Publications by authors named "Santiago Naranjo"

11 Publications

  • Page 1 of 1

Epigenomic State Transitions Characterize Tumor Progression in Mouse Lung Adenocarcinoma.

Cancer Cell 2020 08 23;38(2):212-228.e13. Epub 2020 Jul 23.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address:

Regulatory networks that maintain functional, differentiated cell states are often dysregulated in tumor development. Here, we use single-cell epigenomics to profile chromatin state transitions in a mouse model of lung adenocarcinoma (LUAD). We identify an epigenomic continuum representing loss of cellular identity and progression toward a metastatic state. We define co-accessible regulatory programs and infer key activating and repressive chromatin regulators of these cell states. Among these co-accessibility programs, we identify a pre-metastatic transition, characterized by activation of RUNX transcription factors, which mediates extracellular matrix remodeling to promote metastasis and is predictive of survival across human LUAD patients. Together, these results demonstrate the power of single-cell epigenomics to identify regulatory programs to uncover mechanisms and key biomarkers of tumor progression.
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http://dx.doi.org/10.1016/j.ccell.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641015PMC
August 2020

Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1.

Nat Cancer 2020 Jun 8;1(6):589-602. Epub 2020 Jun 8.

Koch Institute for Integrative Cancer Research, Cambridge, MA, 02139, USA.

Approximately 20-30% of human lung adenocarcinomas (LUAD) harbor loss-of-function (LOF) mutations in Kelch-like ECH Associated-Protein 1 (), which lead to hyperactivation of the nuclear factor, erythroid 2-like 2 (NRF2) antioxidant pathway and correlate with poor prognosis. We previously showed that mutation accelerates KRAS-driven LUAD and produces a marked dependency on glutaminolysis. To extend the investigation of genetic dependencies in the context of mutation, we performed a druggable genome CRISPR-Cas9 screen in -mutant cells. This analysis uncovered a profound mutant-specific dependency on solute carrier family 33 member 1 (), an endomembrane-associated protein with roles in autophagy regulation, as well as a series of functionally-related genes implicated in the unfolded protein response. Targeted genetic and biochemical experiments using mouse and human -mutant tumor lines, as well as preclinical genetically-engineered mouse models (GEMMs) of LUAD, validate as a robust -mutant-specific dependency. Furthermore, unbiased genome-wide CRISPR screening identified additional genes related to dependency. Overall, our study provides a strong rationale for stratification of patients harboring -mutant or NRF2-hyperactivated tumors as likely responders to targeted SLC33A1 inhibition and underscores the value of integrating functional genetic approaches with GEMMs to identify and validate genotype-specific therapeutic targets.
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http://dx.doi.org/10.1038/s43018-020-0071-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373048PMC
June 2020

Pulmonary carcinoid presenting with persistent pneumothorax.

BMJ Case Rep 2019 Nov 10;12(11). Epub 2019 Nov 10.

Division of Endocrinology, Department of Internal Medicine, Duke University Hospital, Durham, North Carolina, USA

Lung neuroendocrine tumours (Lung NETs) are a rare group of pulmonary neoplasms often characterised by insidious clinical behaviour. Lung NET account for ~1%-2% of all lung malignancies in adults and 30% of all NETs. Incidence ranges from 0.2 to 2/100 000 population per year. While some patients may be asymptomatic, others may present with obstructive symptoms due to mass effect. Incidence of spontaneous pneumothorax as a complication of lung neoplasms is rare (0.05%-1.4% of all pneumothoraces). In this report, we present a case of recurrent pneumothorax due to Lung NET that was refractory to conservative management. We also discuss the diagnostic methods as well as surgical management approach, which is considered the treatment of choice in such tumours.
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http://dx.doi.org/10.1136/bcr-2019-231083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855850PMC
November 2019

Long-term Results of Corneal Wedge Resection for High Postkeratoplasty Astigmatism.

Cornea 2020 May;39(5):535-539

Ophthalmology Research Service, School of Medicine, CES University, Medellín, Colombia.

Purpose: To present the results of corneal wedge resection in postkeratoplasty astigmatism, performed by the same surgeon using the same nomogram over a 25-year period.

Methods: This is a retrospective observational study. The sample was obtained from the medical records of all patients who underwent penetrating or deep lamellar keratoplasty, performed by a single surgeon from 1993 to 2018. All surgeries were performed using a diamond knife, on the flat meridian, involving the keratoplasty scar and closed with five 10-0 nylon sutures.

Results: A total of 39 eyes were included. The keratometry measured cylinder improved from 7.99 ± 0.25 to 2.5 ± 0.3 D at 12 months and remained stable thereafter (a mean follow-up of 76.3 months). Best spectacle corrected visual acuity increased from 0.35 ± 0.01 to 0.57 ± 0.02 at 12 months and remained stable thereafter. There was a coupling ratio of 0.08 ± 0.03 D at 12 months. There were no corneal graft rejections or loss of best spectacle corrected visual acuity on this series.

