International
Symposiumon
on Tumor
Tumor Biology
Biology inin Kanazawa
Kanazawa 2021
2021

Nov.
Nov. 26,,2021
2021

Program and Abstract

International Symposium on Tumor Biology in Kanazawa 2021
November 26(Fri), 2021
Cancer Research Institute, Kanazawa University(KU CRI), Japan
Venue: NanoLSI Main Conference Room, Kanazawa University (on-site),zoom webinar (online)

Program
17:00-17:10(JST) Opening Remarks
Takashi Wada (Vice President, KU)

Session I : Stem Cell, Embryogenesis and Development(Chair: Masanobu Oshima, KU CRI, NanoLSI, Masaya Ueno, KU CRI)
17:10-17:40(JST)Kim Jensen (Biotech Research & Innovation Centre & Novo Nordisk Foundation Center

for Stem Cell Biology, University of Copenhagen, Denmark)Intestinal Stem Cells in Development and Disease
17:40-18:05(JST)Yusuke Miyanari (KU NanoLSI)

Dissecting Molecular Mechanisms to Regulate Chromatin Structure
18:05-18:35(JST)Maria Elena Torres-Padilla (IES, Helmholtz Zentrum, Munich, Germany)

Epigenetic Mechanisms of Cellular Plasticity and Reprogramming to Totipotency
BREAK

Session II : Cellular Functions and Tumor Biology(Chair: Chiaki Takahashi, KU CRI, Ryu Imamura, KU CRI)
18:50-19:15(JST)Atsuko Kasahara (KU CRI, InFiniti)

Mitochondrial Dynamics: A New Therapeutic Target to Beat Malignant Tumour Cells
19:15-19:40(JST)Eishu Hirata (KU CRI)

Multifaceted Interactions Between Cancer Cells and Glial Cells in Brain Metastasis
19:40-20:10(JST)Erik Sahai (The Francis Crick Institute, UK)
A New Player in the Tumour Microenvironment of Dormant Cancer Cells
20:10-20:20(JST) Closing Remarks
Kunio Matsumoto (Director, KU CRI)
Organizing committee: Atsushi Hirao, Kazuhiro Murakami, Yusuke Miyanari, Eishu Hirata, Yoshio Endo

Kim B Jensen
Biotech Research and Innovation Center (BRIC)
Novo Nordisk Foundation Center for Stem Cell Biology (DanStem)
Faculty of Health and Medical Sciences University of Copenhagen
Contact: kim.jensen [at sign] bric.ku.dk
Please replace [at sign] with @Education:
2000

M.Sc. in Molecular biology and chemistry, Department for Molecular and Structural Biology, Universityof Aarhus, Denmark

2003

Ph.D. in Science, Department for Molecular and Structural Biology, University of Aarhus, Denmark

Professional Career:
2003-2010

Research fellow with Dr Fiona Watt in London and Cambridge, UK

2010-2014

Group leader, The Cambridge Stem Cell Institute, University of Cambridge, UK

2013-

Group Leader BRIC and DanStem, University of Copenhagen

Research Interests:
Kim Jensen is a Professor at the University of Copenhagen, Denmark. Kim Jensen did his PhD at the University of
Aarhus, and joined Fiona Watt’s group for his postdoctoral training. He held his first faculty position at the Stem Cell
Institute, University of Cambridge, UK, before moving to Copenhagen in 2013, where he in 2019 was promoted tofull Professor. Dr Jensen is interested in the molecular mechanisms that govern stem cell fate specification, and how
extracellular signals integrates with gene regulatory networks to control tissue maturation and cellular plasticity indeveloping and adult epithelia. By combining studies using mouse models and clinical specimens the long-term aimof the research in the Jensen lab is to translate result from in vitro and in vivo models into regenerative therapies.
Selected Awards and Honors:
2015

