Publications by authors named "Daniel H Miller"

21 Publications

  • Page 1 of 1

Improving identification of candidates for lung cancer screening in a high risk population.

Lung Cancer 2020 10 7;148:79-85. Epub 2020 Aug 7.

Division of Pulmonary Medicine, Mayo Clinic, Jacksonville, FL, United States.

Background: Low dose computerized tomography (LDCT) has been shown to reduce lung cancer specific mortality by 20 %. Despite U.S. Preventive Services Task Force (USPSTF) endorsement, screening of appropriate patients in the U.S. remains low, at 1.9 %. The goal of this study was to assess the number and type of patients that would qualify for lung cancer screening based upon recommendations by various guidelines.

Methods: We prospectively collected a patient reported questionnaire, including smoking history, family history, exposure history, and demographics, from April-October 2017 from new consults in the Department of Radiation Oncology and Otolaryngology (ORL). Patients smoking status and patient factors were collected and reported. Patients qualifying for screening by USPSTF, the National Comprehensive Cancer Network (NCCN), and Tammemagi scoring criteria were identified. Multivariate analysis assessed the factors associated with positive criteria for screening and the sensitivity of each criterion was calculated.

Results: There were 546 new consults during the study period and 528 successfully completed the questionnaire. A total of 104/528 (20 %) patients who completed questionnaires qualified for screening based on any guideline. After exclusion of active lung cancer (n = 19), poor prognosis (n = 24), and CT as part of surveillance (n = 16), 45 (8.5 %) patients would require LDCT. Of the entire population, 10 %, 11 % and 18 % of patients qualified based on USPSTF, NCCN, and Tammemagi, which was reduced to 4.9 %, 5.3 %, and 7.8 %, respectively after exclusions. Patients with head and neck cancer (40 %), skin cancer (27 %), and prostate cancer (11 %) accounted for the majority of patients eligible for screening after exclusions. The sensitivity of the USPSTF, NCCN, and Tammemagi criteria in patients with a diagnosis of lung cancer (n = 26) was 38.5 % (CI 20.2 %-59.4 %), 46.2 % (CI 26.6 %-66.6 %), and 61.5 % (CI 40.6 %-79.8 %), respectively.

Conclusions: We successfully identified 9 % of an oncology population at consultation who could benefit from lung cancer screening in survivorship. Distribution of a written or electronic questionnaire at consultation is a simple, low cost, effective method of identifying patients who would benefit from LDCT.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.036DOI Listing
October 2020

Google Search Trends in Oncology and the Impact of Celebrity Cancer Awareness.

Cureus 2019 Aug 10;11(8):e5360. Epub 2019 Aug 10.

Department of Radiation Oncology, Mayo Clinic Florida, Jacksonville, USA.

Introduction There is widespread public interest when celebrities are diagnosed with cancer. We sought to assess how this interest impacts awareness of prevalent cancers. Methods We reviewed common cancer-related search terms using Google Trends (Google LLC, Mountain View, CA) between the years 2004 and 2017 and retrospectively correlated these findings with media or celebrity-related events. The Google Trends application was used to obtain the "search volume index" (SVI), defined as the number of searches for a specific term standardized to the total number of searches over that time period. Data were presented in a graphical format. Isolated peaks of greater than 25% from the baseline SVI were identified. Using the date of the peaks, a further search was performed to determine if any event in the media triggered the peak. Results "Lung Cancer," "Pancreas Cancer," "Endometrial Cancer," "Cervical Cancer," "Brain Cancer," and "Glioblastoma" each had the highest peak correspond with a celebrity-related event covered in the media. These search terms displayed several additional isolated peaks, the majority of which could all be correlated with a significant media event (%). The search term "Breast Cancer" consistently had a peaked interest during October (breast cancer awareness month). Breast cancer events relating to public figures had little to no relative impact on search volume during this period. None of the other cancer search terms displayed the same cyclical pattern during their respective awareness months. Colon, rectal, and prostate cancer demonstrated stable search volumes over time, without an isolated peak. Conclusion Internet search activity among English speakers of most general cancer terms exhibit peaks coinciding with events that occur to celebrity figures or advances in medicines that are substantially covered in the media. In all cases but "breast cancer," these events lend to higher search activity as compared to campaigns and awareness months. Our study suggests that media coverage of public figures with cancer may trigger substantial Internet interest in non-breast cancers, more so than traditional efforts to raise awareness.
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http://dx.doi.org/10.7759/cureus.5360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783227PMC
August 2019

