Snapshot of Science for June 2019

June 2019

Here's a quick look at recent publications in high impact journals from investigators at the Massachusetts General Hospital Research Institute.

MI-2β IS CRITICAL FOR PRODUCING B CELLS
Chromatin Restriction by the Nucleosome Remodeler Mi-2β and Functional Interplay with Lineage-specific Transcription Regulators Control B-cell Differentiation
Yoshida T, Hu Y, Zhang Z, Emmanuel AO, Galani K [et al.], Georgopoulos K.
Published in Genes & Development on May 23, 2019 | *Summary available below

NOREPINEPHRINE ACTIVITY AND ITS ROLE IN ALZHEIMER'S
Alzheimer's Disease Pathology: Pathways Between Central Norepinephrine Activity, Memory, and Neuropsychiatric Symptoms
Jacobs HIL, Riphagen JM, Ramakers IHGB, Verhey FRJ.
Published in Molecular Psychiatry on May 28, 2019 | *Summary available below

NEW INSIGHTS INTO THE ORIGINS OF SYMPTOMS OF INHERITED METABOLIC DISEASES
A Model of Hereditary Sensory and Autonomic Neuropathy Type 1 Reveals a Role of Glycosphingolipids in Neuronal Polarity
Cui M, Ying R, Jiang X, Li G, Zhang X [et al.] Zhang H.
Published in Journal of Neuroscience on May 28, 2019

GENDER DISPARITIES IN ACADEMIC MEDICINE
Trends in Proportion of Women as Authors of Medical Journal Articles, 2008-2018
Hart KL, Perlis RH.
Published in JAMA Internal Medicine on May 28, 2019 | *Summary available below

THE ROLE OF LYSOSOMES IN STARVATION
Surviving Starvation Simply Without TFEB
Soukas AA, Zhou B.
Published in PLOS Biology on May 28, 2019 | *Summary available below

FURTHER DEFINING HEART FAILURE WITH PRESERVED EJECTION FRACTION
Differential Clinical Profiles, Exercise Responses and Outcomes Associated with Existing HFpEF Definitions
Ho JE, Zern EK, Wooster L, Bailey CS, Cunnigham T [et al.] Lewis GD.
Published in Circulation on May 28, 2019 | *Summary available below

ALTERATIONS IN THE MICROBIOMES OF IBD PATIENTS
Multi-omics of the Gut Microbial Ecosystem in Inflammatory Bowel Diseases
Lloyd-Price J, Arze C, Ananthakrishnan AN, Schirmer M, Avila-Pacheco J [et al.], Xavier RJ.
Published in Nature on May 29, 2019 | *Summary available below

GENETIC MECHANISMS OF CHRONIC LYMPHOCYTIC LEUKAEMIA
Growth Dynamics in Naturally Progressing Chronic Lymphocytic Leukaemia
Gruber M, Bozic I, Leshchiner I, Livitz D, Stevenson K [et al.], Getz G.
Published in Nature on May 29, 2019 | *Summary available below

A POTENTIAL THERAPY FOR EARLY TRIPLE-NEGATIVE BREAST CANCER
FAIRLANE, a Double-blind Placebo-controlled Randomized Phase II Trial of Neoadjuvant Ipatasertib Plus Paclitaxel for Early Triple-negative Breast Cancer.
Oliveira M, Saura C, Nuciforo P, Calvo I, Andersen J [et al.] Isakoff SJ.
Published in Annals of Oncology on May 30, 2019

THE MECHANISMS BEHIND PANCREATIC CANCER'S AGGRESSIVE NATURE
Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer
Ligorio M, Sil S, Malagon-Lopez J, Nieman LT, Misale S [et al.], Ting DT.
Published in Cell on May 30, 2019 | *Summary available below

STRATIFYING THE CELLS THAT MAKE UP THE WALL OF A BLOOD VESSEL
Single Cell Analysis of the Normal Mouse Aorta Reveals Functionally Distinct Endothelial Cell Populations
Kalluri AS, Vellarikkal SK, Edelman ER, Nguyen L, Subramanian A [et al.], Gupta RM.
Published in Circulation on May 31, 2019 | *Summary available below

