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CANCER CELL BIOLOGY 2020
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CANCER CELL BIOLOGY 2020
T
he Journal of Cell Biology (JCB) publishes new cellular and
molecular advances in any area of basic cell biology as well
as studies that describe applied cell biology to translational
fields like cancer biology. This collection celebrates works
that advance our understanding of the fundamental molecular and
cellular events shaping tumors and suggest novel potential therapeutic
avenues, reflecting JCB’s scope and interest in cancer research, from
core mechanistic findings to translational studies. Connect with JCB
(jcellbiol@rockefeller.edu) with any feedback or questions, and visit
www.jcb.org.
5 Tumor suppressor genes set the dividing line
The highly conserved tumor suppressor genes Scribbled and Discs large work together with 14-3-3 proteins to
control mitotic spindle positioning
Yu-ichiro Nakajima … Matthew Gibson
6 Novel pro-invasive endosome feedback loop is amplified in mutant p53 cancer cells
Researchers use new technique to follow fast recycling endosomes
Ashley Lakoduk … Sandra Schmid and Ping-Hung Chen
7 A druggable target for metastatic prostate cancer
Identification of the phosphatase PHLPP2’s role in controlling MYC stability could also have implications for many
other cancers
Dawid G. Nowak … Lloyd C. Trotman
8 Cell death pathway provides possible anti-cancer targets
Modulating cell stress pathways that regulate levels of the pro-apoptotic protein BIK could help treat deadly triple-
negative breast cancer
Fei-Yun Chen … Ruey-Hwa Chen
9 SRC targets the tumor suppressor DLC1
Interaction between DLC1 and tumor promoting kinase SRC reveals a possible new treatment route for DLC1-
positive tumors
Brajendra K. Tripathi … Douglas R. Lowy
10 Hair follicles restrict cancer growth
Normal skin corrals cancer-causing mutations and reveals how tissue can subvert tumorigenesis
Cristiana M. Pineda … Valentina Greco
11 Protein involved in cancer metastasis hijacks another for transport
A critical protease for metastasis uses a protein involved in intracellular transport to get to the cell surface
Takuya Miyagawa, Kana Hasegawa, Yoko Aoki, Takuya Watanabe ... Hiroki Inoue
12 Cancer cells turn to cannibalism to survive chemotherapy
Senescent cancer cells can engulf and digest their neighbors, allowing them to stay alive and initiate tumor relapse
Crystal A. Tonnessen-Murray … James G. Jackson
13 Importin-11 mediates nuclear import of βcatenin
Targeting this transport step may block the growth of colorectal cancers caused by mutations in APC
Monika Mis … Stephane Angers
Brochure articles: Ben Short, PhD, Christina 14 Chromosomes are a barrier to normal cell division in polyploid cells
Szalinski, PhD, and Brittany Carson, PhD Duplicated chromosome sets is common in cancer, but the extra chromosomes act as a barrier to typical “bipolar”
cell division
Design: Christine Candia Alix Goupil, Maddalena Nano … Renata Basto
On the cover: “The collagen trail: Journey
to the microenvironment.” Ovarian cancer
cell migrating along a collagen fiber, imaged
using scanning electron microscopy. Image ©
Elizabeth Harper, University of Notre Dame,
Notre Dame, IN. This image was featured on
the January 2020 cover of JCB.
3
Editor-In-Chief Editorial Board
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TUMOR SUPPRESSOR GENES SET THE
DIVIDING LINE
The highly-conserved tumor suppressor genes Scribbled and Discs large work
together with 14-3-3 proteins to control mitotic spindle positioning
Tumor suppressor genes keep normal understand how mitotic spindle move-
cells in check, but precisely how some of ments are controlled by these proteins in
these genes function remains unknown. real time, Nakajima and colleagues used
Matt Gibson, Investigator and Dean of the live imaging in developing Drosophila
Graduate School at the Stowers Institute wing epithelia where either Mud, Scrib
for Medical Research, together with first or Dlg were depleted. The knockdown
author and former postdoc Yu-ichiro of Scrib or Dlg in the developing wing
Nakajima, now an Assistant Professor disc caused random spindle movements,
at Tohoku University, used the fruit fly “suggesting that Scrib and Dlg control
Drosophila to provide new insights into spindle rotation and restrict spindle posi-
the mechanism of action of the highly tioning,” Nakajima says.
conserved tumor suppressor proteins
Scribbled (Scrib) and Discs large (Dlg). During cell division in the wing disc
epithelium, Mud accumulates at spindle
The vast majority of cells in our bodies re- poles and is also localized to the cell
side in epithelial layers—polarized sheets junctions, where both Scrib and Dlg
of cells that tightly stick together. During accumulate. Though Scrib and Dlg are In the Drosophila wing disc epithe-
epithelial cell proliferation, each mitotic found together, it was not known whether lium, Scrib (green) is found along
spindle (the microtubule structure that they interact at the junction, so the team junctions, while Mud (red) localizes at
works to separate chromosomes into two expressed mutated versions of Scrib with spindle poles during mitosis. DNA is
daughter cells) typically aligns parallel to various domains missing. The authors shown in blue.
the epithelial plane to ensure that the two found that Scrib missing all of its PDZ Credit: Nakajima et al., 2019
daughter cells properly integrate into the domains reduced Dlg localization to junc-
tissue. This process is known as planar tions. Demonstrating a role for Scrib-Dlg
cell division. If the spindle is not aligned interaction in planar spindle orientation,
between Scrib and Mud. “14-3-3 proteins
properly when it comes time for a cell cells expressing that particular Scrib
could function as a molecular link that
to divide, tumors can develop or metas- mutant also had abnormal planar spindle
connects the junction-associated proteins
tasis can occur. Nevertheless, exactly orientation.
