomb group protein enhancer of zeste homologue 2 (EZH2) occurs in diverse malignancies, including prostate cancer, breast cancer, and glioblastoma multiforme (GBM). Based on its ability to modulate transcription of key genes implicated in cell cycle control, DNA repair, and cell differentiati...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-09-1622

    authors: Suvà ML,Riggi N,Janiszewska M,Radovanovic I,Provero P,Stehle JC,Baumer K,Le Bitoux MA,Marino D,Cironi L,Marquez VE,Clément V,Stamenkovic I

    更新日期:2009-12-15 00:00:00

  • Receptor and centriole pathways of steroid action in normal and neoplastic cells.

    abstract::An experimental system designed for tracing the estradiol kinetics in target cells by specific antibodies has been applied to human breast cancer. Several major defects of the estradiol receptor mechanism have been demonstrated. The detected changes (lack of cytoplasmic receptors, impaired nuclear transfer of estradio...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Nenci I

    更新日期:1978-11-01 00:00:00

  • Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues.

    abstract::We examined mutations in BRAF exons 11 and 15 and N-RAS exons 2 and 3, in 77 metastatic melanoma cases and 11 melanoma cell lines. Significant differences in the mutation rates observed at different metastatic sites could not be detected. The most frequent mutation, the V599E amino acid substitution in BRAF exon 15, w...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Gorden A,Osman I,Gai W,He D,Huang W,Davidson A,Houghton AN,Busam K,Polsky D

    更新日期:2003-07-15 00:00:00

  • Fatty acid composition transport and metabolism in doxorubicin-sensitive and-resistant rat glioblastoma cells.

    abstract::We have studied the lipid composition and the acyl group composition, transport, and metabolism of doxorubicin-sensitive and -resistant rat glioblastoma cells in monolayer cultures (C6 clone). No difference in lipid composition was evidenced; the acyl group composition was, in contrast, highly modified in resistant ce...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Vrignaud P,Montaudon D,Londos-Gagliardi D,Robert J

    更新日期:1986-07-01 00:00:00

  • Host-mediated therapeutic effects produced by appropriately timed administration of bleomycin on a rat fibrosarcoma.

    abstract::The timing of bleomycin (BLM) administration after KMT-17 tumor inoculation was found to be important for optimizing its therapeutic effect on tumor-bearing rats. A remarkable therapeutic effect was observed when BLM (5 mg/kg/day) was administered i.p. for 5 days from the eighth day after tumor inoculation (Day 8 to D...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Morikawa K,Hosokawa M,Hamada J,Sugawara M,Kobayashi H

    更新日期:1985-04-01 00:00:00

  • High basal nuclear levels of Nrf2 in acute myeloid leukemia reduces sensitivity to proteasome inhibitors.

    abstract::Proteasome inhibitors such as bortezomib exhibit clinical efficacy in multiple myeloma, but studies in acute myeloid leukemia (AML) have been disappointing to date. The apparent failure in AML likely reflects a lack of biological understanding that might clarify applications of proteosome inhibitors in this disease. H...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-10-3018

    authors: Rushworth SA,Bowles KM,MacEwan DJ

    更新日期:2011-03-01 00:00:00

  • An osteoprotegerin-like peptidomimetic inhibits osteoclastic bone resorption and osteolytic bone disease in myeloma.

    abstract::Multiple myeloma is a B-cell malignancy characterized by the uncontrolled growth of plasma cells in the bone marrow and the development of osteolytic bone disease. Myeloma cells express the receptor activator of nuclear factor kappaB ligand (RANKL), induce RANKL expression in the bone marrow, and down-regulate express...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-06-1287

    authors: Heath DJ,Vanderkerken K,Cheng X,Gallagher O,Prideaux M,Murali R,Croucher PI

    更新日期:2007-01-01 00:00:00

  • Internucleosomal cleavage and chromosomal degradation by bleomycin and phleomycin in yeast.

    abstract::Native chromosomal structure, breakage, and overall degradation were studied following the reaction of whole cells with the anticancer drug bleomycin and structurally related phleomycin. Electrophoretic analyses of cellular DNA established that phleomycin was more reactive with DNA than equimolar bleomycin in the rang...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Moore CW

