On Tuesday, May 10, 2016 from 11:30am– 1:30pm in Hedco Neurosciences Building Auditorium (HNB 100) representatives from the Institute of International Education, the organization that oversees the Fulbright, will talk about the program.
Tuesday, April 26, 2016
Increasing Openness & Reproducibility in Quantitative Research
The Office of Research and the Center for Open Science (COS) is hosting a workshop on Increasing Openness & Reproducibility in Quantitative Research on Monday, May 2nd, from 1-4 PM at the Gerontology Auditorium.
CB Colloquium | "Why don't transcription factors get lost?"
Barak Cohen
Washington University in St. Louis,
Department of Genetics
Abstract: The majority of signals from human genetic studies reside in non-coding DNA. Presumably, a large fraction of these variants exert their effects by influencing the functions of cis-regulatory elements. An important goal is to understand the sequence features that comprise cis-regulatory elements to the point where we can predict the effects of sequence variants on gene expression. Transcription Factor Binding Sites (TFBS) are key components of cis-regulatory elements, however, because TFBS are short, degenerate sequences they occur millions of times in mammalian genomes. This leads to a major problem: The vast majority of sequences that match TFBS are non-functional. My lab is studying the sequence determinants that specify active from inactive instances of TFBS. Some of these features include general sequence properties such as the local GC-content or intrinsic shape of DNA, while other features specify the cooperative interactions between TFs. We aim to develop quantitative models that discriminate active from inactive occurrences of TFBS and to use these models to understand the impact of genetic variation in non-coding DNA.
Thursday, April 28, 2016
2:00 PM
RRI 101
Host: Remo Rohs
Washington University in St. Louis,
Department of Genetics
Abstract: The majority of signals from human genetic studies reside in non-coding DNA. Presumably, a large fraction of these variants exert their effects by influencing the functions of cis-regulatory elements. An important goal is to understand the sequence features that comprise cis-regulatory elements to the point where we can predict the effects of sequence variants on gene expression. Transcription Factor Binding Sites (TFBS) are key components of cis-regulatory elements, however, because TFBS are short, degenerate sequences they occur millions of times in mammalian genomes. This leads to a major problem: The vast majority of sequences that match TFBS are non-functional. My lab is studying the sequence determinants that specify active from inactive instances of TFBS. Some of these features include general sequence properties such as the local GC-content or intrinsic shape of DNA, while other features specify the cooperative interactions between TFs. We aim to develop quantitative models that discriminate active from inactive occurrences of TFBS and to use these models to understand the impact of genetic variation in non-coding DNA.
Thursday, April 28, 2016
2:00 PM
RRI 101
Host: Remo Rohs
MB Seminar Series | "The genetic basis of non-genetic heterogeneity”
Mark Siegal
New York University,
Department of Biology,
Center for Genomics and Systems Biology
Abstract: Genetically identical cells growing in the same environment often display striking cell-to-cell heterogeneity in gene expression and other traits. Such heterogeneity is clinically important, as it is seen in microbial responses to antibiotics and in tumor cells. Nonetheless, molecular mechanisms that promote or suppress heterogeneity are poorly understood, particularly in eukaryotic organisms. We use the model eukaryote and opportunistic pathogen Saccharomyces cerevisiae (budding yeast) to study these mechanisms. I will present our work using high-throughput morphometric analysis of individual yeast cells to identify genes controlling the amount of variation in cell shape. I will also present our work on a form of evolutionarily adaptive heterogeneity in yeast. We developed a highly parallel, time-lapse microscopy assay to monitor variable protein expression, growth rate and survival outcomes of tens of thousands of yeast microcolonies simultaneously. Genetically identical cells display high variation in growth rate, and slow growth correlates with higher expression of stress-protective gene products and with higher tolerance of acute heat stress. Thus, heterogeneity can serve as a bet-hedging mechanism against environmental uncertainty. I will present our work to dissect the molecular mechanism of bet hedging and to map natural variation in growth strategies across yeast strains.
