Table Of ContentAdvances in Experimental Medicine and Biology 1287
Jörg Reichrath
Sandra Reichrath Editors
Notch
Signaling in
Embryology
and Cancer
Notch Signaling in Cancer
Advances in Experimental Medicine
and Biology
Volume 1287
Series Editors
Wim E. Crusio, Institut de Neurosciences Cognitives et Intégratives
d’Aquitaine, CNRS and University of Bordeaux UMR 5287,
Pessac Cedex, France
Haidong Dong, Departments of Urology and Immunology,
Mayo Clinic, Rochester, MN, USA
Heinfried H. Radeke, Institute of Pharmacology & Toxicology, Clinic of the
Goethe University Frankfurt Main, Frankfurt am Main, Hessen, Germany
Nima Rezaei, Research Center for Immunodeficiencies, Children's Medical
Center, Tehran University of Medical Sciences, Tehran, Iran
Junjie Xiao, Cardiac Regeneration and Ageing Lab,
Institute of Cardiovascular Sciences, School of Life Science,
Shanghai University, Shanghai, China
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Jörg Reichrath • Sandra Reichrath
Editors
Notch Signaling
in Embryology
and Cancer
Notch Signaling in Cancer
Editors
Jörg Reichrath Sandra Reichrath
Department of Dermatology Department of Dermatology
Saarland University Medical Center Saarland University Medical Center
Homburg, Saarland, Germany Homburg, Saarland, Germany
School of Health Professions
Saarland University Medical Center
Homburg, Saarland, Germany
ISSN 0065-2598 ISSN 2214-8019 (electronic)
Advances in Experimental Medicine and Biology
ISBN 978-3-030-55030-1 ISBN 978-3-030-55031-8 (eBook)
https://doi.org/10.1007/978-3-030-55031-8
© Springer Nature Switzerland AG 2021
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We dedicate this book to our sons, Benjamin and Niklas, the
absolute joy of our lives
Preface
Notch and Cancer: Lessons Learned from Failure – or on the Long and
Winding Road from John S. Dexter’s mutant Fruit Flies to Synthetic
Notch Receptors, and beyond
This book was motivated by the desire we and others have to further the
evolution of the many fascinating facets of Notch’s role for biology and
medicine. To stimulate the interest of potential readers, this preface has
several purposes, which include providing some brief information (a) con-
cerning its content with a focus on potential future developments, (b) how
the book came about, and (c) acknowledging the long list of authors and
other individuals who helped move forward this project. The success of the
first edition of Notch Signaling in Embryology and Cancer, which was pub-
lished by Landes and Springer in 2012 in the prestigious series Advances in
Experimental Medicine and Biology (Reichrath and Reichrath 2012),
clearly indicated that this text met an important need in this exciting field.
It was a benchmark in its field, fulfilling the need to provide a broad audi-
ence (ranging from medical students to basic scientists, physicians and all
other health care professionals) with up-to-date information in a compre-
hensive, highly readable format, with individual chapters written by highly
respected experts. We were aware from the beginning that undertaking the
first edition would include a commitment to producing a second one. The
enormous advances that have been made in recent years on this topic, mov-
ing forward at a dizzying pace, now clearly justify the need for a second
edition. We decided to publish this updated and extended new edition as
three separate volumes, featuring chapters written by both new and return-
ing authors, to add to the content of the first edition. Each volume contains
a separate table of contents and full index to help the reader find specific
information. In the different volumes of Notch Signaling in Embryology
and Cancer, leading experts in the field present a comprehensive, highly
readable overview on selected aspects of three important topics related to
Notch signaling, namely the underlying molecular mechanisms that medi-
ate its biological effects (Volume I) (Reichrath and Reichrath 2020a) (add-
ing to the recent important book publication on this topic from Tilman
Borggrefe and Benedetto Daniele Giaimo; Borggrefe and Giaimo 2018), its
role in embryogenesis (Volume II) (Reichrath and Reichrath 2020b), and
last but not least its relevance for pathogenesis, progression, and therapy of
vii
viii Preface
cancer (Volume III) (Reichrath and Reichrath 2020c). This third volume of
Notch Signaling in Embryology and Cancer summarizes the fascinating
role of this pathway, which first developed during evolution in metazoans
and was first discovered in the fruit fly drosophila melanogaster, for cancer
(Reichrath and Reichrath 2020c). When the American scientist John
S. Dexter published in 1914 the characteristic notched-wing phenotype (a
nick or notch in the wingtip that earned the mutant gene the name Notch)
that he had recognized in mutant fruit flies (drosophila melanogaster), he
couldn’t have expected the tremendous impact that this finding would later
have for cancer and many other fields in biology and medicine. This
thoughtful observation made in his research laboratory at Olivet College
(Olivet, Michigan, USA) opened many fascinating avenues for a better
understanding of carcinogenesis and for the development of promising new
anti-cancer therapeutics that target Notch signaling pharmacologically.
During the last decades, a great deal of impressive scientific progress has
demonstrated that Notch signaling represents a master pathway involved in
carcinogenesis and cancer progression, with many types of cancer having
been found to contain Notch mutations. On a first look, the Notch pathway,
which governs in oncology so many key cell fate decisions and other cel-
lular core processes, seems phantasmally simple, because a direct link
between an extracellular signal and transcriptional output without the
requirement of an extended chain of protein intermediaries (as needed by so
many other signaling pathways) represents one of its key features (Reichrath
and Reichrath 2020a, b). However, on a second, closer look, this obvious
simplicity hides remarkable complexity and, consistent with its central role
in many aspects of development, adult tissue homeostasis, and cancer, it
can be recognized that Notch signaling depends on an extensive collection
of mechanisms that it employs alongside of its core transcriptional machin-
ery. It has to be noted that many early attempts to target Notch signaling for
cancer treatment represented major setbacks, since they did not lead as
expected to good clinical response rates. Notch antagonistic antibodies and
gamma secretase inhibitors (GSI) may serve here as examples, showing
promising results in preclinical studies but disappointing results in clinical
trials. However, our understanding of the molecular biology of Notch sig-
naling has now opened exciting perspectives to overcome these obstacles.