    更新日期:1988-12-01 00:00:00

  • Pattern of antioxidant and DNA repair gene expression in normal airway epithelium associated with lung cancer diagnosis.

    abstract::In previous studies, we reported that key antioxidant and DNA repair genes are regulated differently in normal bronchial epithelial cells of lung cancer cases compared with non-lung cancer controls. In an effort to develop a biomarker for lung cancer risk, we evaluated the transcript expressions of 14 antioxidant, DNA...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-09-1568

    authors: Blomquist T,Crawford EL,Mullins D,Yoon Y,Hernandez DA,Khuder S,Ruppel PL,Peters E,Oldfield DJ,Austermiller B,Anders JC,Willey JC

    更新日期:2009-11-15 00:00:00

  • Increased expression of cyclooxygenase-2 protein in 4-nitroquinoline-1-oxide-induced rat tongue carcinomas and chemopreventive efficacy of a specific inhibitor, nimesulide.

    abstract::Expression of cyclooxygenase (COX)-2 protein in 4-nitroquinoline-1-oxide (4-NQO)-induced rat tongue lesions and the postinitiation chemopreventive potential of a selective COX-2 inhibitor, nimesulide (NIM), were examined in Fischer 344 male rats. NIM was administered in the diet at doses of 150, 300, and 600 ppm for 1...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Shiotani H,Denda A,Yamamoto K,Kitayama W,Endoh T,Sasaki Y,Tsutsumi N,Sugimura M,Konishi Y

    更新日期:2001-02-15 00:00:00

  • Presence of RNA in the nucleoprotein complex spontaneously released by human lymphocytes and frog auricles in culture.

    abstract::Cell systems as different as normal human blood lymphocytes and frog auricles release spontaneously a nucleoprotein complex in their culture medium. This release seems to be an active mechanism that is unrelated to cell death. The presence of RNA in this complex is demonstrated. The amount of extracellular RNA is regu...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Stroun M,Anker P,Beljanski M,Henri J,Lederrey C,Ojha M,Maurice PA

    更新日期:1978-10-01 00:00:00

  • Decrease in susceptibility toward induction of apoptosis and alteration in G1 checkpoint function as determinants of resistance of human lung cancer cells against the antisignaling drug UCN-01 (7-Hydroxystaurosporine).

    abstract::7-Hydroxystaurosporine (UCN-01) is a protein kinase inhibitor that is under development as an anticancer agent in the United States and Japan. Long-term exposure of human A549 non-small cell lung cancer cells to UCN-01 furnished cells (A549/UCN) with acquired resistance against UCN-01. In this study, the sensitivity o...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Sugiyama K,Akiyama T,Shimizu M,Tamaoki T,Courage C,Gescher A,Akinaga S

    更新日期:1999-09-01 00:00:00

  • Effect of heterogeneity of carcinoembryonic antigen on liver cell membrane binding and its kinetics of removal from circulation.

    abstract::Carcinoembryonic antigen (CEA) is a glycoprotein metabolized primarily by the liver. Subcellular fractions of rat liver were examined for CEA binding activity. Hepatocyte plasma membrane and microsome fractions bound CEA, and this binding shared the calcium requirement, neuraminidase sensitivity, and carbohydrate spec...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Byrn RA,Medrek P,Thomas P,Jeanloz RW,Zamcheck N

    更新日期:1985-07-01 00:00:00

  • Tumor-derived osteopontin suppresses antitumor immunity by promoting extramedullary myelopoiesis.

    abstract::Extramedullary myelopoiesis occurs commonly in tumor-bearing animals and is known to lead to accumulation of peripheral myeloid-derived suppressor cells (MDSC), which play an important role in immune escape. However, the cellular and molecular mechanisms by which tumors induce extramedullary myelopoiesis are poorly un...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-14-1482

    authors: Kim EK,Jeon I,Seo H,Park YJ,Song B,Lee KA,Jang Y,Chung Y,Kang CY

    更新日期:2014-11-15 00:00:00

  • Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer.

    abstract::To examine genetic instability during carcinogenesis, we screened 171 carcinomas of the breast, liver, proximal colon, stomach, pancreas, uterine cervix, and ovary for replication error at four microsatellite marker loci on chromosome 2, 3, and 17. A significantly high incidence of genetic instability was observed in ...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Han HJ,Yanagisawa A,Kato Y,Park JG,Nakamura Y

