Publications by authors named "Rebecca L Porter"

11 Publications

  • Page 1 of 1

Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma.

Proc Natl Acad Sci U S A 2019 12 16. Epub 2019 Dec 16.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114;

Transcriptional profiling has defined pancreatic ductal adenocarcinoma (PDAC) into distinct subtypes with the majority being classical epithelial (E) or quasi-mesenchymal (QM). Despite clear differences in clinical behavior, growing evidence indicates these subtypes exist on a continuum with features of both subtypes present and suggestive of interconverting cell states. Here, we investigated the impact of different therapies being evaluated in PDAC on the phenotypic spectrum of the E/QM state. We demonstrate using RNA-sequencing and RNA-in situ hybridization (RNA-ISH) that FOLFIRINOX combination chemotherapy induces a common shift of both E and QM PDAC toward a more QM state in cell lines and patient tumors. In contrast, Vitamin D, another drug under clinical investigation in PDAC, induces distinct transcriptional responses in each PDAC subtype, with augmentation of the baseline E and QM state. Importantly, this translates to functional changes that increase metastatic propensity in QM PDAC, but decrease dissemination in E PDAC in vivo models. These data exemplify the importance of both the initial E/QM subtype and the plasticity of E/QM states in PDAC in influencing response to therapy, which highlights their relevance in guiding clinical trials.
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http://dx.doi.org/10.1073/pnas.1914915116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936349PMC
December 2019

Clinicopathologic Features of NSCLC Diagnosed During Pregnancy or the Peripartum Period in the Era of Molecular Genotyping.

J Thorac Oncol 2016 09 11;11(9):1522-8. Epub 2016 Jun 11.

Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Introduction: Cancer will be diagnosed in one in 1000 women during pregnancy. The outcomes of NSCLC diagnosed during pregnancy are dismal, with most patients dying within 1 year. Actionable mutations are more likely to be found among younger patients with NSCLC. However, most previous reports of NSCLC diagnosed during pregnancy did not include molecular genotyping.

Methods: We performed a retrospective analysis of patients seen at our institution between 2009 and 2015 to identify women in whom NSCLC was diagnosed during pregnancy or the peripartum period and determined clinicopathologic features, including molecular genotype.

Results: We identified 2422 women with NSCLC, including 160 women of reproductive age. Among the women of reproductive age, eight cases of NSCLC diagnosed during pregnancy or the peripartum period were identified; all were diagnosed in minimal or never-smokers with metastatic adenocarcinoma. Six of these patients were found to have anaplastic lymphoma kinase gene (ALK) rearrangements, whereas the remaining two were EGFR mutation positive. We observed a borderline significant association between a diagnosis of NSCLC during pregnancy or the peripartum period and ALK positivity (p = 0.053). All eight women in whom NSCLC was diagnosed during pregnancy or the peripartum period received treatment with genotype-directed therapies after delivery. The median overall survival has not been reached at a median follow-up of 30 months.

Conclusions: Although a diagnosis of NSCLC during pregnancy or the peripartum period is rare, diagnostic evaluation should not be delayed in pregnant women presenting with symptoms worrisome for lung cancer. Evaluation should include testing for targetable molecular alterations.
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http://dx.doi.org/10.1016/j.jtho.2016.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002360PMC
September 2016

Prostaglandin E2 increases hematopoietic stem cell survival and accelerates hematopoietic recovery after radiation injury.

Stem Cells 2013 Feb;31(2):372-83

Department of Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA.

Hematopoietic stem and progenitor cells (HSPCs), which continuously maintain all mature blood cells, are regulated within the marrow microenvironment. We previously reported that pharmacologic treatment of naïve mice with prostaglandin E2 (PGE2) expands HSPCs. However, the cellular mechanisms mediating this expansion remain unknown. Here, we demonstrate that PGE2 treatment in naïve mice inhibits apoptosis of HSPCs without changing their proliferation rate. In a murine model of sublethal total body irradiation (TBI), in which HSPCs are rapidly lost, treatment with a long-acting PGE2 analog (dmPGE2) reversed the apoptotic program initiated by TBI. dmPGE2 treatment in vivo decreased the loss of functional HSPCs following radiation injury, as demonstrated both phenotypically and by their increased reconstitution capacity. The antiapoptotic effect of dmPGE2 on HSPCs did not impair their ability to differentiate in vivo, resulting instead in improved hematopoietic recovery after TBI. dmPGE2 also increased microenvironmental cyclooxygenase-2 expression and expanded the α-smooth muscle actin-expressing subset of marrow macrophages, thus enhancing the bone marrow microenvironmental response to TBI. Therefore, in vivo treatment with PGE2 analogs may be particularly beneficial to HSPCs in the setting of injury by targeting them both directly and also through their niche. The current data provide rationale for in vivo manipulation of the HSPC pool as a strategy to improve recovery after myelosuppression.
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http://dx.doi.org/10.1002/stem.1286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580384PMC
February 2013

Osteoblastic N-cadherin is not required for microenvironmental support and regulation of hematopoietic stem and progenitor cells.

Blood 2012 Jul 17;120(2):303-13. Epub 2012 May 17.