Friday, April 29, 2016
12:00 PM
RRI 101
Host: Ian Ehrenreich
New York University,
Department of Biology,
Center for Genomics and Systems Biology
Abstract: Genetically identical cells growing in the same environment often display striking cell-to-cell heterogeneity in gene expression and other traits. Such heterogeneity is clinically important, as it is seen in microbial responses to antibiotics and in tumor cells. Nonetheless, molecular mechanisms that promote or suppress heterogeneity are poorly understood, particularly in eukaryotic organisms. We use the model eukaryote and opportunistic pathogen Saccharomyces cerevisiae (budding yeast) to study these mechanisms. I will present our work using high-throughput morphometric analysis of individual yeast cells to identify genes controlling the amount of variation in cell shape. I will also present our work on a form of evolutionarily adaptive heterogeneity in yeast. We developed a highly parallel, time-lapse microscopy assay to monitor variable protein expression, growth rate and survival outcomes of tens of thousands of yeast microcolonies simultaneously. Genetically identical cells display high variation in growth rate, and slow growth correlates with higher expression of stress-protective gene products and with higher tolerance of acute heat stress. Thus, heterogeneity can serve as a bet-hedging mechanism against environmental uncertainty. I will present our work to dissect the molecular mechanism of bet hedging and to map natural variation in growth strategies across yeast strains.
Friday, April 29, 2016
12:00 PM
RRI 101
Host: Ian Ehrenreich
ChemBio Seminar Series | "Discovery of Functional Ligands from Genetically-Encoded Libraries of Peptide Derivatives"
Dr. Ratmir Derda
Department of Chemistry and Alberta Glycomics Center,
University of Alberta, Canada
Abstract:
Phage display accelerates the discovery of peptide-derived drugs, some of which have been FDA-approved, and many are progressing through the clinical pipeline. However, the building blocks and diversity of phage libraries is limited to amino acids. Our group uses phage display as a foundation for multi-step organic synthesis to produce libraries of peptide derivatives displayed on phage. We developed the methodology for quantification of yield, purity and kinetics of reactions on phage-displayed peptide libraries; examples are N-terminal conjugation1 and cyclization of linear peptides.2 Chemical modification of libraries allowed us to develop Genetically-Encoded Fragment-Based Discovery (GE-FBD) platform,3 which combines >108 peptide fragments with variable, genetically-encoded modifications.4 For example, GE-FBD can be used to select phage-displayed glycopeptides to dock a glycan fragment at the carbohydrate-binding site and guide selection of synergistic peptide motifs adjacent to the pocket.3 We believe that display of peptide derivatives on phage can be developed into an efficient platform for discovery of biological probes and drug leads that combine advantages of small-molecule and “biological” classes of drugs.
1. (a) J. Am. Chem. Soc., 2014, 136, 8149; (b) ACS Chem. Biol., 2012, 7 (9), 1482
2. ACS Chem. Biol., 2014, 9, 443.
3. Ng et al., J. Am. Chem. Soc., 2015, 137, 5248
4. Tjhung et al., J. Am. Chem. Soc., 2016, DOI: 10.1021/jacs.5b10390
Thursday, April 28, 2016
12:30pm in the Seaver Science Auditorium
SSL next to the library
The scientific community is invited to attend.
Department of Chemistry and Alberta Glycomics Center,
University of Alberta, Canada
Abstract:
Phage display accelerates the discovery of peptide-derived drugs, some of which have been FDA-approved, and many are progressing through the clinical pipeline. However, the building blocks and diversity of phage libraries is limited to amino acids. Our group uses phage display as a foundation for multi-step organic synthesis to produce libraries of peptide derivatives displayed on phage. We developed the methodology for quantification of yield, purity and kinetics of reactions on phage-displayed peptide libraries; examples are N-terminal conjugation1 and cyclization of linear peptides.2 Chemical modification of libraries allowed us to develop Genetically-Encoded Fragment-Based Discovery (GE-FBD) platform,3 which combines >108 peptide fragments with variable, genetically-encoded modifications.4 For example, GE-FBD can be used to select phage-displayed glycopeptides to dock a glycan fragment at the carbohydrate-binding site and guide selection of synergistic peptide motifs adjacent to the pocket.3 We believe that display of peptide derivatives on phage can be developed into an efficient platform for discovery of biological probes and drug leads that combine advantages of small-molecule and “biological” classes of drugs.