Primary histiocytic sarcoma of the central nervous system: a case report with platelet derived growth factor receptor mutation and PD-L1/PD-L2 expression and literature review.

Radiat Oncol 2018 Sep 5;13(1):167. Epub 2018 Sep 5.

Department of Radiation Oncology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA.

Background: Histiocytic sarcoma (HS) is an aggressive malignant neoplasm. HS in the central nervous system is exceptionally rare and associated with a poor prognosis. This report documents a case of primary HS of the central nervous system with treatment including surgery, radiotherapy, and chemotherapy.

Case Presentation: Our patient was a 47 year old female presenting with progressive ataxia, headaches, imbalance, nausea, vomiting, and diplopia. MRI showed a heterogeneously enhancing lesion approximately 2.9 × 3.0 × 2.3 cm centered upon the cerebellar vermis with mild surrounding vasogenic edema and abnormal enhancement of multiple cranial nerves. The patient underwent surgical debulking, which revealed histiocytic sarcoma with grossly purulent drainage. Staging revealed diffuse leptomeningeal involvement, primarily involving the brain and lower thoracic and lumbar spine. She underwent adjuvant radiotherapy to the brain and lower spine and was started on high dose methotrexate. However, she experienced progressive disease in the cervical and thoracic spine as well as pulmonary involvement. Genomic sequencing of her tumor showed a mutation in the platelet-derived growth factor receptor A (p.V0681) which could be targeted with Dasatinib. However, she did not tolerate Dasatinib and she succumbed to progressive disseminated disease eight months from original diagnosis. Our pathologic evaluation also revealed expression of PD-L1 and PD-L2 by tumor cells raising the potential therapeutic role for immune checkpoint inhibition.

Conclusions: This case provides an example of effective CNS control with resection and moderate doses of radiation therapy. A review of the literature confirms aggressive multidisciplinary treatment is the most effective treatment against this disease. In addition, genomic sequencing may play an important role in determining new therapeutic options. However, CNS histiocytic sarcoma remains an aggressive disease with a propensity for early widespread dissemination and few long term survivors.
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http://dx.doi.org/10.1186/s13014-018-1115-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126020PMC
September 2018

BCL11B Drives Human Mammary Stem Cell Self-Renewal In Vitro by Inhibiting Basal Differentiation.

Stem Cell Reports 2018 03 1;10(3):1131-1145. Epub 2018 Mar 1.

Whitehead Institute for Biomedical Research, 455 Main St., Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address:

The epithelial compartment of the mammary gland contains basal and luminal cell lineages, as well as stem and progenitor cells that reside upstream in the differentiation hierarchy. Stem and progenitor cell differentiation is regulated to maintain adult tissue and mediate expansion during pregnancy and lactation. The genetic factors that regulate the transition of cells between differentiation states remain incompletely understood. Here, we present a genome-scale method to discover genes driving cell-state specification. Applying this method, we identify a transcription factor, BCL11B, which drives stem cell self-renewal in vitro, by inhibiting differentiation into the basal lineage. To validate BCL11B's functional role, we use two-dimensional colony-forming and three-dimensional tissue differentiation assays to assess the lineage differentiation potential and functional abilities of primary human mammary cells. These findings show that BCL11B regulates mammary cell differentiation and demonstrate the utility of our proposed genome-scale strategy for identifying lineage regulators in mammalian tissues.
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http://dx.doi.org/10.1016/j.stemcr.2018.01.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918530PMC
March 2018

Treatment of a glioblastoma multiforme dural metastasis with stereotactic radiosurgery: A case report and select review of the literature.