ERC consolidator award

2021

EMBO Member

Publications:
1. Bornholdt, J., et al., (2020) Personalized B cell response to the Lactobacillus rhamnosus GG probiotic in healthy
human subjects: a randomized trial. Gut Microbes 12:1-14.
2. Andersen, M.S. et al., (2019) Tracing the cellular dynamics of sebaceous gland development in normal andperturbed states. Nature Cell Biology 21: 924–32
3. Guiu, J. et al. (2019) Tracing the origin of adult intestinal stem cells. Nature 570: 107–111

Intestinal Stem Cells in Development and Disease
Kim B. Jensen
Biotech Research and Innovation Center (BRIC) andNovo Nordisk Foundation Center for Stem Cell Biology (DanStem)
Faculty of Health and Medical Sciences
University of Copenhagen

The intestine is essential for digestion and absorption of nutrients. Moreover, the epithelium, which lines theluminal surface, constitutes a barrier that protects our body from gut microbiota. Adult stem cells located at thebottom of crypts are responsible for the life-long replenishment of the epithelium by giving rise to differentiatedoffspring. Using a combination of mouse models and tissue biopsies from human fetuses, we recently outlined
the relationship between fetal progenitors in the developing epithelium and adult stem cells (Guiu et al., 2019,
Nature). Here we observed that fetal cells are not organised in a strict cellular hierarchy as has been observed
for adult epithelium and appear to be inherently more plastic. Moreover, during injury of the adult epithelium,
which is associated with cellular dedifferentiation, the adult epithelial cells transition into a fetal-like state (Yuiet al., 2018, Cell Stem Cell). Given the complexity of the intestinal epithelium along its axis it will be importantto understand the mechanisms that fuel the first rudimental patterning of the epithelium providing spatial context
for a differentiated and a proliferative state, and also to address whether similar mechanisms are recapitulated
in diseases such as cancer.

References:Guiu, J., Hannezo, E., Yui, S., Demharter, S., Ulyanchenko, S., Maimets, M., Jorgensen, A., Perlman, S., Lundvall,L., Mamsen, L.S., et al. (2019). Tracing the origin of adult intestinal stem cells. Nature 570, 107-111.
Yui, S., Azzolin, L., Maimets, M., Pedersen, M.T., Fordham, R.P., Hansen, S.L., Larsen, H.L., Guiu, J., Alves, M.R.P.,
Rundsten, C.F., et al. (2018). YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodelingto Tissue Regeneration. Cell stem cell 22, 35-49 e37.

Yusuke Miyanari
Nano Life Science Institute (WPI-NanoLSI), Kanazawa University
Contact: miyanari [at sign]staff.kanazawa-u.ac.jp
Please replace [at sign] with @Education:
2006

PhD, Department of Human Tumor Viruses, Graduate School of Biostudies, Kyoto University

Professional Career:
2006-2009

Postdoc, National Institute of Genetics (NIG), JAPAN (Hiro Sasaki Lab)

2009-2014

Postdoc, IGBMC, Strasbourg, FRANCE (Maria-Eleana TP Lab)

2014-2020

Associate Professor (PI), National Institute of Basic Biology (NIBB), JAPAN

2020-present

Associate Professor (PI), NanoLSI, Kanazawa U.

Scientific Activities:
2001-2006

Studies on Hepatitis C virus

2006-present Epigenetic regulation of cell lineage allocation
Research Interests:
Epigenetics, Stem cell, chromatin, transcription
Honors:2015

The Young Scientists’ Prize, The Commendation for Science and Technology by the MEXT

2015

Takenaka Promotion Prize

Publications:

1. Miyanari Y. et al, Nature. 483.470-473. 2012
2. Miyanari Y. et al, Nature Structural & Molecular Biology, 2013 Nov;20(11):1321-4
3. Kurihara M. et al, Molecular Cell, S1097-2765(20)30230-6. 2020

Dissecting Molecular Mechanisms to Regulate Local Chromatin Structure
Yusuke Miyanari
NanoLSI, Kanazawa University