Conclusions: Corneal wedge resection is a valuable resource for the management of high postkeratoplasty astigmatism. It is a safe and reproducible procedure, with stable results at 12 months and thereafter.
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http://dx.doi.org/10.1097/ICO.0000000000002176DOI Listing
May 2020

Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium.

Nature 2019 07 10;571(7765):398-402. Epub 2019 Jul 10.

Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.

A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche. Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age owing to defects in both stem cells and their niche. The functional decline was caused by a decrease in stemness-maintaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells. Mechanistically, high activity of mammalian target of rapamycin complex 1 (mTORC1) in aged Paneth cells inhibits activity of peroxisome proliferator activated receptor α (PPAR-α), and lowered PPAR-α activity increased Notum expression. Genetic targeting of Notum or Wnt supplementation restored function of aged intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged stem cells and promoted recovery from chemotherapy-induced damage. Our results reveal a role of the stem cell niche in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues.
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http://dx.doi.org/10.1038/s41586-019-1383-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151802PMC
July 2019

Hmga2 is dispensable for pancreatic cancer development, metastasis, and therapy resistance.

Sci Rep 2018 09 18;8(1):14008. Epub 2018 Sep 18.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Expression of the chromatin-associated protein HMGA2 correlates with progression, metastasis and therapy resistance in pancreatic ductal adenocarcinoma (PDAC). Hmga2 has also been identified as a marker of a transient subpopulation of PDAC cells that has increased metastatic ability. Here, we characterize the requirement for Hmga2 during growth, dissemination, and metastasis of PDAC in vivo using conditional inactivation of Hmga2 in well-established autochthonous mouse models of PDAC. Overall survival, primary tumour burden, presence of disseminated tumour cells in the peritoneal cavity or circulating tumour cells in the blood, and presence and number of metastases were not significantly different between mice with Hmga2-wildtype or Hmga2-deficient tumours. Treatment of mice with Hmga2-wildtype and Hmga2-deficient tumours with gemcitabine did not uncover a significant impact of Hmga2-deficiency on gemcitabine sensitivity. Hmga1 and Hmga2 overlap in their expression in both human and murine PDAC, however knockdown of Hmga1 in Hmga2-deficient cancer cells also did not decrease metastatic ability. Thus, Hmga2 remains a prognostic marker which identifies a metastatic cancer cell state in primary PDAC, however Hmga2 has limited if any direct functional impact on PDAC progression and therapy resistance.
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http://dx.doi.org/10.1038/s41598-018-32159-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143627PMC
September 2018

A quantitative and multiplexed approach to uncover the fitness landscape of tumor suppression in vivo.

Nat Methods 2017 Jul 22;14(7):737-742. Epub 2017 May 22.

Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

Cancer growth is a multistage, stochastic evolutionary process. While cancer genome sequencing has been instrumental in identifying the genomic alterations that occur in human tumors, the consequences of these alterations on tumor growth remain largely unexplored. Conventional genetically engineered mouse models enable the study of tumor growth in vivo, but they are neither readily scalable nor sufficiently quantitative to unravel the magnitude and mode of action of many tumor-suppressor genes. Here, we present a method that integrates tumor barcoding with ultradeep barcode sequencing (Tuba-seq) to interrogate tumor-suppressor function in mouse models of human cancer. Tuba-seq uncovers genotype-dependent distributions of tumor sizes. By combining Tuba-seq with multiplexed CRISPR-Cas9-mediated genome editing, we quantified the effects of 11 tumor-suppressor pathways that are frequently altered in human lung adenocarcinoma. Tuba-seq enables the broad quantification of the function of tumor-suppressor genes with unprecedented resolution, parallelization, and precision.
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http://dx.doi.org/10.1038/nmeth.4297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495136PMC
July 2017

Dissecting the Genetic Basis of a Complex cis-Regulatory Adaptation.

PLoS Genet 2015 Dec 29;11(12):e1005751. Epub 2015 Dec 29.

Department of Biology, Stanford University, Stanford, California, United States of America.