J Clin Neurosci 2018 Feb 26;48:118-121. Epub 2017 Nov 26.

Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, USA. Electronic address:

Glioblastoma multiforme (GBM) is a primary brain neoplasm accounting for approximately 75% of all high grade gliomas. It is diffusely infiltrative and exhibits rapid proliferation with a poor overall prognosis. Maximum surgical resection and postoperative radiotherapy, accompanied by concurrent and adjuvant temozolomide chemotherapy, remain the standard of care without major therapeutic advances over the past 10 years. Herein, we present the case of a 64-year-old Caucasian male with a GBM who subsequently developed a left frontal dural metastasis, subsequently treated with stereotactic radiosurgery (20 Gy in 1 fraction). With six month follow-up, the patient showed near complete resolution of his dural metastases and no overall change in neurological symptoms or side effects following radiosurgery. Due to the paucity of clinical literature regarding dural metastases from GBM, its optimal treatment remains unknown. While the role of SRS has yet to be defined in this setting, here we provide evidence suggesting its overall efficacy in the treatment of select dural GBM metastases.
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http://dx.doi.org/10.1016/j.jocn.2017.11.003DOI Listing
February 2018

Cancer-specific PERK signaling drives invasion and metastasis through CREB3L1.

Nat Commun 2017 10 20;8(1):1079. Epub 2017 Oct 20.

Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA, 02142, USA.

PERK signaling is required for cancer invasion and there is interest in targeting this pathway for therapy. Unfortunately, chemical inhibitors of PERK's kinase activity cause on-target side effects that have precluded their further development. One strategy for resolving this difficulty would be to target downstream components of the pathway that specifically mediate PERK's pro-invasive and metastatic functions. Here we identify the transcription factor CREB3L1 as an essential mediator of PERK's pro-metastatic functions in breast cancer. CREB3L1 acts downstream of PERK, specifically in the mesenchymal subtype of triple-negative tumors, and its inhibition by genetic or pharmacological methods suppresses cancer cell invasion and metastasis. In patients with this tumor subtype, CREB3L1 expression is predictive of distant metastasis. These findings establish CREB3L1 as a key downstream mediator of PERK-driven metastasis and a druggable target for breast cancer therapy.
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http://dx.doi.org/10.1038/s41467-017-01052-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651903PMC
October 2017

3D Primary Culture Model to Study Human Mammary Development.

Methods Mol Biol 2017 ;1612:139-147

Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA, 02142, USA.

We present a protocol for expanding human mammary tissues from primary patient-derived cells in three-dimensional (3D) cultures. The primary epithelial cells are seeded into 3D hydrogels with defined components, which include both proteins and carbohydrates present in mammary tissue. Over a span of 10-14 days, the seeded cells form mammary tissues with complex ductal-lobular topologies and include luminal and basal cells in the correct orientation, together with cells that stain positively for stem cell markers. In addition to recapitulating key architectural features of human mammary tissue, the expanded tissues also respond to lactogenic hormones including estrogen, progesterone, and prolactin. We anticipate that these cultures will prove useful for studies of mammary development and breast cancer.
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http://dx.doi.org/10.1007/978-1-4939-7021-6_10DOI Listing
March 2018

Recurrent myxoinflammatory fibroblastic sarcoma: a case report.

Clin Case Rep 2017 06 20;5(6):871-875. Epub 2017 Apr 20.

Department of Radiation Oncology Mayo Clinic Jacksonville Florida.

Myxoinflammatory fibroblastic sarcoma is a rare sarcoma which typically presents in the extremities and is treated by definitive surgery. In recurrent disease, the reported utilization of radiotherapy is increasing, and more modern techniques such as intensity-modulated radiotherapy may be improving long-term outcomes.
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http://dx.doi.org/10.1002/ccr3.949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458025PMC
June 2017

SMARCE1 is required for the invasive progression of in situ cancers.