EVALUATING THE COMBINED TRANSPLANTS FROM HALF-MATCHED ORGAN DONORS
Haploidentical Hematopoietic Cell and Kidney Transplantation for Hematological Malignancies and End-Stage Renal Failure
Chen YB, Elias N, Heher E, McCune JS, Collier K [et al.], Spitzer TR.
Published in Blood on May 31, 2019 | *Summary available below

CHANGES IN ECONOMIC AND CLINICAL OUTCOMES OF THE JOINT REPLACEMENT MODEL
Evaluation of Economic and Clinical Outcomes Under Centers for Medicare & Medicaid Services Mandatory Bundled Payments for Joint Replacements
Haas DA, Zhang X, Kaplan RS, Song Z.
Published in JAMA Internal Medicine on June 3, 2019 | *Summary available below

IDENTIFYING HIGH-RISK PANCREATIC CYSTIC LESIONS
Cross Validation of the Monoclonal Antibody Das-1 in Identification of High-risk Mucinous Pancreatic Cystic Lesions
Das KK, Geng X, Brown JW, Morales-Oyarvide V, Huynh T [et al.], Mino-Kenudson M.
Published in Gastroenterology on June 5, 2019 | *Summary available below

STUDYING THE SIDE EFFECTS OF TARGETED THERAPY FOR BRAF MUTANT MELANOMA
Atezolizumab Plus Cobimetinib and Vemurafenib in BRAF-mutated Melanoma Patients
Sullivan RJ, Hamid O, Gonzalez R, Infante JR, Patel MR [et al.], Hwu P.
Published in Nature Medicine on June 6, 2019 | *Summary available below

THE IMPORTANCE OF CBX2 IN PHASE SEPARATION
Phase Separation of Polycomb-repressive Complex 1 is Governed by a Charged Disordered Region of CBX2
Plys AJ, Davis CP, Kim J, Rizki G, Keenen MM [et al.], Kingston RE.
Published in Genes & Development on June 6, 2019 | *Summary available below

MACROSCOPIC CLONAL EXPRESSION IN HUMAN TISSUES
RNA Sequence Analysis Reveals Macroscopic Somatic Clonal Expansion Across Normal Tissues
Yizhak K, Aguet F, Kim J, Hess JM, Kübler K [et al.], Getz G.
Published in Science on June 7, 2019 | *Summary available below

DISTINGUISHING BETWEEN DAMAGING AND BENEFICIAL IMMUNE RESPONSES
An Activatable PET Imaging Radioprobe is a Dynamic Reporter of Myeloperoxidase Activity In Vivo
Wang C, Keliher E, Zeller MWG, Wojtkiewicz GR, Aguirre AD [et al.], Chen JW.
Published in PNAS on June 11, 2019 | *Summary available below

EVALUATING BRENTUXIMAB AS A TREATMENT FOR HODGKIN LYMPHOMA
Brentuximab Vedotin, Doxorubicin, Vinblastine and Dacarbazine for Non-bulky Limited Stage Classical Hodgkin Lymphoma
Abramson JS, Arnason JE, LaCasce AS, Redd R, Barnes JA [et al.], Bello CM.
Published in Blood on June 11, 2019

HOW TISSUE STROMA RESPONDS TO MALIGNANT CELLS
A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia
Baryawno N, Przybylski D, Kowalczyk MS, Kfoury Y, Severe N [et al.], Scadden DT.
Published in Cell on June 13, 2019 | *Summary available below

DELINEATING FEATURES OF BRAIN CELL IDENTITY
Single-Cell Multi-omic Integration Compares and Contrasts Features of Brain Cell Identity
Welch JD, Kozareva V, Ferreira A, Vanderburg C, Martin C, Macosko EZ.
Published in Cell on June 13, 2019

ANALYZING LUPUS LEUKOCYTES TO DISCOVER NOVEL TREATMENTS
The Immune Cell Landscape in Kidneys of Patients with Lupus Nephritis
Arazi A, Rao DA, Berthier CC, Davidson A, Liu Y [et al.], Hacohen N.
Published in Nature Immunology on June 17, 2019 | *Summary available below