Chromatin is organized in a non-random fashion within 3D nuclear space. During developmental processes, thenuclear architecture is dramatically reconstructed, resulting in the establishment of cell-type specific nuclear
organization. Defects in structural components of the nucleus are responsible for developmental aberrations andseveral human diseases. Remodeling of the nuclear architecture leads to spatial arrangement of genes, which
could affect genome functions including gene expression. We aim to reveal the role of chromatin dynamics incell lineage-allocation by deciphering the molecular mechanisms underlying the remodeling of nuclear
organization and their effects on developmental gene expression, using mouse early embryos and embryonicstem (ES) cells as model systems. We recently conducted genome-wide screening to discover novel players
involved in regulation of chromatin accessibility, and found that some key players have significant roles toestablish global chromatin accessibility. Manipulation of these key players allowed us to boost genetic andepigenetic reprogramming of cells.

Maria-Elena Torres-Padilla
Director, Institute of Epigenetics & Stem Cells Helmholtz Zentrum Munich
Professor, Chair of Stem Cell Biology at the Faculty of Biology
Ludwig-Maximilians-University MunichContact: torres-padilla [at sign] helmholtz-muenchen.dePlease replace [at sign] with @Education:
1998

University Degree in Biology. Faculty of Sciences, National University of Mexico, Mexico

2002

Ph.D. Institut Pasteur/University of Paris V, France

2008

Habilitation. Université Louis Pasteur, Strasbourg, France

Professional Career:
2002-2006

Postdoctoral EMBO fellow, The Gurdon Institute, University of Cambridge, UK

2006-2008

Senior Scientist, IGBMC, Strasbourg, France

2007

Nominated Chargee de Recherche (INSERM)

2009

Independent Group leader, IGBMC, Strasbourg, France

2010-2012

Deputy Director of Developmental and Stem Cell Biology Department,
IGBMC,Strasbourg, France

2012

Nominated Director of Research (INSERM)

2016-

Professor, Chair of Stem Cell Biology, Faculty of Biology, Ludwig-MaximiliansUniversity Munich, Germany

2016-

Director, Institute of Epigenetics & Stem Cells,Helmholtz Zentrum Munich, Germany

Selected Awards and Honors:
2015

Elected EMBO Member

2018

Female Award of the German Stem Cell Network

2019

Honorary Professor, University of Aarhus Denmark

Selected Publications:
1. Canat A. & Torres-Padilla ME. 2021. Retrotransposing a promoter for development. Nature Cell Biology, In
press (2021)
2. Burton A. & Torres-Padilla ME. 2021. Deconfining heterochromatin for expression. Nature Cell Biology,
Aug;23(8):814-816. (2021)
3. Iturbide A. Ruiz Tejeda Segura ML. Noll C. Schorpp K. Rothenaigner I. Ruiz-Morales ER. Lubatti G. Agami A.
Hadian K. Scialdone A & Torres-Padilla ME. 2021. Retinoic acid signalling is critical during the totipotency
window in early mammalian development. Nature Structural & Molecular Biology, Jun;28(6):521-532. (2021)

Epigenetic Mechanisms of Cellular Plasticity and Reprogramming to Totipotency
Maria-Elena Torres-PadillaInstitute of Epigenetics & Stem Cells,
Helmholtz Centre Munich, Munich,Germany

Totipotency is a fundamental cellular feature. In mammals, the terminally differentiated sperm and oocyte fuseto create a totipotent zygote upon fertilisation. The mechanisms underlying the epigenetic reprogramming
towards totipotency that follows fertilisation are not fully understood, and the molecular features of totipotent
cells remain scarce. Embryonic cells remain totipotent only for a restricted time window. During this time,embryonic cells are characterised by an atypical chromatin structure and reactivation of specific families ofretrotransposons. Recently, it was reported that totipotent-like cells arise in ES cell cultures in vitro. Like inthe embryo, these cells are characterized by the expression of MERVL LTR retrotransposons. To address how
the expression of these elements is regulated during the transition between totipotent and pluripotent states, wefirst examined histone modifications and chromatin structure in early mouse embryos. Remarkably, we havefound that specific features of embryonic chromatin are also present in totipotent-like cells in vitro. Based on
this analysis, we have begun to decipher key molecular regulators of repetitive elements in the embryo, andhow they contribute to shaping the regulatory programme of the newly formed embryo. Our results haveidentified candidate pathways that regulate chromatin function and expression of these elements and show thatthey can promote totipotency. We will present our latest results that reveal a new role for chromatin integrity
in promoting epigenetic reprogramming and sustaining molecular features of totipotent cells in vivo.