1. (a) J. Am. Chem. Soc., 2014, 136, 8149; (b) ACS Chem. Biol., 2012, 7 (9), 1482
2. ACS Chem. Biol., 2014, 9, 443.
3. Ng et al., J. Am. Chem. Soc., 2015, 137, 5248
4. Tjhung et al., J. Am. Chem. Soc., 2016, DOI: 10.1021/jacs.5b10390
Thursday, April 28, 2016
12:30pm in the Seaver Science Auditorium
SSL next to the library
The scientific community is invited to attend.
Tuesday, April 19, 2016
MB Seminar Series | "DNA Repair and Precision Medicine.”
Richard Pomerantz
Temple University
Lewis Katz School of Medicine
Fels Institute for Cancer Research
Friday, April 22, 2016
12:00 PM
RRI 101
Host: Xiaojiang Chen
Temple University
Lewis Katz School of Medicine
Fels Institute for Cancer Research
Friday, April 22, 2016
12:00 PM
RRI 101
Host: Xiaojiang Chen
Monday, April 11, 2016
Microorganisms battle it out within algal blooms
Jed Fuhrman and David Needham of biological sciences discover that algal blooms in the ocean encompass microscopic skirmishes, with the front lines shifting on a daily basis.
By Robert Perkins - March 8, 2016
A microscopic image shows the type of phytoplankton and bacteria observed by USC researchers during a study of algal blooms. Photo courtesy of David Needham and Jed Fuhrman.
An unseen war raging among the ocean’s tiniest organisms has significant implications for understanding the ocean’s role in climate change, according to a new study...
For the full story, click here.
By Robert Perkins - March 8, 2016
A microscopic image shows the type of phytoplankton and bacteria observed by USC researchers during a study of algal blooms. Photo courtesy of David Needham and Jed Fuhrman.
An unseen war raging among the ocean’s tiniest organisms has significant implications for understanding the ocean’s role in climate change, according to a new study...
For the full story, click here.
Summer Fellowship Boot Camp
Dear colleagues, we are delighted to let you know that as part of our DIA initiative, the Graduate School will host an expanded Summer Fellowship Boot Camp for incoming and rising second year PhD students. If appropriate, please share the information below with eligible candidates.
The boot camp is a 10-day intensive writing workshop in which participants will complete an application for one of the following opportunities:
• National Science Foundation, Graduate Research Fellowship Program
• Ford Foundation Pre-Doctoral Fellowship
• Paul and Daisy Soros Fellowship for New Americans
Participants will receive a $1,000 stipend for housing and other expenses while attending the boot camp. In addition, participants who submit a complete application to one of the identified fellowships in fall 2016 may be eligible for a travel or research award of up to $1,000.
Participants are expected to attend all of the scheduled activities and to work on drafts of their proposals while not in sessions. Participants will meet as a large group on Wednesday August 3 for a full day of activities. Subsequent sessions will be organized around specific fellowship applications. Students from STEM fields interested in applying for the NSF GRFP will meet in the mornings. Students interested in the Ford, Soros or NSF GRFP in social science fields will meet in the afternoons. On most session days, there will be an optional lunch for all students from 12:00 - 1:00 pm.
Eligibility: Boot camp applicants must meet the requirements of the identified fellowships. Applicants must be a US citizen, US national, or permanent resident and either a newly admitted PhD student or a rising second year PhD student in fall 2016.
Information about specific eligibility requirements for the various fellowships is available on these websites:
NSF GRFP: https://www.nsfgrfp.org/
Ford Pre-Doctoral: http://sites.nationalacademies.org/PGA/FordFellowships/index.htm
Soros: http://www.pdsoros.org/competition/
To apply, please complete the form located here: https://goo.gl/3mTsfA. More information is available from the USC Graduate School at gradfllw@usc.edu. Applications are due on June 3, 2016. Applications will be reviewed by an interdisciplinary faculty committee and acceptance decisions will be sent out before the end of the month.
All the best, Meredith
Meredith Drake Reitan, MPL, PhD
Associate Dean for Graduate Fellowships
Graduate School
Office of the Provost
Adjunct Associate Professor
Sol Price School of Public Policy
University of Southern California
mereditd@usc.edu
The boot camp is a 10-day intensive writing workshop in which participants will complete an application for one of the following opportunities:
• National Science Foundation, Graduate Research Fellowship Program
• Ford Foundation Pre-Doctoral Fellowship
• Paul and Daisy Soros Fellowship for New Americans
Participants will receive a $1,000 stipend for housing and other expenses while attending the boot camp. In addition, participants who submit a complete application to one of the identified fellowships in fall 2016 may be eligible for a travel or research award of up to $1,000.