THERAPEUTIC-RESISTANCE IN EGFR-MUTATED LUNG CANCER
Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity
Marcar L, Bardhan K, Gheorghiu L, Dinkelborg P, Pfäffle H [et al.] Willers H.
Published in Cell Reports on June 18, 2019 | *Summary available below

DISCOVERING GENES THAT REGULATE NEURONAL POLARITY
Regulation of Caenorhabditis Elegans Neuronal Polarity by Heterochronic Genes
Armakola M, Ruvkun G.
Published in PNAS on June 18, 2019 | *Summary available below

COLLEGE AFFIRMATIVE ACTION BANS AND RATES OF SMOKING AND ALCOHOL USE
College Affirmative Action Bans and Smoking and Alcohol Use Among Underrepresented Minority Adolescents in the United States: A Difference-in-Differences Study
Venkataramani AS, Cook E, O'Brien RL, Kawachi I, Jena AB, Tsai AC.
Published in PLOS Medicine on June 18, 2019 | *Summary available below

REINVIGORATING THE ANTIMICROBIAL PIPELINE
Large-scale Chemical-genetics Yields New M. Tuberculosis Inhibitor Classes
Johnson EO, LaVerriere E, Office E, Stanley M, Meyer E [et al.] Hung DT.
Published in Nature on June 19, 2019 | *Summary available below

A VOUCHER PROGRAM TO REDUCE UNINTENDED PREGNANCIES
Provision of Family Planning Vouchers and Early Initiation of Postpartum Contraceptive Use Among Women Living with HIV in Southwestern Uganda: A Randomized Controlled Trial
Atukunda EC, Mugyenyi GR, Obua C, Atuhumuza EB, Lukyamuzi EJ [et al.] Matthews LT.
Published in PLOS Medicine on June 21, 2019

THE EFFECTS OF THE MIS HORMONE ON EMBRYONIC DEVELOPMENT
Single-cell Sequencing of Neonatal Uterus Reveals an Endometrial Progenitor Indispensable for Fertility
Saatcioglu HD, Kano M, Horn H, Zhang L, Samore W [et al.], Pépin D.
Published in eLife on June 24, 2019 | *Summary available below

HOW SOCIOECONOMIC DISPARITIES AFFECT HEART HEALTH
Stress-associated Neurobiological Pathway Linking Socioeconomic Disparities to Cardiovascular Disease
Tawakol A, Osborne MT, Wang Y, Hammed B, Tung [et al.], Armstrong KA.
Published in Journal of the American College of Cardiology on June 24, 2019 | *Summary available below

THE MECHANISMS BEHIND UNICELLULAR TUBES
A Tensile Trilayered Cytoskeletal Endotube Drives Capillary-like Lumenogenesis
Khan LA, Jafari G, Zhang N, Membreno E, Yan S [et al.], Gobel V.
Published in Journal of Cell Biology on June 25, 2019 | *Summary available below

HOW AGING CONTRIBUTES TO THE SPREADING OF TAU
Experimental Evidence for the Age Dependence of Tau Protein Spread in the Brain
Wegmann S, Bennett RE, Delorme L, Robbins AB, Hu M [et al.], Hyman BT.
Published in Science Advances on June 26, 2019 | *Summary available below

ANTIBODY TRANSFERENCE FROM MOTHER TO CHILD
Fc Glycan-mediated Regulation of Placental Antibody Transfer
Jennewein MF, Goldfarb I, Dolatshahi S, Cosgrove C, Noelette FJ [et al.], Alter G.
Published in Cell on June 27, 2019 | *Summary available below

IDENTIFYING PASSENGER HOTSPOTS IN CANCER
Passenger Hotspot Mutations in Cancer Driven by APOBEC3A and Mesoscale Genomic Features
Buisson R, Langenbucher A, Bowen D, Kwan EE, Benes CH [et al.], Lawrence MS.
Published in Science on June 28, 2019 | *Summary available below

LOSS OF SETD1A LEADS TO AGING OF CANCER CELLS
SETD1A Protects from Senescence Through Regulation of the Mitotic Gene Expression Program
Tajima K, Matsuda S, Yae T, Drapkin BJ, Morris R [et al.], Maheswaran S.
Published in Nature Communications on June 28, 2019 | *Summary available below