    更新日期:1993-11-01 00:00:00

  • Quantitative interlake comparison of thyroid pathology in Great Lakes coho (Oncorhynchus kisutch) and chinook (Oncorhynchus tschawytscha) salmon.

    abstract::Coho salmon (Oncorhynchus kisutch) and chinook salmon (Oncorhynchus tshawytscha) from Lakes Ontario, Michigan, Erie, or Huron were found to suffer epizootics of thyroid hyperplasia and goiters which appeared to have an environmental etiology. There were 13-fold differences in goiter prevalence within the Great Lakes, ...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Moccia RD,Leatherland JF,Sonstegard RA

    更新日期:1981-06-01 00:00:00

  • Prevention of both direct and cross-priming of antitumor CD8+ T-cell responses following overproduction of prostaglandin E2 by tumor cells in vivo.

    abstract::Defects in antitumor immune responses have been associated with increased release of prostaglandin E(2) (PGE(2)) as a result of overexpression of cyclooxygenase (COX)-2 by tumors. In this report, we examine the effects of PGE(2) on antitumor CD8(+) T-cell responses generated both by cross-presenting dendritic cells an...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-08-1060

    authors: Ahmadi M,Emery DC,Morgan DJ

    更新日期:2008-09-15 00:00:00

  • Cigarette smoke induces DNA deletions in the mouse embryo.

    abstract::Cigarette smoking causes cancer and DNA mutations. However, long-term chronic exposure to smoke is believed to be necessary for carcinogenesis. Here, we investigate the relationship between short-term exposure to smoke and the frequency of deletions in the mouse embryo. Deletions and other genome rearrangements are as...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Jalili T,Murthy GG,Schiestl RH

    更新日期:1998-06-15 00:00:00

  • miR-182-5p Induced by STAT3 Activation Promotes Glioma Tumorigenesis.

    abstract::Malignant glioma is an often fatal type of cancer. Aberrant activation of STAT3 leads to glioma tumorigenesis. STAT3-induced transcription of protein-coding genes has been extensively studied; however, little is known about STAT3-regulated miRNA gene transcription in glioma tumorigenesis. In this study, we found that ...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-15-3073

    authors: Xue J,Zhou A,Wu Y,Morris SA,Lin K,Amin S,Verhaak R,Fuller G,Xie K,Heimberger AB,Huang S

    更新日期:2016-07-15 00:00:00

  • High serum iron is associated with increased cancer risk.

    abstract::Epidemiologic studies linking high serum iron with cancer risks are limited and inconclusive, despite evidence implicating body iron in human carcinogenesis. A cohort of 309,443 adults in Taiwan who had no history of cancer had serum iron levels tested at the time of recruitment (1997-2008). Initially measured iron le...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-14-0360

    authors: Wen CP,Lee JH,Tai YP,Wen C,Wu SB,Tsai MK,Hsieh DP,Chiang HC,Hsiung CA,Hsu CY,Wu X

    更新日期:2014-11-15 00:00:00

  • Effects of tocopherol (vitamin E) acid succinate on morphological alterations and growth inhibition in melanoma cells in culture.

    abstract::The effects of various forms of tocopherol (vitamin E) on the growth and differentiation of mouse melanoma (B-16) and mouse fibroblast (L-cells) cells in culture were studied. D-alpha-tocopherol acid succinate induced morphological alterations and growth inhibition in melanoma cells. When vitamin E acid succinate was ...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Prasad KN,Edwards-Prasad J

    更新日期:1982-02-01 00:00:00

  • Multimodality therapy with a replication-conditional herpes simplex virus 1 mutant that expresses yeast cytosine deaminase for intratumoral conversion of 5-fluorocytosine to 5-fluorouracil.

    abstract::Infection of tumor cells by herpes simplex virus 1 (HSV-1) results in cell destruction and production of progeny virion in a process referred to as viral oncolysis. In this study, an HSV-1 mutant (HSV1yCD) was engineered such that the viral ribonucleotide reductase gene is disrupted by sequences encoding yeast cytosin...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Nakamura H,Mullen JT,Chandrasekhar S,Pawlik TM,Yoon SS,Tanabe KK