Participants are expected to attend all of the scheduled activities and to work on drafts of their proposals while not in sessions. Participants will meet as a large group on Wednesday August 3 for a full day of activities. Subsequent sessions will be organized around specific fellowship applications. Students from STEM fields interested in applying for the NSF GRFP will meet in the mornings. Students interested in the Ford, Soros or NSF GRFP in social science fields will meet in the afternoons. On most session days, there will be an optional lunch for all students from 12:00 - 1:00 pm.
Eligibility: Boot camp applicants must meet the requirements of the identified fellowships. Applicants must be a US citizen, US national, or permanent resident and either a newly admitted PhD student or a rising second year PhD student in fall 2016.
Information about specific eligibility requirements for the various fellowships is available on these websites:
NSF GRFP: https://www.nsfgrfp.org/
Ford Pre-Doctoral: http://sites.nationalacademies.org/PGA/FordFellowships/index.htm
Soros: http://www.pdsoros.org/competition/
To apply, please complete the form located here: https://goo.gl/3mTsfA. More information is available from the USC Graduate School at gradfllw@usc.edu. Applications are due on June 3, 2016. Applications will be reviewed by an interdisciplinary faculty committee and acceptance decisions will be sent out before the end of the month.
All the best, Meredith
Meredith Drake Reitan, MPL, PhD
Associate Dean for Graduate Fellowships
Graduate School
Office of the Provost
Adjunct Associate Professor
Sol Price School of Public Policy
University of Southern California
mereditd@usc.edu
2016 Mentoring Award Recipient | Dr. Remo Rohs
Each year the University of Southern California recognizes faculty members across the university who have demonstrated a commitment to mentoring. This year over 150 deserving faculty were nominated and 21 were selected.
Recipient List
Recipient List
ChemBio Seminar Series | "High Resolution CryoEM Structural Analysis of Heterogeneous Macromolecular Machines"
Thursday, April 14, 2016, 12:30pm in the Seaver Science Auditorium
SSL next to the library
Dr. Dmitry Lyumkis
Salk Helmsley Fellow, Laboratory of Genetics
The Salk Institute for Biological Studies
Abstract:
Single particle cryo-electron microscopy (cryoEM) is becoming a fundamental component of a
structural biologist’s toolkit, as improvements in instrumentation, software, automation, and
specimen preparation are making this technique increasingly powerful for the analysis of
macromolecules and macromolecular complexes. One of the primary advantages of the
methodology is the ability to analyze heterogeneous macromolecular assemblies, i.e. those that
exhibit either conformational mobility within distinct regions or compositional heterogeneity
exhibited by loosely and sub-stoichiometrically associated components. By employing
classification techniques, it is possible to place each individual particle image into one of several,
potentially many, groups, according to homogeneity. I will present three biological stories, which
center around and build upon the principles of high resolution cryoEM imaging and heterogeneity
analysis, each differing in the level of structural complexity. First, I will describe our structural
insights into a novel architecture of a retroviral integration complex called an intasome. I will then
describe how we used cryoEM to solve the structure of a very small protein complex by cryoEM
standards (150 kDa) to near-atomic resolution, wherein, crucially, we teased out the functionally
relevant enzymatic form using just 2% of the data. Finally, I will describe our current efforts
toward understanding the structural complexity and dynamic assembly underlying ribosome
biogenesis.
The scientific community is invited to attend.
SSL next to the library
Dr. Dmitry Lyumkis
Salk Helmsley Fellow, Laboratory of Genetics
The Salk Institute for Biological Studies
Abstract:
Single particle cryo-electron microscopy (cryoEM) is becoming a fundamental component of a
structural biologist’s toolkit, as improvements in instrumentation, software, automation, and
specimen preparation are making this technique increasingly powerful for the analysis of
macromolecules and macromolecular complexes. One of the primary advantages of the
methodology is the ability to analyze heterogeneous macromolecular assemblies, i.e. those that
exhibit either conformational mobility within distinct regions or compositional heterogeneity
exhibited by loosely and sub-stoichiometrically associated components. By employing
classification techniques, it is possible to place each individual particle image into one of several,
potentially many, groups, according to homogeneity. I will present three biological stories, which
center around and build upon the principles of high resolution cryoEM imaging and heterogeneity
analysis, each differing in the level of structural complexity. First, I will describe our structural
insights into a novel architecture of a retroviral integration complex called an intasome. I will then
describe how we used cryoEM to solve the structure of a very small protein complex by cryoEM
standards (150 kDa) to near-atomic resolution, wherein, crucially, we teased out the functionally
relevant enzymatic form using just 2% of the data. Finally, I will describe our current efforts
toward understanding the structural complexity and dynamic assembly underlying ribosome
biogenesis.