Endocrine Division, Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Ave, Rochester, NY 14642, USA.

Hematopoietic stem cell (HSC) regulation is highly dependent on interactions with the marrow microenvironment. Controversy exists on N-cadherin's role in support of HSCs. Specifically, it is unknown whether microenvironmental N-cadherin is required for normal marrow microarchitecture and for hematopoiesis. To determine whether osteoblastic N-cadherin is required for HSC regulation, we used a genetic murine model in which deletion of Cdh2, the gene encoding N-cadherin, has been targeted to cells of the osteoblastic lineage. Targeted deletion of N-cadherin resulted in an age-dependent bone phenotype, ultimately characterized by decreased mineralized bone, but no difference in steady-state HSC numbers or function at any time tested, and normal recovery from myeloablative injury. Intermittent parathyroid hormone (PTH) treatment is well established as anabolic to bone and to increase marrow HSCs through microenvironmental interactions. Lack of osteoblastic N-cadherin did not block the bone anabolic or the HSC effects of PTH treatment. This report demonstrates that osteoblastic N-cadherin is not required for regulation of steady-state hematopoiesis, HSC response to myeloablation, or for rapid expansion of HSCs through intermittent treatment with PTH.
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http://dx.doi.org/10.1182/blood-2011-09-377853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398755PMC
July 2012

Clr4/Suv39 and RNA quality control factors cooperate to trigger RNAi and suppress antisense RNA.

Science 2011 Mar;331(6024):1624-7

Laboratory of Biochemistry and Molecular Biology, National Cancer Institute/NIH, Bethesda, MD 20892, USA.

Pervasive transcription of eukaryotic genomes generates a plethora of noncoding RNAs. In fission yeast, the heterochromatin factor Clr4/Suv39 methyltransferase facilitates RNA interference (RNAi)-mediated processing of centromeric transcripts into small interfering RNAs (siRNAs). Clr4 also mediates degradation of antisense RNAs at euchromatic loci, but the underlying mechanism has remained elusive. We show that Clr4 and the RNAi effector RITS (RNA-induced transcriptional silencing) interact with Mlo3, a protein related to mRNA quality control and export factors. Loss of Clr4 impairs RITS interaction with Mlo3, which is required for centromeric siRNA production and antisense suppression. Mlo3 also interacts with the RNA surveillance factor TRAMP, which suppresses antisense RNAs targeted by Clr4 and RNAi. These findings link Clr4 to RNA quality control machinery and suggest a pathway for processing potentially deleterious RNAs through the coordinated actions of RNAi and other RNA processing activities.
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http://dx.doi.org/10.1126/science.1198712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309853PMC
March 2011

X-ray diffraction evidence for myosin-troponin connections and tropomyosin movement during stretch activation of insect flight muscle.

Proc Natl Acad Sci U S A 2011 Jan 9;108(1):120-5. Epub 2010 Dec 9.

Department of Cell Biology, Box 3011, Duke University, Durham, NC 27710, USA.

Stretch activation is important in the mechanical properties of vertebrate cardiac muscle and essential to the flight muscles of most insects. Despite decades of investigation, the underlying molecular mechanism of stretch activation is unknown. We investigated the role of recently observed connections between myosin and troponin, called "troponin bridges," by analyzing real-time X-ray diffraction "movies" from sinusoidally stretch-activated Lethocerus muscles. Observed changes in X-ray reflections arising from myosin heads, actin filaments, troponin, and tropomyosin were consistent with the hypothesis that troponin bridges are the key agent of mechanical signal transduction. The time-resolved sequence of molecular changes suggests a mechanism for stretch activation, in which troponin bridges mechanically tug tropomyosin aside to relieve tropomyosin's steric blocking of myosin-actin binding. This enables subsequent force production, with cross-bridge targeting further enhanced by stretch-induced lattice compression and thick-filament twisting. Similar linkages may operate in other muscle systems, such as mammalian cardiac muscle, where stretch activation is thought to aid in cardiac ejection.
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http://dx.doi.org/10.1073/pnas.1014599107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017141PMC
January 2011

In vivo prostaglandin E2 treatment alters the bone marrow microenvironment and preferentially expands short-term hematopoietic stem cells.

Blood 2009 Nov 2;114(19):4054-63. Epub 2009 Sep 2.

Endocrine Division, University of Rochester School of Medicine, Rochester, NY 14642, USA.