Atsuko Kasahara
Cancer Research Institute, Institute for Frontier Science Initiative, WPI Nano
Life Science Institute (WPI- Nano LSI), Kanazawa University
Contact : akasahara [at sign] staff.kanazawa-u.ac.jp
Please replace [at sign] with @Education
2002

B.Sc.

Biological Science Degree, University of Tsukuba, Japan

2004

M.Sc.

Dept. of Biosystem Studies, University of Tsukuba, Japan (Molecular and Cellular Biology)

2006

Ph.D.

Dept. of Biological Sciences, University of Tsukuba, Japan (Molecular and Cellular Biology)

Professional Career
2006-2008 Postdoctoral Research Fellow, Graduate School of Life and Environmental Sciences, Institute of
Biological Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Japan
2008-2013 Postdoctoral Research Fellow, Department of Physiology and Metabolism, Centre Médical
Universitaire (CMU), University of Geneva, Switzerland
2013-2014 Postdoctoral Research Fellow, Department of Pathology and Immunology, Centre Médical Universitaire(CMU), University of Geneva, Switzerland
2015

Postdoctoral Research Fellow, Department of Biology, University of Padua, Italy, Lab of Molecular
Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan

2016-

Assistant Professor, Cancer Research Institute, Institute for Frontier Science Initiative, Kanazawa
University, Japan

Research Interests:
Mitochondrial dynamics, organeller communications
Publications:
1. Bassoy EY*, Kasahara A*, Chiusolo V, Jacquemin G, Boydell E, Zamorano S, Riccadonna C, Pellegatta S,
Hulo N, Dutoit V, Derouazi M, Dietrich PY, Walker PR, Martinvalet D. ER-mitochondria contacts control GSC
surface glycan expression and sensitivity to killer lymphocytes. EMBO J. 2017 36: 1493-1512. *Contributed
equally to this work
2. Kasahara A, Scorrano L. Mitochondria: from cell death executioners to regulators of cell differentiation. Trends
Cell Biol. 2014 24: 761-770. Review

3. Kasahara A, Cipolat S, Chen Y, Dorn GW 2nd, Scorrano L. Mitochondrial fusion directs cardiomyocyte
differentiation via calcineurin and Notch signaling. Science. 2013 342: 734-737.

Mitochondrial Dynamics: A New Therapeutic Target to Beat Malignant Tumour
Atsuko Kasahara
Cancer Research Institute, Institute for Frontier Science Initiative, WPI Nano Life Science Institute (WPINano LSI), Kanazawa University