The scientific community is invited to attend.
NSF CAREER Award Educational Outreach Workshop
Tuesday, May 17, Noon - 1:30pm
Loker Hydrocarbon Institute (LHI) 307, Olah Library
Co-Sponsored by the Loker Hydrocarbon Research Institute
Most NSF funding programs prioritize an integrated educational/outreach program as part of the proposed project. This is particularly critical for CAREER projects. Because many NSF applicants find it challenging to identify strong educational/outreach plans for NSF awards, the CET is reprising its popular workshop in which recent NSF grantees and panelists will provide feedback on proposals in development and discuss how they might review or what changes could optimize their probability of funding.
Participants are encouraged to submit a pre-copy or summary of their educational/outreach plan to the host to ensure that appropriate reviewers are in attendance.
All NSF applicants and prospective applicants are welcomed.
Presented by: Travis Williams, CET Faculty Fellow and Associate Professor of Chemistry and recent CAREER Recipient, Philip Taylor, USC Dornsife Executive Director of Research Advancement; and a panel of recent NSF grantees and reviewers.
RSVP to travisw@usc.edu
Loker Hydrocarbon Institute (LHI) 307, Olah Library
Co-Sponsored by the Loker Hydrocarbon Research Institute
Most NSF funding programs prioritize an integrated educational/outreach program as part of the proposed project. This is particularly critical for CAREER projects. Because many NSF applicants find it challenging to identify strong educational/outreach plans for NSF awards, the CET is reprising its popular workshop in which recent NSF grantees and panelists will provide feedback on proposals in development and discuss how they might review or what changes could optimize their probability of funding.
Participants are encouraged to submit a pre-copy or summary of their educational/outreach plan to the host to ensure that appropriate reviewers are in attendance.
All NSF applicants and prospective applicants are welcomed.
Presented by: Travis Williams, CET Faculty Fellow and Associate Professor of Chemistry and recent CAREER Recipient, Philip Taylor, USC Dornsife Executive Director of Research Advancement; and a panel of recent NSF grantees and reviewers.
RSVP to travisw@usc.edu
2016 Teaching Award Recipient | Dr. Susan Forsburg
With notable pleasure the Center for Excellence in Teaching reports that at this year's Academic Honors Convocation on April 12, 2016 the Associates Award for Excellence in Teaching and the University Outstanding Teaching Assistant Awards will be presented. Please join us in congratulating these dedicated professors and teaching assistants.
Associates Award for Excellence in Teaching - citations
Susan L. Forsburg, Professor of Biological Sciences
USC Dornsife College of Letters, Arts and Sciences
Associates Award for Excellence in Teaching - citations
Susan L. Forsburg, Professor of Biological Sciences
USC Dornsife College of Letters, Arts and Sciences
C.-C. Jay Kuo, Dean's Professor of Electrical Engineering-Systems, Computer Science, and Mathematics
USC Viterbi School of Engineering
University Outstanding Teaching Assistant Award - citations
Tushar Bharati, Economics
Jose Raul Gonzalez Alonso, Physics and Astronomy
Christopher Muniz, Creative Writing
Passing of Bob Bils, retired BISC faculty member
Dear BISC Faculty & Staff Members,
I am sad to inform you that one of our former faculty members, Prof. Robert Bils, passed away at his home on March 26 at the age of 85. Bob joined our faculty in 1962 and served 37 years before retiring in 1999. Many of us "old-timers" will remember him as a skilled electron microscopist and a very decent man. Among his many accomplishments was his pivotal role in founding of the Center for Electron Microscopy and Microanalysis. His funeral will be held tomorrow, April 12, at 11:00 am at Rose Hills Memorial Park in Whittier, with a Celebration of Life to follow at Coco's Restaurant in Montebello at 12:30 pm. Details and directions, and a brief biography of Bob, can be found at http://www.rishermortuary.com/obituaries/Robert-Bils/#!/Obituary.