Proc Natl Acad Sci U S A 2017 04 4;114(16):4153-4158. Epub 2017 Apr 4.

Whitehead Institute for Biomedical Research, Cambridge, MA 02142;

Advances in mammography have sparked an exponential increase in the detection of early-stage breast lesions, most commonly ductal carcinoma in situ (DCIS). More than 50% of DCIS lesions are benign and will remain indolent, never progressing to invasive cancers. However, the factors that promote DCIS invasion remain poorly understood. Here, we show that SMARCE1 is required for the invasive progression of DCIS and other early-stage tumors. We show that SMARCE1 drives invasion by regulating the expression of secreted proteases that degrade basement membrane, an ECM barrier surrounding all epithelial tissues. In functional studies, SMARCE1 promotes invasion of in situ cancers growing within primary human mammary tissues and is also required for metastasis in vivo. Mechanistically, SMARCE1 drives invasion by forming a SWI/SNF-independent complex with the transcription factor ILF3. In patients diagnosed with early-stage cancers, SMARCE1 expression is a strong predictor of eventual relapse and metastasis. Collectively, these findings establish SMARCE1 as a key driver of invasive progression in early-stage tumors.
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http://dx.doi.org/10.1073/pnas.1703931114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402464PMC
April 2017

Dedifferentiated Liposarcoma of the Esophagus: A Case Report and Selected Review of the Literature.

Rare Tumors 2016 Nov 20;8(4):6791. Epub 2016 Dec 20.

Departments of Oncology Radiation, Clinic Mayo , Jacksonville, FL, USA.

Soft tissue sarcomas of the esophagus represent an extremely rare cause of esophageal masses, and an even smaller proportion of these tumors represent dedifferentiated liposarcomas. We present a case of a 75-year-old gentleman presenting with dysphagia found to have a 5 cm pedunculated mass in the cervical esophagus, originating at the cricopharyngeus. This was found to have involvement limited to the superficial mucosa by endoscopic ultrasound, and the lesion was subsequently resected endoscopically. Pathology demonstrated an undifferentiated pleomorphic sarcoma later determined to represent dedifferentiated liposarcoma after fluorescence hybridization analysis. The patient received no additional adjuvant therapy and remains disease free 20 months from the procedure. While treatment experience is limited, our case demonstrates that in selected patients, sustained local control can be obtained without radical resection.
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http://dx.doi.org/10.4081/rt.2016.6791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226054PMC
November 2016

Small Cell Carcinoma of the Prostate in an Elderly Patient: A Case Report and Review of the Literature.

Rare Tumors 2016 Nov 20;8(4):6657. Epub 2016 Dec 20.

Departments of Radiation Oncology, Mayo Clinic , Jacksonville, FL, USA.

Prostate cancer is the most common malignancy of men in the United States. Small-cell carcinoma (SCC), which typically presents as an aggressive lung malignancy, is a rare diagnosis within the setting of prostate cancer pathology. Due to its limited prevalence, little information regarding the treatment and prognosis of this disease in large populations is available. To date our current knowledge base is largely limited to case reports and retrospective case reviews. The mainstay of treatment for this particular histology most often involves a multimodality approach utilizing chemotherapy in conjunction with radiation therapy, androgen deprivation therapy, or prostatectomy. Here we present the case of an elderly 89-year-old Caucasian male who was diagnosed with SCC of the prostate. Despite proceeding with a course of definitive radiotherapy, the patient experienced rapid progression of disease and ultimately elected to discontinue radiation therapy and receive hospice care.
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http://dx.doi.org/10.4081/rt.2016.6657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226053PMC
November 2016

Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors.

PLoS One 2016 17;11(3):e0151089. Epub 2016 Mar 17.

Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 02139.

The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05) (S2 Table). Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151089PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795743PMC
August 2016

Growth of human breast tissues from patient cells in 3D hydrogel scaffolds.