    更新日期:2001-07-15 00:00:00

  • The octamer binding transcription factor Oct-1 is a stress sensor.

    abstract::The POU-domain transcription factor Oct-1 is widely expressed in adult tissues and has been proposed to regulate a large group of target genes. Microarray expression profiling was used to evaluate gene expression changes in Oct-1-deficient mouse fibroblasts. A number of genes associated with cellular stress exhibited ...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-05-2399

    authors: Tantin D,Schild-Poulter C,Wang V,Haché RJ,Sharp PA

    更新日期:2005-12-01 00:00:00

  • Chemoprevention of spontaneous intestinal adenomas in the Apc Min mouse model by the nonsteroidal anti-inflammatory drug piroxicam.

    abstract::C57BL/6J-Min/+mice (n = 56), heterozygous for a nonsense mutation in the Apc gene, were randomized at weaning to seven groups, including groups treated with piroxicam at 0, 50, 100, and 200 ppm in the AIN93G diet. After only 6 weeks of treatment, intestinal adenomas and aberrant crypt foci were counted, and serum leve...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Jacoby RF,Marshall DJ,Newton MA,Novakovic K,Tutsch K,Cole CE,Lubet RA,Kelloff GJ,Verma A,Moser AR,Dove WF

    更新日期:1996-02-15 00:00:00

  • Acidity generated by the tumor microenvironment drives local invasion.

    abstract::The pH of solid tumors is acidic due to increased fermentative metabolism and poor perfusion. It has been hypothesized that acid pH promotes local invasive growth and metastasis. The hypothesis that acid mediates invasion proposes that H(+) diffuses from the proximal tumor microenvironment into adjacent normal tissues...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-12-2796

    authors: Estrella V,Chen T,Lloyd M,Wojtkowiak J,Cornnell HH,Ibrahim-Hashim A,Bailey K,Balagurunathan Y,Rothberg JM,Sloane BF,Johnson J,Gatenby RA,Gillies RJ

    更新日期:2013-03-01 00:00:00

  • DNA strand breaks induced in human T-lymphocytes by the combination of deoxyadenosine and deoxycoformycin.

    abstract::There is a progressive loss of human T-lymphocyte viability upon incubation with deoxycoformycin, an adenosine deaminase inhibitor, and low concentrations of deoxyadenosine (drug concentration that reduced cell count at 48 hr after initiation to 50% of value for untreated control culture, less than 1 microM). The loss...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Brox L,Ng A,Pollock E,Belch A

    更新日期:1984-03-01 00:00:00

  • Inhibition of cyclic AMP-triggered aromatase gene expression in human choriocarcinoma cells by antisense oligodeoxynucleotide.

    abstract::Aromatase, an endomembrane-bound cytochrome P450, is the key enzyme of estrogen biosynthesis. Aromatase inhibitors, therefore, are clinically important tools in the treatment of estrogen-dependent tumor growth. To improve the specificity of these tools, inhibition at the nucleic acid level was examined. An antisense o...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Ackermann K,Fauss J,Pyerin W

    更新日期:1994-09-15 00:00:00

  • Evidence for single-cell origin of 3-methylcholanthrene-induced fibrosarcomas in mice with cellular mosaicism.

    abstract::Fibrosarcomas produced by s.c. injection of 5 micrograms of 3-methylcholanthrene in Pgk-1a/Pgk-1b mice carrying X-chromosome inactivation mosaicism for the phosphoglycerate kinase (PGK-1) gene contained only one type of phosphoglycerate kinase in seven of eight cases (88%), as judged from its electrophoretic mobility,...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Tanooka H,Tanaka K

    更新日期:1982-05-01 00:00:00

  • Targeting leukemia-initiating cells in acute lymphoblastic leukemia (ALL).

    abstract::The concept that different leukemias are developmentally distinct and, like in normal hematopoiesis, generated by restricted populations of cells named leukemia-initiating cells (LIC), is becoming more established. These cancer stem-like cells have been assumed to have unique properties, including the capability of se...

    journal_title:Cancer research

    pub_type: 杂志文章,评审

    doi:10.1158/0008-5472.CAN-20-2571

    authors: Tamiro F,Weng AP,Giambra V

    更新日期:2021-01-07 00:00:00