Mitochondria are the power supply of the cell, also in cancer cells to maintain their continuous proliferation. In
addition to ATP production through oxidative phosphorylation, mitochondria play crucial roles in metabolic
pathways, calcium and redox homeostasis, and apoptosis. These multiple mitochondrial functions are reflectedby their extremely dynamic morphology in the cells, which is modulated and maintained by their fusion anddivision. The dynamin-related GTPases Mitofusin (Mfn) 1 and 2, and Optic Atrophy 1 (OPA1) fusemitochondria, and the cytosolic dynamin-related protein 1 (DRP1) divides mitochondria.
These “mitochondria-shaping proteins” also play roles in the malignant characteristics of cancer cells. In
glioblastoma cell lines, we found that mitochondria are fragmented with up-regulation of DRP1 in a tumorigenic
stem-like population, and down-regulation of DRP1 lose their tumorigenic potential (Bassoy EY, Kasahara A,
et al., EMBO J 2017). Glioma stem-like populations (GSCs) are resistant to chemotherapy, therefore, targeting
GSCs is crucial for the complete eradication of glioblastoma. Interestingly, cytotoxic T lymphocytes (CTL) killmore preferentially GSCs than glioma differentiated cells (GDCs). Mitochondria in GSCs are fragmented,
distant from the endoplasmic reticulum (ER), and show fewer contact sites with the ER compared to GDCs.
This specific mitochondrial morphology and the distance between ER and mitochondria are important for
sialylated glycan expressions at the plasma membrane, which directly influence the CTL physiological contact
to the target glioma cells (Bassoy EY, Kasahara A, et al., EMBO J 2017).
Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are commonly usedmolecular target drugs against non-small-cell lung cancer; however, the appearance of resistant lungadenocarcinoma cells after a certain period of treatment hinders the complete eradication of the cancer cells.
Although several molecular mechanisms underlying this acquired resistance to the EGFR-TKIs have been
demonstrated, the mitochondrial dynamics and functions can also be one of the molecular mechanisms used bylung adenocarcinoma cells for acquiring resistance to the EGFR-TKIs. In fact, we have identified the upregulation of mitochondrial inner membrane profusion protein OPA1 in a gefitinib-resistant lungadenocarcinoma cell line, which contributes to the maintenance of the resistance. OPA1 protects cells from
apoptosis by keeping the cristae junction tight to prevent cytochrome c release. OPA1 is also required for thestabilisation of the respiratory chain supercomplexes, and efficient respiration activity. We have observed
elongated mitochondria and tightened cristae lumen in the resistant cells compared to that in the sensitive cells.
The resistant cells showed anti-apoptotic cell death induced by gefitinib as well as intrinsic apoptotic stimuli
via OPA1 up-regulation. The resistant cells also showed increased mitochondrial respiration; thus, inhibition of
mitochondrial respiration restored the sensitivity to gefitinib. Ablation of OPA1, as well as a small molecule
specific OPA1 inhibitor, restored the sensitivity to gefitinib (manuscript in preparation).
Our results suggest that “mitochondria-shaping proteins”, which regulate the shape and structure of the organelle
for efficient activities of the enzymes embedded, can be used to target the malignant cancer cells.

Eishu Hirata
Division of Tumor Cell Biology and Bioimaging, Cancer Research Institute ofKanazawa University
Contact:ehirata [at sign] staff.kanazawa-u.ac.jp
Please replace [at sign] with @Education:
2002

Kyoto University School of Medicine (MD)2010

Kyoto University Graduate School of Medicine (PhD)

Professional Career:
2002

Resident, Kyoto University Hospital

2003

Resident, Ako City Hospital

2004

Medical Staff, Kokura Memorial Hospital

2005

Medical Staff, Shinko Hospital

2010

Assistant Professor, Kyoto University

2011

Research Fellow, Cancer Research UK London Research Institute2015

Research Fellow, Francis-Crick Institute2015

Senior Assistant Professor, Kanazawa Medical University

2018-present

Associate Professor, Kanazawa University

Scientific Activities:
2010-

Board certified neurosurgeon, Japanese Neurosurgical Association

2022-

Councilor, Japanese Cancer Association

Publications:1.

Hirata et al., The brain microenvironment induces DNMT1 suppression and indolence of metastatic cancer
cells. iScience. 23(9):101480, 2020.

2.

Hirata et al., Intravital imaging reveals how BRAF inhibition generates drug tolerant microenvironments withhigh integrin β1/FAK signaling. Cancer Cell. 27: 1-15, 2015.

3.

Hirata et al., In vivo fluorescence resonance energy transfer imaging reveals differential activation of Rhofamily GTPases in glioblastoma cell invasion. J Cell Sci. 125: 858-68. 2012.