Publication Summaries

Coordinated induction and repression of genes is critical in the developing immune system. In this study, we show that Mi-2β, an enzyme that controls chromatin accessibility, is critical for production of B cells, the mediators of humoral immunity. Mi-2β physically and functionally interacts with B cell-lineage transcriptional regulators to control B cell differentiation. Mi-2β induces genes regulated by IL-7-receptor signaling and promotes growth and survival in collaboration with EBF1. In partnership with IKAROS, Mi-2β represses genes involved in adhesion signaling, normally active in earlier progenitors. These positive and negative effects of Mi-2β on gene expression are critical for normal B cell differentiation and function.

(Summary submitted by Toshimi Yoshida, PhD, Cutaneous Biology Research Center, Department of Dermatology)

Tau protein, one of the two major proteins—the other is amyloid-beta—in Alzheimer’s disease accumulates first in the locus coeruleus, which produces norepinephrine. The relationships between norepinephrine, tau, memory and behavioral problems in Alzheimer’s disease are unclear. We examined blood and cerebrospinal fluid measurements from memory clinic patients and found that norepinephrine metabolism was related to memory and behavioral problems through tau. Norepinephrine metabolism was linked to memory via amyloid-beta only when inflammation levels were elevated. These findings illustrate the complexity of Alzheimer’s disease and suggest that interventions also targeting the norepinephrine system hold promise.

(Summary submitted by Heidi Jacobs, PhD, Gordon Center for Medical Imaging, Department of Radiology)

GENDER DISPARITIES IN ACADEMIC MEDICINE
Trends in Proportion of Women as Authors of Medical Journal Articles, 2008-2018
Hart KL, Perlis RH.
Published in JAMA Internal Medicine on May 28, 2019

Women are historically underrepresented in academic medicine. Since publications are a measure of academic success, we conducted a large-scale analysis of the representation of women as authors of journal articles across nine medical specialties and four high impact cross specialty journals over the last 10 years. We found differences between specialties in the representation of women as authors, and in the rate of increase in the representation of women as authors over the past decade highlighting opportunities for continued improvement. Overall, while there has been improvement over the last decade, the gender disparity in academic medicine remains.

(Summary submitted by Kamber Hart, BA, Center for Genomic Medicine, Center for Qualitative Health)

THE ROLE OF LYSOSOMES IN STARVATION
Surviving Starvation Simply Without TFEB
Soukas AA, Zhou B.
Published in PLOS Biology on May 28, 2019

Over millions of years, organisms have evolved elaborate means of surviving cycles of feast and famine. Lysosomes are acidified cellular compartments that play critical roles in the response to starvation. Without proper lysosomal function, cells can neither survive starvation nor recover from starvation when food is available. In this study we discuss the role of the lysosome in starvation and recent findings that two simple nutrients, glucose and the polyunsaturated fatty acid linoleate, are sufficient to activate starvation recovery pathways, bypassing the requirement for functioning lysosomes. These data shed light on the exact role of lysosomes in starvation resistance and recovery.

(Summary submitted by Alex Soukas MD, PhD, Center for Genomic Medicine)

Heart failure with preserved left ventricular ejection fraction (HFpEF) is increasingly common, yet there is currently no consensus on how to even define HFpEF. In a carefully characterized group of more than 500 patients presenting to Mass General with shortness of breath and suspected HFpEF we found striking differences in the number of patients fulfilling various diagnostic criteria for HFpEF. Importantly, current societal HFpEF definitions often missed patients who demonstrate physiologic evidence of HFpEF during exercise and experience future adverse outcomes. Our study highlights limitations in how HFpEF is currently defined and the merit of carefully defining HFpEF subgroups in an effort to improve targeted treatment for HFpEF.

(Summary submitted by Jennifer Ho, MD, Department of Cardiology)

Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the digestive tract. Genetics, environment and the gut microbiome contribute to these complex diseases and are the subjects of extensive research. As part of the Integrative Human Microbiome Project that aims to determine how microbiomes influence human health and disease, we collected data for one year to survey alterations within IBD patients and their microbiomes during states of remission and relapse. The most comprehensive description of dynamic perturbations in IBD to date, this study identifies factors central to disease activity and paves the way for future research and clinical advances.