Although single genes underlying several evolutionary adaptations have been identified, the genetic basis of complex, polygenic adaptations has been far more challenging to pinpoint. Here we report that the budding yeast Saccharomyces paradoxus has recently evolved resistance to citrinin, a naturally occurring mycotoxin. Applying a genome-wide test for selection on cis-regulation, we identified five genes involved in the citrinin response that are constitutively up-regulated in S. paradoxus. Four of these genes are necessary for resistance, and are also sufficient to increase the resistance of a sensitive strain when over-expressed. Moreover, cis-regulatory divergence in the promoters of these genes contributes to resistance, while exacting a cost in the absence of citrinin. Our results demonstrate how the subtle effects of individual regulatory elements can be combined, via natural selection, into a complex adaptation. Our approach can be applied to dissect the genetic basis of polygenic adaptations in a wide range of species.
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http://dx.doi.org/10.1371/journal.pgen.1005751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694769PMC
December 2015

Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing.

Genes Dev 2015 Jul 15;29(14):1576-85. Epub 2015 Jul 15.

Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA; Cancer Biology Program, Stanford University School of Medicine, Stanford, California 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.

Pancreatic ductal adenocarcinoma (PDAC) is a genomically diverse, prevalent, and almost invariably fatal malignancy. Although conventional genetically engineered mouse models of human PDAC have been instrumental in understanding pancreatic cancer development, these models are much too labor-intensive, expensive, and slow to perform the extensive molecular analyses needed to adequately understand this disease. Here we demonstrate that retrograde pancreatic ductal injection of either adenoviral-Cre or lentiviral-Cre vectors allows titratable initiation of pancreatic neoplasias that progress into invasive and metastatic PDAC. To enable in vivo CRISPR/Cas9-mediated gene inactivation in the pancreas, we generated a Cre-regulated Cas9 allele and lentiviral vectors that express Cre and a single-guide RNA. CRISPR-mediated targeting of Lkb1 in combination with oncogenic Kras expression led to selection for inactivating genomic alterations, absence of Lkb1 protein, and rapid tumor growth that phenocopied Cre-mediated genetic deletion of Lkb1. This method will transform our ability to rapidly interrogate gene function during the development of this recalcitrant cancer.
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http://dx.doi.org/10.1101/gad.264861.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526740PMC
July 2015

[Distribution and abundance of the ascidian Ecteinascidia turbinata (Ascidiacea: Perophoridae) in Cuba].

Rev Biol Trop 2007 Mar;55(1):247-54

Instituto de Oceanología del Ministerio de Ciencia Tecnologia y Medio Ambiente de Cuba. Ave. lera y 186 No. 18406, Ciudad Habana, Cuba.

Permanently submerged mangrove roots (Rhizophora mangle) are the main habitat of the ascidian Ecteinascidia turbinata in Cuba. It was occasionally found on black coral (Antiphates caribeana) between 22 and 38 meters deep. This species exhibits a wide distribution in all the mangrove keys surrounding the Island of Cuba but does not occur in riparian or fringing mangroves. Populations of this species are abundant in Cuba: in 75% of the 58 localities sampled the species was present and in 57% more than 50% of the roots held at least one colony. The highest colony densities were found in the northern coast of Pinar del Rio province with values near one colony per lineal meter of mangrove root. We found the highest density (1.46 col/m) and greatest biomass at Jutías Key, with values between 25 and 660 g/m. The average of wet biomass in the studied mangroves was 73.63 g/m.
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March 2007

Environmental assessment of a large industrial marine complex based on a community of benthic filter-feeders.

Mar Pollut Bull 2002 Jul;44(7):605-10

Laboratorio de Ecología del Bentos, Instituto de Ciencias del Mar y Limnología, UNAM, Mazatlán, Mexico.

Biological quality in a bay affected by man's activities was evaluated by means of the composition of assemblages of sponges and ascidians. Our results showed that the structure of these two groups of filter-feeders aided in discriminating between undisturbed and disturbed areas, establishing different "environmental health categories" from moderately to strongly disturbed areas, and in ascertaining the extension of the area of each "health category". We were able to divide the bay into four zones based on type of disturbance or anthropogenic source: (1) stations free of any source of disturbance, (2) stations under moderate disturbance, located close to industrial ports, millworks, etc., (3) stations that are under the direct influence of industrial wastes such as a power station and oil refinery, and (4) stations near strongly disturbed areas, influenced directly by harmful steelworks activities. We differentiated clearly between four large species assemblages, and related the composition of these assemblages to different kinds of disturbances. Thus, these species could be used to manage the marine environment in this bay by comparing the observed fauna, with expected fauna in an unstressed site. Moreover, the joint presence of the sponge Cliona vastifica and tunicate Policitor adriaticum seems always to indicate a more or less pristine environmental situation, functioning as bioindicators of normal conditions. We think that the use of specific bioindicators for monitoring disturbance is a valid tool to establish baselines to predict impacts associated with industrial development in many marine ecosystems. The advantages to monitoring communities on hard rocks versus sandy or muddy bottoms are also commented upon.
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http://dx.doi.org/10.1016/s0025-326x(01)00295-8DOI Listing
July 2002
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