Multifaceted Interactions Between Cancer Cells and Glial Cells in Brain Metastasis
Eishu Hirata
Division of Tumor Cell Biology and Bioimaging,
Cancer Research Institute of Kanazawa University

The tumor microenvironment is deeply involved in cancer cell growth, invasion, metastasis, and resistance totherapy. It is composed of a variety of stromal cells, including fibroblasts, vascular endothelial cells, and cells of
the immune system. There are also some organ-specific cell types, such as osteoblasts in the bone tissue, and glial
cells in the brain tissue. In the process of brain metastasis formation, the emerging and progressive interactions
between cancer cells and glial cells play a very important role; however, there are few methods to stably analyze
these events for a long period in vitro. Recently, we have developed a simple and stable culture method for prolonged
observation of astrocytes and microglia. Mixed-glial culture on soft substrate (MGS) not only enables long-term
culture of primary microglia, but also maintains the reactive expression of glial fibrillary acidic protein in astrocytes,
a characteristic response observed in disease-related astrocytes, including those in cancer brain metastasis. These
astrocytes maintain astrocytic gene expression signatures compared to those prepared and cultured using a
conventional method. The growth abilities of cancer cells in mouse brains positively correlate with those in MGS,
and cancer cells cultured in MGS for a long period acquire growth ability in mouse brains. These results suggestthat MGS well mimics the brain microenvironment for cancer cells and is a useful system to investigate cancer-glia
interactions. Three-dimensional live imaging with chemical and/or genetic manipulations in the co-culture system
reveals complicated and multifaceted interactions between cancer cells, astrocytes, and microglia, whichcollectively configurates cancer-promotive and/or -suppressive microenvironment.

References:[1] Hirata E, Ishibashi K, Kohsaka S, Shinjo K, Kojima S, Kondo Y, Mano H, Yano S, Kiyokawa E, Sahai E. The
brain microenvironment induces DNMT1 suppression and indolence of metastatic cancer cells. iScience.
23(9):101480, 2020.
[2] Hirata E and Sahai E. Tumor Microenvironment and Differential Responses to Therapy. Cold Spring Harb
Perspect Med. 7(7):a026781, 2017.
[3] Seifert H, Hirata E, Gore M, Khabra K, Messiou C, Larkin J, Sahai E. Extrinsic factors can mediate resistanceto BRAF inhibition in CNS melanoma metastases. Pigment Cell Melanoma Res. 29(1):92-100, 2016.
[4] Hirata E, Girotti MR, Viros A, Hooper S, Spencer-Dene B, Matsuda M, Larkin J, Marais R and Sahai E. Intravital
imaging reveals how BRAF inhibition generates drug tolerant microenvironments with high integrinβ1/FAK
signaling. Cancer Cell. 27: 1-15, 2015.

Erik Sahai
The Francis Crick InstiuteContact: erik.sahai [at sign] crick.ac.uk
Please replace [at sign] with @Education:
1991 - 1994

Emmanuel College, University of Cambridge
First Class degree – Zoology

1994 - 1998

University College London, University of London
Doctor of Philosophy - Biochemistry

Professional Career:Nov ‘98 – June ‘03

Post-doc - Institute of Cancer Research, 237 Fulham Road, London, UK

June ‘03 – June ‘04

Research Fellow - Albert Einstein College of Medicine, 1300 Morris Park Ave,
Bronx, New York, USA

Aug ‘04 – March ‘15Group Leader - Cancer Research UK London Research Institute 44 Lincoln's Inn
Fields, London, UK

April ’15 – present

Senior Group Leader - The Francis Crick Institute 1 Midland Road, London, NW1
1AT UK

Honors:Elected to the Academy of Medical Sciences – 2021
Elected Fellow of the European Academy of Cancer Sciences – 2017
Elected EMBO member – 2014
British Society for Cell Biology Hooke Medal - 2009
EMBO Young Investigator Programme Member – 2008
UICC Translational Cancer Research Fellowship - 2003-2004
University of Cambridge Frank Smart Prize for Zoology - 1994
Top 3 Publications in last 3 years:(selected from >100 papers published during career, h-index 72, >28000 citations Google Scholar metrics)
1. Arwert EN, Milford EL, Rullan A, … Sahai E. Nature Cell Biology. 2020 Jul;22(7):758-766. doi:
10.1038/s41556-020-0527-7
2. Montagner M, …Sahai E. Nature Cell Biology 2020 Mar;22(3):289-296. doi: 10.1038/s41556-020-0474-3
PMID: 32094692
3. Park D, … Sahai E. Nature Materials 2020 Feb;19(2):227-238. doi: 10.1038/s41563-019-0504-3.. PMID:
31659294