(Summary submitted by Ramnik Xavier, MD, PhD, and Theresa Reimels, Department of Gastroenterology, Department of Molecular Biology)

The disease course of chronic lymphocytic leukaemia (CLL) is currently unpredictable, with some patients progressing rapidly while others live with stable and non-symptomatic disease for years. Similar to assembling a generational family tree, a computational method called PhylogicNDT analyzes DNA alterations and identifies relationships among clones of cells (like parents/siblings) to give us a peek into each CLL’s genetic history. This innovative analysis revealed that a given CLL’s growth pattern, either exponential growth or growth reaching saturation, can be predetermined by the genetic mutations acquired early in the disease process. Additionally, the data enable estimation of the growth advantage conferred by specific mutations. These findings present an opportunity to predict a patient’s disease course and intervene early with therapy.

(Summary submitted by Mendy Miller, PhD, Broad Institute)

Pancreatic cancer is a highly aggressive cancer that is defined by a robust stromal microenvironment. We combined single-cell RNA sequencing and next generation protein analytics to uncover the programs driven by the microenvironment that shape individual cancer cells to invade the blood stream to spread or replicate to grow the tumor. Using high content digital imaging, we analyzed 319,626 individual cancer cells. This analysis revealed different cancer cell phenotypes that can combine to form distinct tumor glands that behave as separate cancer cell units within the same tumor. This explains the aggressive nature of pancreatic cancer and has now provided new mechanistic insight to develop novel therapies.

(Summary submitted by David Ting, MD, Mass General Cancer Center, Department of Primary Care)

Blood vessels play an important role in many diseases, including heart disease, cancer, and neurological disorders. We asked a simple question: What are the different cells that make up the wall of a blood vessel? We used a new technology called single cell RNA-sequencing to analyze over 6000 mouse cells from the largest blood vessel in the body. We identified three types of endothelial cells. These groups of cells may contribute to disease because they seem to specialize in important processes like cholesterol transport, inflammation, and blood vessel growth.

(Summary submitted by Rajat Gupta, MD, Department of Cardiology)

EVALUATING COMBINED TRANSPLANTS FROM HALF-MATCHED ORGAN DONORS
Haploidentical Hematopoietic Cell and Kidney Transplantation for Hematological Malignancies and End-Stage Renal Failure
Chen YB, Elias N, Heher E, McCune JS, Collier K [et al.], Spitzer TR.
Published in Blood on May 31, 2019

The induction of immune tolerance, where a transplanted organ can be accepted without anti-rejection drugs, has been pioneered at Mass General through combined bone marrow and kidney transplantation, for patients with kidney failure, with or without cancer. A successful 20-year experience with this approach, initially with transplants from genetically matched family members, has more recently included transplants from half-matched family members. Here, we describe the first six patients who received a combined transplant from half-matched donors. Prolonged remissions of the myeloma with normal kidney function, with discontinuation of anti-rejection drugs in some cases, were achieved.

(Summary submitted by Thomas Spitzer, MD, Mass General Cancer Center)

We examined the impact of the first two years of Medicare’s mandatory bundled payment program for knee and hip replacements that began in 2016. The bundled payment program included care at the hospital through 90-days post-discharge. Hospitals that successfully managed a patient’s care over this time frame received savings back from Medicare up to a cap. We found that hospitals in metropolitan areas where participation was mandatory lowered their total episode spending (primarily post-acute care spending) by more than hospitals in metropolitan areas that were not required to participate. There were no observable differences in quality due to the program.

(Summary submitted by Derek Haas, MBA, Avant-garde Health)

Pancreatic cystic lesions (PCL) are frequently, incidentally identified in patients, while only a small fraction of them have a high risk of malignancy. There is a dearth of biomarkers that can reliably identify those high-risk lesions. We previously demonstrated in a pilot study that mAb Das-1 in cyst fluid specifically and sensitively identifies high-risk intraductal papillary mucinous neoplasm. In a large, multicenter, validation study of perioperatively aspirated PCL, mAb Das-1 was 88% sensitive and 99% specific and significantly more accurate than clinical guidelines in identifying high-risk PCL. The inclusion of the Das-1 marker into the cyst fluid analysis may aid in the preoperative diagnosis and risk stratification of patients with PCL.