Breast Cancer Res 2016 Mar 1;18(1):19. Epub 2016 Mar 1.

Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA.

Background: Three-dimensional (3D) cultures have proven invaluable for expanding human tissues for basic research and clinical applications. In both contexts, 3D cultures are most useful when they (1) support the outgrowth of tissues from primary human cells that have not been immortalized through extensive culture or viral infection and (2) include defined, physiologically relevant components. Here we describe a 3D culture system with both of these properties that stimulates the outgrowth of morphologically complex and hormone-responsive mammary tissues from primary human breast epithelial cells.

Methods: Primary human breast epithelial cells isolated from patient reduction mammoplasty tissues were seeded into 3D hydrogels. The hydrogel scaffolds were composed of extracellular proteins and carbohydrates present in human breast tissue and were cultured in serum-free medium containing only defined components. The physical properties of these hydrogels were determined using atomic force microscopy. Tissue growth was monitored over time using bright-field and fluorescence microscopy, and maturation was assessed using morphological metrics and by immunostaining for markers of stem cells and differentiated cell types. The hydrogel tissues were also studied by fabricating physical models from confocal images using a 3D printer.

Results: When seeded into these 3D hydrogels, primary human breast epithelial cells rapidly self-organized in the absence of stromal cells and within 2 weeks expanded to form mature mammary tissues. The mature tissues contained luminal, basal, and stem cells in the correct topological orientation and also exhibited the complex ductal and lobular morphologies observed in the human breast. The expanded tissues became hollow when treated with estrogen and progesterone, and with the further addition of prolactin produced lipid droplets, indicating that they were responding to hormones. Ductal branching was initiated by clusters of cells expressing putative mammary stem cell markers, which subsequently localized to the leading edges of the tissue outgrowths. Ductal elongation was preceded by leader cells that protruded from the tips of ducts and engaged with the extracellular matrix.

Conclusions: These 3D hydrogel scaffolds support the growth of complex mammary tissues from primary patient-derived cells. We anticipate that this culture system will empower future studies of human mammary gland development and biology.
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http://dx.doi.org/10.1186/s13058-016-0677-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772689PMC
March 2016

Management of Metastatic Apocrine Hidradenocarcinoma with Chemotherapy and Radiation.

Rare Tumors 2015 Sep 5;7(3):6082. Epub 2015 Oct 5.

Department of Radiation Oncology, Mayo Clinic , Jacksonville, FL, USA.

Hidradenocarcinoma is a rare aggressive form of cutaneous adnexal skin carcinoma originating from the sweat gland. Due to its low incidence, prognostic and treatment strategies are still being explored both for primary and advanced disease. This tumor most often presents as either solid or cystic appearing subcutaneous nodules, which may be associated with pruritus or ulceration. To date the mainstay of treatment for local disease has been surgical excision; however, the paucity of historical data available has shown that these tumors often behave aggressively with high rates of local recurrence, metastasis, and poor overall outcomes. There are few case reports describing the utility of radiation therapy in the treatment of hidradenocarcinoma. Herein, we present a case of metastatic apocrine hidradenocarcinoma in a 32-year-old Caucasian male. The patient initially underwent excisional biopsy which confirmed the diagnosis of poorly differentiated, highly infiltrative, apocrine hidradenocarcinoma. He received systemic chemotherapy for metastatic disease, followed by radiation therapy to areas of grossly palpable adenopathy. Prior to radiation therapy the patient had an enlarged hypermetabolic conglomerate of lymph nodes in the right axilla, and borderline enlarged low activity nodes within the left axilla. He received 3 cycles of chemotherapy followed by tamoxifen and radiation therapy (50.4 Gy in 28 fractions) to areas of progressive disease in the bilateral axilla, lower neck, and axillary skin. Following treatment, the patient had complete resolution of skin nodules and improvement of his pruritus. While the role of radiation therapy in the treatment of hidradenocarcinoma has not been well established, this case report demonstrated the potential benefit of external beam radiotherapy in the management of this rare disease.
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http://dx.doi.org/10.4081/rt.2015.6082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600998PMC
September 2015

Perturbation-expression analysis identifies RUNX1 as a regulator of human mammary stem cell differentiation.