A New Player in the Tumour Microenvironment of Dormant Cancer Cells
Erik Sahai
The Francis Crick Institute
Delayed relapses at distant sites are common for certain types of cancers after removal of primary tumor, suchas breast and prostate cancer. This implies that disseminated cancer cells can persist in an indolent or dormant
state for long periods of time. Because of the asymptomatic nature of this phenomenon, isolation, and analysis
of disseminated dormant cancer cells from clinically disease-free patients is ethically and technically highly
problematic. To overcome this major limitation, we have developed in vitro models of the metastatic niche fordifferent organs and different types of cancers. In particular, we have developed a lung ‘organotypic’ system
and used this in combination with in vivo assays of breast cancer dormancy. This reveals how the behaviour ofindolent breast cancer cells in the lung is determined by their interactions with alveolar epithelial cells, inparticular alveolar type 1 cells. This promotes the formation of fibronectin fibrils by indolent cells that drive
integrin-dependent pro-survival signals. Combined in vivo RNA sequencing and drop-out screening identified
secreted frizzled-related protein 2 (SFRP2) as a key mediator of this interaction. Sfrp2 is induced in breast
cancer cells by signals from lung epithelial cells and promotes fibronectin fibril formation and survival, whereas
blockade of Sfrp2 expression reduces the burden of indolent disease. Subsequent analyses show that that the
TFEB-lysosomal axis is activated in dormant cancer cells (DCCs) and that it is modulated by the pro-survival
ephrin receptor EphB6. TFEB lysosomal direct targets are enriched in DCCs in vivo and correlate with relapse
in ER+ breast cancer patients. Direct coculture of DCCs with alveolar type I-like lung epithelial cells anddissemination in the lung drive lysosomal accumulation and EphB6 induction. EphB6 contributes to survival,
TFEB transcriptional activity, and lysosome formation in DCCs in vitro and in vivo. Furthermore, signalingfrom EphB6 promotes the proliferation of surrounding lung parenchymal cells in vivo. Our data provide
evidence that EphB6 is a key factor in the crosstalk between disseminated dormant cancer cells and the lungparenchyma and that the TFEB-lysosomal pathway plays an important role in the persistence of DDCCs.
References
EphB6 Regulates TFEB-Lysosomal Pathway and Survival of Disseminated Indolent Breast Cancer Cells.
Zangrossi M, Romani P, Chakravarty P, Ratcliffe CDH, Hooper S, Dori M, Forcato M, Bicciato S, Dupont S,
Sahai E, Montagner M. Cancers (Basel). 2021 Mar 3;13(5):1079. doi: 10.3390/cancers13051079.
A Lung Organotypic Coculture Reveals a Role for TFEB-Lysosomal Axis in the Survival of DisseminatedDormant Cancer Cells. Zangrossi M, Chakravarty P, Romani P, Dupont S, Hooper S, Sahai E, Montagner M.
Cancers (Basel). 2021 Feb 28;13(5):1007. doi: 10.3390/cancers13051007.
In vitro Models of Breast Cancer Metastatic Dormancy. Montagner M, Sahai E. Front Cell Dev Biol. 2020 Mar
3;8:37. doi: 10.3389/fcell.2020.00037.
Crosstalk with lung epithelial cells regulates Sfrp2-mediated latency in breast cancer dissemination. Montagner
M, Bhome R, Hooper S, Chakravarty P, Qin X, Sufi J, Bhargava A, Ratcliffe CDH, Naito Y, Pocaterra A, TapeCJ, Sahai E. Nat Cell Biol. 2020 Mar;22(3):289-296. doi: 10.1038/s41556-020-0474-3

Secretariat
Kakuma-machi, Kanazawa, Japan
Kanazawa University Cancer Research InstituteTel : 076-264-6702 Fax : 076-234-4527
E-mail : y-kenkyo@adm.kanazawa-u.ac.jp
URL : http://ganken.cri.kanazawa-u.ac.jp/