Microenvironmental signals can determine hematopoietic stem cell (HSC) fate choices both directly and through stimulation of niche cells. In the bone marrow, prostaglandin E(2) (PGE(2)) is known to affect both osteoblasts and osteoclasts, whereas in vitro it expands HSCs and affects differentiation of hematopoietic progenitors. We hypothesized that in vivo PGE(2) treatment could expand HSCs through effects on both HSCs and their microenvironment. PGE(2)-treated mice had significantly decreased number of bone trabeculae, suggesting disruption of their microarchitecture. In addition, in vivo PGE(2) increased lineage(-) Sca-1(+) c-kit(+) bone marrow cells without inhibiting their differentiation. However, detailed immunophenotyping demonstrated a PGE(2)-dependent increase in short-term HSCs/multipotent progenitors (ST-HSCs/MPPs) only. Bone marrow cells transplanted from PGE(2) versus vehicle-treated donors had superior lymphomyeloid reconstitution, which ceased by 16 weeks, also suggesting that ST-HSCs were preferentially expanded. This was confirmed by serial transplantation studies. Thus in vivo PGE(2) treatment, probably through a combination of direct and microenvironmental actions, preferentially expands ST-HSCs in the absence of marrow injury, with no negative impact on hematopoietic progenitors or long-term HSCs. These novel effects of PGE(2) could be exploited clinically to increase donor ST-HSCs, which are highly proliferative and could accelerate hematopoietic recovery after stem cell transplantation.
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http://dx.doi.org/10.1182/blood-2009-03-205823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774547PMC
November 2009

Key endothelial signals required for hematopoietic recovery.

Cell Stem Cell 2009 Mar;4(3):187-8

Wilmot Cancer Center and Endocrine Division, University of Rochester School of Medicine, 601 Elmwood Avenue, Box 693, Rochester, NY 14642, USA.

In this issue of Cell Stem Cell, Hooper et al. (2009) use a combination of immunohistochemistry and flow cytometry to characterize the bone marrow vasculature both before and after injury. The authors demonstrate that recovery of normal hematopoiesis after myelosuppressive insult is dependent upon endothelial VEGFR2.
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http://dx.doi.org/10.1016/j.stem.2009.02.005DOI Listing
March 2009

Improving the retention of child welfare workers by strengthening skills and increasing support for supervisors.

Child Welfare 2009 ;88(5):109-27

The University of Iowa, School of Social Work, Iowa City, Iowa 52242, USA.

Increasingly, effective supervision has been found to be critical in the retention of child welfare workers. In 2006 the State of Missouri Children's Division implemented a supervisory strategic plan to concentrate on supervisory training and effectiveness, with the expectation that emphasis on supervision would improve the retention of frontline workers. Using annual responses to the survey of organizational excellence and retention data, this study examines perceptions of child welfare workers and supervisors on three workplace constructs. Analyses support hypotheses that retention of workers improved in the year following the implementation of the supervisory plan, and measures of supervisor effectiveness, team effectiveness, and job satisfaction also increased. Explanations of primary findings are provided and implications for practice and policy are discussed.
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April 2010

Hematopoietic niche and bone meet.

Curr Opin Support Palliat Care 2008 Sep;2(3):211-7

Endocrine Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.

Purpose Of Review: To provide an overview of the hematopoietic stem cell (HSC) niche in the bone marrow. In addition to highlighting recent advances in the field, we will also discuss components of the niche that may contribute to the development of cancer, or cancer metastases to the bone.

Recent Findings: Much progress has been very recently made in the understanding of the cellular and molecular interactions in the HSC microenvironment. These recent findings point out the extraordinary complexity of the HSC microenvironment. Emerging data also suggest convergence of signals important for HSC and for leukemia or metastatic disease support.

Summary: The HSC niche comprises complex interactions between multiple cell types and molecules requiring cell-cell signaling as well as local secretion. These components can be thought of as therapeutic targets not only for HSC expansion, but also to modify behavior of hematopoietic malignancies and cancer metastases to the bone.
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http://dx.doi.org/10.1097/SPC.0b013e32830d5c12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572865PMC
September 2008

Enucleation of primitive erythroid cells generates a transient population of "pyrenocytes" in the mammalian fetus.

Blood 2008 Feb 21;111(4):2409-17. Epub 2007 Nov 21.

University of Rochester Medical Center, Department of Pediatrics, Center for Pediatric Biomedical Research, Rochester, NY 14642, USA.

Enucleation is the hallmark of erythropoiesis in mammals. Previously, we determined that yolk sac-derived primitive erythroblasts mature in the bloodstream and enucleate between embryonic day (E)14.5 and E16.5 of mouse gestation. While definitive erythroblasts enucleate by nuclear extrusion, generating reticulocytes and small, nucleated cells with a thin rim of cytoplasm ("pyrenocytes"), it is unclear by what mechanism primitive erythroblasts enucleate. Immunohistochemical examination of fetal blood revealed primitive pyrenocytes that were confirmed by multispectral imaging flow cytometry to constitute a distinct, transient cell population. The frequency of primitive erythroblasts was higher in the liver than the bloodstream, suggesting that they enucleate in the liver, a possibility supported by their proximity to liver macrophages and the isolation of erythroblast islands containing primitive erythroblasts. Furthermore, primitive erythroblasts can reconstitute erythroblast islands in vitro by attaching to fetal liver-derived macrophages, an association mediated in part by alpha4 integrin. Late-stage primitive erythroblasts fail to enucleate in vitro unless cocultured with macrophage cells. Our studies indicate that primitive erythroblasts enucleate by nuclear extrusion to generate erythrocytes and pyrenocytes and suggest this occurs in the fetal liver in association with macrophages. Continued studies comparing primitive and definitive erythropoiesis will lead to an improved understanding of terminal erythroid maturation.
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http://dx.doi.org/10.1182/blood-2007-08-107581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2234067PMC
February 2008