(Summary submitted by Mari Mino-Kenudson, MD, Department of Pathology)

SIDE EFFECTS OF TARGETED THERAPY FOR BRAF MUTANT MELANOMA
Atezolizumab Plus Cobimetinib and Vemurafenib in BRAF-mutated Melanoma Patients
Sullivan RJ, Hamid O, Gonzalez R, Infante JR, Patel MR [et al.], Hwu P.
Published in Nature Medicine on June 6, 2019

We studied the effects of combining BRAF-targeted therapy with immune checkpoint inhibitor therapy in patients with advanced, BRAF mutant melanoma. In 39 patients who received the three drugs in combination, over 70% responded. The side effects were higher than would be predicted by any of the therapies by themselves but were managed successfully. The next step in the development of this combination is the completion of a randomized trial of these three drugs compared to vemurafenib and cobimetinib combination, to see if three drugs are better than two.

(Summary submitted by Ryan Sullivan, MD, Mass General Cancer Center)

Stable repression plays a critical role in the regulation of genes that specify tissue types. The polycomb repressive complex 1 (PRC1) family complexes in mammals are central to maintaining stable repression. We show that PRC1 can phase separate in vitro and generate dynamic phase separated puncta in cells. Phase separation is similar to how oil and vinegar behave as separate liquids in salad dressing. Mutations in PRC1 that were previously shown to impair repression and proper axial development in mice were shown to disrupt phase separation. These observations have intriguing implications, as the significantly increased concentration of PRC1 within phase separated bodies could facilitate maintenance of a repressive chromatin state during development.

(Summary submitted by Aaron Plys, PhD, Department of Genetics)

Within normal cells, genomic events can create somatic (i.e., acquired) mutations, some of which promote cell division into a clone, or a cluster of cells with shared mutations. While most clones pose no danger, some may eventually become cancer. Computational analysis of RNA shows that a surprising 95% of ~500 healthy individuals contained clones in at least one of the 29 tissues tested, some harboring mutations in known cancer genes. Lung, sun-exposed skin and the esophagus––tissues routinely exposed to the environment––acquire the most clones as an individual ages. This comprehensive study adjusts our understanding of what normal is and has implications for interpreting screening results from cancer and pre-cancer lesions, wherein detecting a known cancer mutation may not necessarily indicate the presence of cancer.

(Summary submitted by Mendy Miller, PhD, Broad Institute)

The immune response mediates tissue damage in many diseases, but available clinical imaging technologies do not distinguish between damaging and beneficial responses. We developed an imaging radioprobe to noninvasively report the activity of the damaging enzyme myeloperoxidase. The radioprobe can cross the blood-brain barrier and is highly sensitive and specific. It enables detection of damaging inflammation at an earlier stage than currently possible and could lead to early treatment before irreversible damage occurs. This radioprobe is a promising translational candidate to monitor many diseases, including cardiovascular, neurological and rheumatological diseases.

(Summary submitted by John Chen, MD, Department of Radiology, Center for Systems Biology)

All of our organs have cells that are considered the business side of the organ and cells that are in support. That is also true of the bone marrow, our body's blood factory. The bone marrow support cells, called stroma, have been shown to be critical for maintaining blood production and participating in blood diseases. This paper defines all the stromal cell types, one cell at a time, quantifying the genes expressed in each. As a result, we now have the complete catalogue of stromal cell types and a dynamic map of how they are changed in leukemia.