Sincerely,
Albert Herrera
I am sad to inform you that one of our former faculty members, Prof. Robert Bils, passed away at his home on March 26 at the age of 85. Bob joined our faculty in 1962 and served 37 years before retiring in 1999. Many of us "old-timers" will remember him as a skilled electron microscopist and a very decent man. Among his many accomplishments was his pivotal role in founding of the Center for Electron Microscopy and Microanalysis. His funeral will be held tomorrow, April 12, at 11:00 am at Rose Hills Memorial Park in Whittier, with a Celebration of Life to follow at Coco's Restaurant in Montebello at 12:30 pm. Details and directions, and a brief biography of Bob, can be found at http://www.rishermortuary.com/obituaries/Robert-Bils/#!/Obituary.
Sincerely,
Albert Herrera
CB Colloquium | “Genomics makes it easier to understand the complexity of Mendelian disorders”
Xiaowu Gai
Keck School of Medicine of USC
Director of Bioinformatics
Center for Personalized Medicine
Children's Hospital Los Angeles
Thursday, April 14, 2016
2:00 pm
RRI 101
Host: Jasmine Zhou
Keck School of Medicine of USC
Director of Bioinformatics
Center for Personalized Medicine
Children's Hospital Los Angeles
Thursday, April 14, 2016
2:00 pm
RRI 101
Host: Jasmine Zhou
MB Seminar Series | "Understanding the biology of dormant disseminated cancer cells: a path to manage late cancer relapse.”
Julio Aguirre-Ghiso
Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Ichan School of Medicine at Mount Sinai
Abstract: Clinical evidence suggests that improved outcomes within the first 5 years are due to advances in early detection, surgery and anti-proliferative therapies. This success has led to patients living longer. Nevertheless, they still die from late cancer recurrence. While a number of mechanisms may contribute, growing evidence suggests that late relapse may be due to the ability of disseminated cancer cells (DCCs) to survive in a quiescent or dormant state and evade therapies. DCCs are thought to originate from invasive primary lesions, but it is now recognized that early-evolved lesions can also generate DCCs. The mechanisms that produce early-disseminated cancer cells (eDCC) during early stages of breast cancer evolution are poorly understood. Here we show that HER2+ cancer cells in mammary intraepithelial neoplasias (MIN), are highly efficient in systemically disseminating from primary sites. These eDCCs were HER2+/P-ATF2lo/E-cadherinlo, and were found also in human DCIS samples. Further, eDCC precursors in MIN lesions underwent a Wnt-dependent EMT that was reversed by HER2 or Wnt signaling blockade. Intra-vital imaging of transgenic HER2-CFP MIN lesions revealed that eDCC precursors invade the local stroma, intravasate and circulate to target organs. This process was aided by macrophages in similar way as they regulate mammary branching morphogenesis. We found that macrophages are localized inside the epithelium of pre-malignant lesions but localize in the stroma of healthy tissue. Macrophage recruitment depends on upregulation of CCL2 in HER2+ mammary epithelial cells via activation of NFkB. Importantly, samples from patients with DCIS frequently contained intra-epithelial macrophages, correlating with E-Cadherin downregulation. Macrophage invasion into ducts disrupted the myoepithelium and further supported the oncogene-driven EMT-like response in luminal cells and their spread. Surprisingly, although the vast majority of eDCCs are non-proliferative, they can still initiate metastasis. However, depletion of macrophages from pre-malignant HER2+ lesions drastically reduces early dissemination and late metastasis. We reveal that during a stage when HER2 still does not fuel proliferation, it aberrantly activates a side-branching morphogenetic program that through macrophage recruitment and an EMT-like response causes early dissemination. That eDCCs carry latent metastatic initiating capacity cancer changes our understanding of metastasis onset and how it might be targeted effectively. For example, if immune therapies depend on a high mutational load, eDCCs may evade immune detection.