Giulia Monticone and Lucio Miele discuss elsewhere in this book
(Monticone and Miele 2020), in their direction-defining contribution, which
reflects the outstanding expertise of the authors, current and new Notch-
targeting therapies with their exciting promises and challenges. As these
authors explain, targeting Notch allows to virtually modulate any aspect of
cancer. However, this means that Notch-targeting must be highly specific
toward the desired target and it seems that we at present still have not unrav-
eled all the secrets and potentials of this pathway (Monticone and Miele
2020). In this context, Notch pleiotropic nature seems to be both the advan-
tage and the challenge of Notch-targeted therapies (Monticone and Miele
2020). The accumulated knowledge about the molecular biology of Notch
signaling in individual types of cancer, for example, whether Notch muta-
Preface ix
tions detected in cancer are assumed to be loss or gain of function depend-
ing on whether Notch is tumor suppressor or oncogenic, respectively,
provides chances for improvements, for it may be possible to identify
responder patients depending on molecular signatures detected in tumors
(Monticone and Miele 2020). It is now becoming evident that while the first
Notch- targeted therapies were designed to inhibit Notch, in certain situa-
tions Notch signaling should be promoted instead of inhibited (Monticone
and Miele 2020). Recent investigations on Notch regulation have revealed
many alternative ways in which Notch can be activated or inhibited, which
involve the extensive collection of mechanisms that Notch employs along-
side of its core transcriptional machinery. Other mechanisms that can be
used as therapeutical targets include the ubiquitination of Notch mediated
by different ubiquitin ligases that orchestrate the degradation and the
ligand-independent activation of Notch. Moreover, Notch’s roles for micro-
environment and for metabolism reprogramming (now considered as a
major hallmark of cancer, through which cancer cells can adapt and survive
different environmental changes, develop resistance to treatments, and
modulate anti-tumor immunity) of many tumor types may represent targets
for anti-cancer treatment (Monticone and Miele 2020). Understanding
whether Notch function is pro- or anti- tumoral is essential, especially
because Notch is differentially expressed in subsets of cells within the
tumor and its microenvironment including tumor- infiltrating immune cells
(Monticone and Miele 2020). Notch is heavily involved in shaping the
immune system in physiological conditions and the pro-tumoral immune
microenvironment in cancer (Monticone and Miele 2020), providing a
strong rational for the evaluation of Notch-targeting strategies as immuno-
modulators (Monticone and Miele 2020). The promises associated with the
many fascinating facets of targeting Notch signaling for cancer treatment
include the generation of synthetic Notch receptors, called synNotches,
which have customizable extracellular and intracellular domains linked by
the transmembrane domain of Notch, thus allowing customizable extra to
intracellular signaling. In conclusion, a more rational use of Notch- targeting
therapeutics should be highly specific, taking into account many aspects,
including the tumor type, patient responders, Notch alterations, “off tar-
gets,” and potential combinatorial treatments. Understanding the precise
mechanism by which Notch is modulated in different sets of cells within the
tumor or its microenvironment including immune cells will be crucial to
predict whether Notch-targeting therapies will be effective and to identify
new druggable targets (Monticone and Miele 2020). Therefore, a patient-
based, mechanistic-based use of Notch-targeting therapies is urgently
needed. The individual chapters of this book give an up-to-date overview on
selected aspects of our present understanding of Notch’s role in cancer. We
have enjoyed very much the task of bringing this second edition to you. We
are convinced that it will be as successful as the previous edition. We are
indebted to our many authors and are very grateful for their willingness to
contribute to this book. We would also like to express our thanks to
Murugesan Tamilselvan, Anthony Dunlap, Larissa Albright, and all the
x Preface
other members of Springer’s staff for their expertise, diligence, and patience
in helping us complete this book.
Enjoy the reading!
Homburg, Saarland, Germany Sandra Reichrath
Jörg Reichrath
References
Borggrefe T, Giaimo BD (eds) (2018) Molecular mechanisms of notch signaling. Adv Exp
Med Biol 1066:1–394
Dexter JS (1914) The analysis of a case of continuous variation in drosophila by a study of
its linkage relations. Am Nat 48:712–758
Monticone G, Miele L (2020) Notch pathway: a journey from notching phenotypes to
cancer immunotherapy. Adv Exp Med Biol 1287:201–222
Reichrath J, Reichrath S (eds) (2012) Notch signaling in embryology and cancer. Adv Exp
Med Biol 727:1–320
Reichrath J, Reichrath S (eds) (2020a) Notch signaling in embryology and cancer (Vol. I).
Molecular biology of notch signaling. Adv Exp Med Biol 1227:1–164
Reichrath J, Reichrath S (eds) (2020b) Notch signaling in embryology and cancer (Vol. II).
Notch signaling in embryology. Adv Exp Med Biol 1218:1–188
Reichrath J, Reichrath S (eds) (2020c) Notch signaling in embryology and cancer (Vol. III).
Notch signaling in cancer. Adv Exp Med Biol 1287:1–222
