For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
Inviting an author to review:
Effect of nuclear spin symmetry in cold and ultracold reactions: D + para/ortho-H2
Find an author and click ‘Invite to review selected article’ near their name.
Search for authorsSearch for similar articles
2
views
62
references
 Top references
cited by
8
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      735
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      DLL3 regulates Notch signaling in small cell lung cancer

      research-article
      Author(s): 1 , 2 , 3 , 1 , 2 , 3 , 1 , 2 , 4 , ∗
      Publication date (Electronic):
      Journal: iScience
      Publisher: Elsevier
      Keywords: Molecular biology, Cancer, In silico biology

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          Tumor heterogeneity plays a critical role in tumor development and response to treatment. In small-cell lung cancer (SCLC), intratumoral heterogeneity is driven in part by the Notch signaling pathway, which reprograms neuroendocrine cancer cells to a less/non-neuroendocrine state. Here we investigated the atypical Notch ligand DLL3 as a biomarker of the neuroendocrine state and a regulator of cell-cell interactions in SCLC. We first built a mathematical model to predict the impact of DLL3 expression on SCLC cell populations. We next tested this model using a single-chain variable fragment (scFv) to track DLL3 expression in vivo and a new mouse model of SCLC with inducible expression of DLL3 in SCLC tumors. We found that high levels of DLL3 promote the expansion of a SCLC cell population with lower expression levels of both neuroendocrine and non-neuroendocrine markers. This work may influence how DLL3-targeting therapies are used in SCLC patients.

          Graphical abstract

          Highlights

          • •

            Ectopic expression of DLL3 suppresses Notch signaling in SCLC cells

          • •

            Lateral inhibition model predicts expression level-dependent effects of DLL3

          • •

            Anti-DLL3 scFv labels SCLC cells in vitro and in vivo

          • •

            DLL3 expression prevents cell-fate bifurcation in mouse model of SCLC

          Abstract

          Molecular biology; Cancer; In silico biology

          Related collections

          Most cited references62

          • Record: found
          • Abstract: found
          • Article: not found

          Tumour heterogeneity and resistance to cancer therapies

          Ibiayi Dagogo-Jack, Alice Shaw (2018)
          Cancer is a dynamic disease. During the course of disease, cancers generally become more heterogeneous. As a result of this heterogeneity, the bulk tumour might include a diverse collection of cells harbouring distinct molecular signatures with differential levels of sensitivity to treatment. This heterogeneity might result in a non-uniform distribution of genetically distinct tumour-cell subpopulations across and within disease sites (spatial heterogeneity) or temporal variations in the molecular makeup of cancer cells (temporal heterogeneity). Heterogeneity provides the fuel for resistance; therefore, an accurate assessment of tumour heterogeneity is essential for the development of effective therapies. Multiregion sequencing, single-cell sequencing, analysis of autopsy samples, and longitudinal analysis of liquid biopsy samples are all emerging technologies with considerable potential to dissect the complex clonal architecture of cancers. In this Review, we discuss the driving forces behind intratumoural heterogeneity and the current approaches used to combat this heterogeneity and its consequences. We also explore how clinical assessments of tumour heterogeneity might facilitate the development of more-effective personalized therapies.
          Article 0 comments Cited 912 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Comprehensive genomic profiles of small cell lung cancer.

            Julie George, Jing Lim, Se Jang … (2015)
            We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
            Article 0 comments Cited 590 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data

              Charles Rudin, John Poirier, Lauren Averett Byers … (2019)
              Small cell lung cancer (SCLC) is an exceptionally lethal malignancy for which more effective therapies are urgently needed. Several lines of evidence, from SCLC primary human tumours, patient-derived xenografts, cancer cell lines and genetically engineered mouse models, appear to be converging on a new model of SCLC subtypes defined by differential expression of four key transcription regulators: achaete-scute homologue 1 (ASCL1; also known as ASH1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). In this Perspective, we review and synthesize these recent lines of evidence and propose a working nomenclature for SCLC subtypes defined by relative expression of these four factors. Defining the unique therapeutic vulnerabilities of these subtypes of SCLC should help to focus and accelerate therapeutic research, leading to rationally targeted approaches that may ultimately improve clinical outcomes for patients with this disease.
              Article 0 comments Cited 373 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Julien Sage
                Journal
                Journal ID (nlm-ta): iScience
                Journal ID (iso-abbrev): iScience
                Title: iScience
                Publisher: Elsevier
                ISSN (Electronic): 2589-0042
                Publication date PMC-release: 16 November 2022
                Publication date Collection: 22 December 2022
                Publication date (Electronic): 16 November 2022
                Volume: 25
                Issue: 12
                Electronic Location Identifier: 105603
                Affiliations
                [1 ]Department of Pediatrics, Stanford University, 265 Campus Drive, SIM1 G2078, Stanford, CA, USA
                [2 ]Department of Genetics, Stanford University, 265 Campus Drive, SIM1 G2078, Stanford, CA, USA
                Author notes
                [∗ ]Corresponding author julsage@ 123456stanford.edu
                [3]

                These authors contributed equally

                [4]

                Lead contact

                Article
                Publisher Item ID: S2589-0042(22)01875-2 Publisher ID: 105603
                DOI: 10.1016/j.isci.2022.105603
                PMC ID: 9722452
                PubMed ID: 36483011
                SO-VID: 419fdb2b-168f-474d-87fd-0bd7be0334fb
                Copyright © © 2022 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 13 September 2022
                Date revision received : 29 October 2022
                Date accepted : 14 November 2022
                Categories
                Subject: Article

                Keywords: molecular biology,cancer,in silico biology
                Data availability:
                Keywords: molecular biology, cancer, in silico biology

                Comments

                Comment on this article

                scite_

                Similar content735

                See all similar

                Cited by8

                See all cited by

                Most referenced authors1,314

                See all reference authors