(Summary submitted by David Scadden, MD, Center for Regenerative Medicine, Mass General Cancer Center)

ANALYZING LUPUS LEUKOCYTES TO EXPLORE NEW IDEAS FOR TREATMENTS
The Immune Cell Landscape in Kidneys of Patients with Lupus Nephritis
Arazi A, Rao DA, Berthier CC, Davidson A, Liu Y [et al.], Hacohen N.
Published in Nature Immunology on June 17, 2019

Lupus is a potentially fatal autoimmune disease, in which the immune system attacks various organs, including the kidney—a severe condition called lupus nephritis. Current treatment for lupus nephritis is ineffective and often toxic. Thus, there is a need to better understand the mechanisms underlying this disease. A consortium including the group of Nir Hacohen recently provided a detailed picture of the network of immune cells driving lupus nephritis. Their work identified novel candidate therapeutic targets and showed that immune cells isolated from urine are highly similar to their kidney counterparts, suggesting urine can be used to monitor kidney inflammation.

(Summary submitted by Arnon Arazi, MSc, PhD, Broad Institute)

Many lung cancers in non-smokers harbor the EGFR oncogene and shrink upon EGFR-directed tyrosine kinase inhibitor (TKI) treatment. However, invariably cancer cells survive, acquire TKI resistance, and cause tumor regrowth. We discovered sensitivity of TKI-resistant tumors to PARP inhibitors (PARPi), which are FDA-approved for some BRCA mutant, DNA repair-defective cancers. Unexpectedly, PARPi sensitivity was not related to faulty DNA repair but reactive oxygen species (ROS), unstable oxygen-containing molecules capable of killing cells. Within weeks, TKI treatment induced dependence on PARP to combat ROS, a vulnerability that appears to persist even after resistance arises (to be tested in clinical trial NCT03891615).

(Summary submitted by Henning Willers, MD, Department of Radiation Oncology)

DISCOVERING GENES THAT REGULATE NEURONAL POLARITY
Regulation of Caenorhabditis Elegans Neuronal Polarity by Heterochronic Genes
Armakola M, Ruvkun G.
Published in PNAS on June 18, 2019

The pattern of synaptic inputs and outputs of neurons is established during development and is maintained throughout adulthood. An unknown set of cellular mechanisms establish and maintain these synaptic connections. We used Caenorhabditis elegans to discover new genes that specify the polarity of a well-studied neuron. We discovered that particular genes regulate neuronal polarity. This work reveals neuronal polarity is maintained in adulthood suggests potential strategies for therapeutic intervention in neurodegenerative diseases and models of cognitive decline.

(Summary submitted by Gary Ruvkun, PhD, Department of Molecular Biology)

This research study found that when states ban affirmative action in college admissions, underrepresented minorities in the 11th and 12th grades show increased rates of cigarette smoking and alcohol use directly coinciding with the years that affirmative action bans are discussed, passed, and implemented. No comparable increases in smoking and alcohol use were observed among non-Hispanic white students—suggesting that the social meaning of these affirmative action bans explained the findings. Furthermore, this research study also found that the impacts of these bans on smoking behavior have persisted into young adulthood.

(Summary submitted by Alexander Tsai, MD, PhD, Department of Psychiatry)

Tuberculosis, caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb), is the deadliest infectious disease, with resistance to the front-line four-drug cocktail rising. Discovery of potential new antibiotics with new targets has seen limited success. Here, we developed a new drug discovery approach, called PROSPECT, which screened large compound libraries against pools of 100-150 genetically-barcoded Mtb strains, each depleted in an essential gene. This allowed compound prioritization by target and detection of compounds which would be missed by conventional methods. Using PROSPECT, we identified and validated more than 40 compounds including inhibitors of a new target, EfpA, opening the pipeline of new potential tuberculosis treatments.

(Summary submitted by Eachan Johnson, PhD, Department of Molecular Biology)

Early mammalian embryos are bipotential, possessing both male and female reproductive tract precursor structures. In the male, the MIS hormone secreted by the testis activates a cell surrounding the female duct to cause its regression. In this study we followed the fate of this gatekeeper cell in the female and found that in the absence of inhibitory signals, it forms the uterine endometrium. Using single-cell RNA sequencing we show that this endometrial progenitor remains sensitive to MIS until the first week after birth in rodents. MIS exposure during this critical period leads to severe uterine hypoplasia and infertility in adulthood.