Friday, April 15, 2016
12:00 PM
RRI 101
Host: Peter Kuhn
Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Ichan School of Medicine at Mount Sinai
Abstract: Clinical evidence suggests that improved outcomes within the first 5 years are due to advances in early detection, surgery and anti-proliferative therapies. This success has led to patients living longer. Nevertheless, they still die from late cancer recurrence. While a number of mechanisms may contribute, growing evidence suggests that late relapse may be due to the ability of disseminated cancer cells (DCCs) to survive in a quiescent or dormant state and evade therapies. DCCs are thought to originate from invasive primary lesions, but it is now recognized that early-evolved lesions can also generate DCCs. The mechanisms that produce early-disseminated cancer cells (eDCC) during early stages of breast cancer evolution are poorly understood. Here we show that HER2+ cancer cells in mammary intraepithelial neoplasias (MIN), are highly efficient in systemically disseminating from primary sites. These eDCCs were HER2+/P-ATF2lo/E-cadherinlo, and were found also in human DCIS samples. Further, eDCC precursors in MIN lesions underwent a Wnt-dependent EMT that was reversed by HER2 or Wnt signaling blockade. Intra-vital imaging of transgenic HER2-CFP MIN lesions revealed that eDCC precursors invade the local stroma, intravasate and circulate to target organs. This process was aided by macrophages in similar way as they regulate mammary branching morphogenesis. We found that macrophages are localized inside the epithelium of pre-malignant lesions but localize in the stroma of healthy tissue. Macrophage recruitment depends on upregulation of CCL2 in HER2+ mammary epithelial cells via activation of NFkB. Importantly, samples from patients with DCIS frequently contained intra-epithelial macrophages, correlating with E-Cadherin downregulation. Macrophage invasion into ducts disrupted the myoepithelium and further supported the oncogene-driven EMT-like response in luminal cells and their spread. Surprisingly, although the vast majority of eDCCs are non-proliferative, they can still initiate metastasis. However, depletion of macrophages from pre-malignant HER2+ lesions drastically reduces early dissemination and late metastasis. We reveal that during a stage when HER2 still does not fuel proliferation, it aberrantly activates a side-branching morphogenetic program that through macrophage recruitment and an EMT-like response causes early dissemination. That eDCCs carry latent metastatic initiating capacity cancer changes our understanding of metastasis onset and how it might be targeted effectively. For example, if immune therapies depend on a high mutational load, eDCCs may evade immune detection.
Friday, April 15, 2016
12:00 PM
RRI 101
Host: Peter Kuhn
NGP Distinguished Speaker Series | Amita Sehgal
Monday, April 11, 2016
4:00 PM to 5:00 PM
University Park Campus
Hedco Neurosciences Building (HNB)
Amita Sehgal is a molecular biologist and chronobiologist in the Department of Neuroscience at the Perelman School of Medicine at the University of Pennsylvania. Sehgal has been involved in the discovery of Drosophila TIM and many other important components of the Drosophila clock mechanism. Sehgal has contributed greatly to the development of Drosophila as a model for the study of sleep. Her research continues to be focused on understanding the genetic basis of sleep and also how circadian systems relate to other aspects of physiology.
Amita Sehgal's major goal is to understand the molecular and cellular networks that drive behavior, in particular rhythmic behaviors such as sleep. Her studies are done largely with the fruit fly, Drosophila melanogaster, and are directed towards elucidating the mechanisms that confer a circadian (~24-hour) periodicity on much of behavior and physiology as well as understanding how and why the need to sleep is generated.
4:00 PM to 5:00 PM
University Park Campus
Hedco Neurosciences Building (HNB)
Amita Sehgal is a molecular biologist and chronobiologist in the Department of Neuroscience at the Perelman School of Medicine at the University of Pennsylvania. Sehgal has been involved in the discovery of Drosophila TIM and many other important components of the Drosophila clock mechanism. Sehgal has contributed greatly to the development of Drosophila as a model for the study of sleep. Her research continues to be focused on understanding the genetic basis of sleep and also how circadian systems relate to other aspects of physiology.
Amita Sehgal's major goal is to understand the molecular and cellular networks that drive behavior, in particular rhythmic behaviors such as sleep. Her studies are done largely with the fruit fly, Drosophila melanogaster, and are directed towards elucidating the mechanisms that confer a circadian (~24-hour) periodicity on much of behavior and physiology as well as understanding how and why the need to sleep is generated.
IEB Grad Student Andrea Currylow in Madagascar
Join Holohil's John Edwards as he travels to southern Madagascar to assist USC biologist Andrea Currylow with her PhD research on Radiated and Spider Tortoises!
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