PLoS Comput Biol 2015 Apr 20;11(4):e1004161. Epub 2015 Apr 20.

Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, United States of America; Harvard Stem Cell Institute, Cambridge, Massachusetts, United States of America.

The search for genes that regulate stem cell self-renewal and differentiation has been hindered by a paucity of markers that uniquely label stem cells and early progenitors. To circumvent this difficulty we have developed a method that identifies cell-state regulators without requiring any markers of differentiation, termed Perturbation-Expression Analysis of Cell States (PEACS). We have applied this marker-free approach to screen for transcription factors that regulate mammary stem cell differentiation in a 3D model of tissue morphogenesis and identified RUNX1 as a stem cell regulator. Inhibition of RUNX1 expanded bipotent stem cells and blocked their differentiation into ductal and lobular tissue rudiments. Reactivation of RUNX1 allowed exit from the bipotent state and subsequent differentiation and mammary morphogenesis. Collectively, our findings show that RUNX1 is required for mammary stem cells to exit a bipotent state, and provide a new method for discovering cell-state regulators when markers are not available.
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http://dx.doi.org/10.1371/journal.pcbi.1004161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404314PMC
April 2015

Oxysterols synergize with statins by inhibiting SREBP-2 in ovarian cancer cells.

Gynecol Oncol 2014 Nov 16;135(2):333-41. Epub 2014 Aug 16.

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02903, USA; Center for Computational Molecular Biology, Brown University, 151 Waterman St., Providence, RI 02912, USA; Center for Genomics and Proteomics, Brown University, 70 Ship St., Providence, RI 02903, USA.

Objective: Determine mechanisms responsible for enhanced statin efficacy in a novel statin combination we name STOX (STatin-OXysterol).

Methods: Ovarian cancer cell lines were treated with combinations of statins and oxysterols. Cell viability was determined by a modified MTT assay. Apoptosis was evaluated by immunoblotting of PARP and DAPI-mediated visualization of apoptotic nuclei. STOX effects on the expression of genes of the mevalonate pathway were assessed by real-time qPCR and immunoblotting. siRNA-mediated gene silencing was used to test the involvement of oxysterol-mediated repression of SREBP-2 in STOX synergy. The impact of statin-mediated inhibition of protein prenylation and on cholesterol homeostasis was evaluated.

Results: Oxysterols dramatically enhance cytotoxicity of statins in ovarian cancer cells through increased apoptosis. Decreased expression of SREBP-2 down-regulates the mevalonate pathway and prevents the active statin-induced sterol feedback, enhancing statin toxicity. Comparison of two ovarian cancer cell lines reveals two distinct mechanisms of statin induced toxicity, namely, dependence on protein geranylgeranylation and/or perturbation of cellular cholesterol levels.

Conclusions: We provide evidence of statins' mechanisms of cytotoxicity in different ovarian cancer cells and discovered a new approach to significantly enhance the anti-tumor activity of statins. These observations provide a potential new path to improve statins as a treatment against ovarian cancer with obtainable dosages.
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http://dx.doi.org/10.1016/j.ygyno.2014.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516475PMC
November 2014

Targeting the disordered C terminus of PTP1B with an allosteric inhibitor.

Nat Chem Biol 2014 Jul 20;10(7):558-66. Epub 2014 May 20.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.

PTP1B, a validated therapeutic target for diabetes and obesity, has a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We define a new mechanism of allosteric inhibition that targets the C-terminal, noncatalytic segment of PTP1B. We present what is to our knowledge the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small-molecule inhibitor MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state. MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. This new approach to inhibition of PTP1B emphasizes the potential of disordered segments of proteins as specific binding sites for therapeutic small molecules.
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http://dx.doi.org/10.1038/nchembio.1528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062594PMC
July 2014

Expression profiling of primary and metastatic ovarian tumors reveals differences indicative of aggressive disease.