(Summary submitted by David Pepin, PhD, Department of Surgery)

Lower socioeconomic status (SES) las been linked to an increased risk of cardiovascular diseases (CVD). To test whether stress-associated mechanisms link SES to CVD, researchers used PET/CT imaging to measure stress-associated brain activity (within the amygdala) and arterial inflammation. Their analyses suggested that lower SES leads to CVD events, (such as heart attacks and strokes) through a serial mechanism that involves higher amygdalar activity and greater arterial inflammation. These findings illuminate a stress-associated neurobiological mechanism by which SES disparities may potentiate adverse health outcomes.

(Summary submitted by Ahmed Tawakol, MD, Department of Cardiology)

THE MECHANISMS BEHIND UNICELLULAR TUBES
A Tensile Trilayered Cytoskeletal Endotube Drives Capillary-like Lumenogenesis.
Khan LA, Jafari G, Zhang N, Membreno E, Yan S [et al.], Gobel V.
Published in Journal of Cell Biology on June 25, 2019

Unicellular tubes are components of all internal organs and the vasculature. They construct a lumen inside a cell rather than between cells, a complex morphogenetic process that is not well understood. Using the unique single-cell C. elegans excretory canal as a model, this study shows that a tensile perilumenal triple intermediate-filament lattice, embedded between microfilaments and microtubules, tunnels a lumen through an extended, ultrathin tubular cell and equilibrates the lumen’s diameter. This finding provides new biomechanical insights into the process of intracellular lumenogenesis, with implications towards understanding congenital tubulogenesis defects, internal organ dysfunction and microvessel disease.

(Summary submitted by Liakot Khan, MD, Department of Pediatrics)

The fact that sporadic Alzheimer’s disease and other neurodegenerative disorders are age-related is evident, but the reasons why are unknown. To overcome this limitation, our team developed a viral gene vector that can be used in young or old animals and induces expression of pathologic and normal forms of human tau. The results suggest that old animals are more vulnerable to the effects of the tau protein than young animals. We hope that learning more about how the physiology of the aging brain contributes to the development of Alzheimer’s disease will lead to better therapeutic options for many neurodegenerative diseases.

(Summary submitted by Bradley Hyman, MD, PhD, Department of Neurology, Mass General Institute for Neurodegenerative Disease)

Vaccines have reduced morbidty and mortality across the globe, but have been found to be less effective in newborns. Throughout pregnancy, mothers transfer antibodies, magic immune bullets that target harmful-microbes via the placenta to help build the infant’s immune system. The rules by which the placenta performs this key immune function could hold the key to generating much more powerful vaccines. We used a novel proprietary tool, Systems Serology, to uncover the highly specialized selection of antibodies and demonstrated that the placenta selects, sieves and transfers only the most functional killer antibodies. This process endows newborns with a chance to fight infections.

(Summary submitted by Galit Alter, PhD, Ragon Institute)

Targeting mutations that drive cancer progression is crucial for developing new treatments, but is challenging because of the number of benign "passenger" mutations. One strategy scientists have used for identifying driver mutations is to look for “hotspot” mutations that recur in multiple patients. In this study, a team showed that this strategy may not always be reliable because certain locations in the genome can fold into "hairpin" structures that are a perfect fit for the DNA-editing enzyme APOBEC3A, causing them to be repeatedly mutated in many different cancers. Understanding how APOBEC3A generates these “passenger hotspots” will help researchers to prioritize real driver hotspots for further research.

(Summary submitted by Michael Lawrence, PhD, Mass General Cancer Center, Department of Pathology)

In this manuscript, we show that loss of SETD1A, an enzyme that maintains the expression of genes, leads to aging of cancer cells, a process known as senescence. Depletion of SETD1A reduces the expression of a class of proteins required for proper cell division leading to severe defects in this process causing the cells to become senescent. A few rare cells escape senescence and continue to cycle but they exhibit defective genomes suggesting that SETD1A maintains the balance between cell growth, senescence and genomic instability. Thus, SETD1A inhibitors may be used to exploit the growth suppressive effects of senescence.

(Summary submitted by Shyamala Maheswaran, PhD, Mass General Cancer Center, Department of Surgery)

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Snapshot of Science for June 2019

Publication Summaries