PLoS One 2014 14;9(4):e94476. Epub 2014 Apr 14.

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America.

The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094476PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986100PMC
January 2015

Identification of ovarian cancer metastatic miRNAs.

PLoS One 2013 12;8(3):e58226. Epub 2013 Mar 12.

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA.

Serous epithelial ovarian cancer (EOC) patients often succumb to aggressive metastatic disease, yet little is known about the behavior and genetics of ovarian cancer metastasis. Here, we aim to understand how omental metastases differ from primary tumors and how these differences may influence chemotherapy. We analyzed the miRNA expression profiles of primary EOC tumors and their respective omental metastases from 9 patients using miRNA Taqman qPCR arrays. We find 17 miRNAs with differential expression in omental lesions compared to primary tumors. miR-21, miR-150, and miR-146a have low expression in most primary tumors with significantly increased expression in omental lesions, with concomitant decreased expression of predicted mRNA targets based on mRNA expression. We find that miR-150 and miR-146a mediate spheroid size. Both miR-146a and miR-150 increase the number of residual surviving cells by 2-4 fold when challenged with lethal cisplatin concentrations. These observations suggest that at least two of the miRNAs, miR-146a and miR-150, up-regulated in omental lesions, stimulate survival and increase drug tolerance. Our observations suggest that cancer cells in omental tumors express key miRNAs differently than primary tumors, and that at least some of these microRNAs may be critical regulators of the emergence of drug resistant disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058226PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595263PMC
September 2013

T0901317 inhibits cisplatin-induced apoptosis in ovarian cancer cells [corrected].

Int J Gynecol Cancer 2011 Nov;21(8):1350-6

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, USA.

Objective: To determine the function of T0901317 in combination treatment with cisplatin in ovarian cancer cells.

Methods: We screened the effects of 3 nuclear hormone receptor ligands on cell viability in a panel of ovarian cancer cell lines. T0901317 regulation of apoptosis and cell cycle regulators was determined when applied as a single agent or in combination with cisplatin.

Results: Surprisingly, the liver X receptor agonist T0901317 had no significant effects on a panel of 7 ovarian cancer cell lines as a single agent. T0901317 does, however, significantly decrease cisplatin efficacy in at least 3 ovarian cancer cell lines. T0901317 reduces cisplatin-induced apoptosis and reverses cisplatin-induced expression of cell cycle regulators. T0901317 seems to work in a liver X receptor-, pregnane X receptor-, and farnesoid X receptor-independent manner, as agonists of these nuclear hormone receptors did not show similar effects. Interestingly, in the A2780-cp drug-resistant cell line, the effect of T0901317 is lost, suggesting that the pathways stimulated by T0901317 to reduce cisplatin efficacy could be inherently active features of the selected resistance.

Conclusions: Together, these data suggest that T0901317 inhibits cisplatin in some ovarian cancer cells. These data provide an avenue to investigate when T0901317 may be acting to promote tumor survival and drug resistance through control of apoptosis and when it may be acting as an antitumor agent as has been previously reported.
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http://dx.doi.org/10.1097/IGC.0b013e318228f558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203312PMC
November 2011

Integrated genomics of ovarian xenograft tumor progression and chemotherapy response.

BMC Cancer 2011 Jul 22;11:308. Epub 2011 Jul 22.

Molecular Therapeutics Laboratory, Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants7 Hospital, Alpert Medical School of Brown University, Providence, RI 02905, USA.

Background: Ovarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function in vivo. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c.

Methods: In order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth.

Results: These data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival.

Conclusions: We have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We propose that a combination of regulated expression and copy number can identify genes that are likely important for chemotherapy response. Our findings suggest a new approach to identify candidate genes that are critical for anti-tumor therapy.
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http://dx.doi.org/10.1186/1471-2407-11-308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155912PMC
July 2011