Scrib/Dlg and the mitotic apparatus,”
how the cell controls this alignment and
A proteomic analysis using Dlg as bait Nakajima says.
coordinates division plane with epithelial
polarity is not well understood. Nakajima revealed 14-3-3 proteins as potential
Because altered expression of Scribbled
and colleagues turned to Drosophila to binding partners. Using various 14-3-3
(Scrib), Discs large (Dlg), and 14-3-3
learn more about the mechanisms of loss-of-function mutants Nakajima and
is associated with epithelial tumors in
planar division. colleagues were able to show that 14-3-3
humans, the next step is to confirm that
proteins are required for proper control
these proteins work the same way in
Scrib and Dlg, along with another of planar spindle alignment. Additionally,
mammalian tissue.
protein named Mud, are known to be knockdown of 14-3-3s or Dlg resulted in
important for spindle orientation. To the reduction of physical associations
RESEARCHER DETAILS ORIGINAL PAPER
Nakajima, Y., Z.T. Lee, S.A. McKinney , S.K. Swanson, L. Florens, and M.C. Gibson.
2019. Junctional tumor suppressors interact with 14-3-3 proteins to control planar
spindle alignment. J. Cell Biol. 218:1824–1838.
https://doi.org/10.1083/jcb.201803116
Yu-ichiro Nakajima Matthew Gibson
Assistant Professor, Tohoku University Investigator and Dean of the Graduate School
yuichiro.nakajima.d2@tohoku.ac.jp at the Stowers Institute for Medical Research
5
NOVEL PRO-INVASIVE ENDOSOME
FEEDBACK LOOP IS AMPLIFIED IN
MUTANT P53 CANCER CELLS
Researchers use new technique to follow fast recycling endosomes
Most cancer-associated deaths occur the signaling scaffold protein APPL1.
due to metastasis—the process through These endosomes serve as hubs to
which tumor cells acquire invasive modulate cell signaling and promote
capacity and disseminate to distant and the rapid recycling of the cell adhesion
often vital organs. The development of molecule β1 integrin and the epithelial
novel cancer treatment requires a better growth factor receptor (EGFR), thereby
understanding of the acquisition of cell enhancing focal adhesion turnover and
invasiveness and of metastasis, with a cell migration. Representative thick-TIRF immunoflu-
more in-depth assessment of pro-met- orescence images of APPL1-positive
astatic cellular processes downstream Although these APPL1-positive endo- endosomes with and without EGF
of the well characterized genetic and somes can be found in both normal and signaling.
epigenetic alterations. tumor cells, their selective redistribution Credit: Lakoduk et al., 2019
to the cell perimeter is enhanced by
A team of researchers led by Sandra GOF p53 through upregulation of both
Schmid and Ping-Hung Chen at the dynamin-1 (Dyn1) and myosin VI. This
organization and functional diversity of
University of Texas Southwestern finding further elucidates the known
early endosomes,” Schmid says.
Medical Center used a newly developed link between GOF p53 mutations and
technique to monitor rapid endocytic endocytosis. Formation of these AP- The findings of this study have yet to be
trafficking, a process known to augment PL1-positive endosomes depends on fully explored in vivo, but the relevance
tumor progression and metastasis. This Akt signaling and, as increased APPL1 to patients and potentially patient care
technique involves thick total internal scaffold formation promotes Akt signal- is supported by online patient databas-
reflection fluorescence (TIRF) micros- ing and dynamin-1 activation, a positive es that have confirmed the link between
copy and analysis using a specialized feedback loop is created and can be p53 mutations and increased Dyn1
analysis platform, cmeAnalysis. The further enhanced with GOF p53. expression.
ability to follow fast recycling endo-
somes, previously a limiting factor in Endosomal recycling–receptor signaling “Our data provide mechanistic insight
studies of endocytic trafficking, sup- crosstalk, in combination with feedback into how selective activation of endo-
ports additional investigation into the loops, can therefore be activated or cytic protein isoforms can alter endo-
role of early endosomes in normal and amplified in cancer cells. somal recycling and receptor signaling
pathologic cell functions. to promote the adaptation required for
“In addition, our studies on the reg-
aggressive phenotypes in cancers,”
The team identified a subpopulation of ulation of early endocytic trafficking
Chen says.
endosomes at the cell edge that carry in cancer cells have revealed added
complexity with regard to the spatial
RESEARCHER DETAILS ORIGINAL PAPER
Lakoduk, A. M., P. Roudot, M. Mettlen, H. M. Grossman, S. L. Schmid, and P.-H.
Chen. 2019. Mutant p53 amplifies a dynamin-1/APPL1 endosome feedback loop that
regulates recycling and migration. J. Cell. Biol. 218:1928–1942.
https://doi.org/10.1083/jcb.201810183
Ashley Lakoduk Ping-Hung Chen Sandra Schmid
Postdoctoral Researcher Assistant Professor Cecil H. Green Distinguished
Cell Biology Department Institute of Biochemistry and Professor in Cellular and
UT Southwestern Medical Molecular Biology, College Molecular Biology; Chair,
Center of Medicine, National Taiwan Cell Biology Department, UT
6 University
pinghungchen@ntu.edu.tw
Southwestern Medical Center;
sandra.schmid@
utsouthwestern.edu
A DRUGGABLE TARGET FOR METASTATIC
PROSTATE CANCER
Identification of the phosphatase PHLPP2’s role in controlling MYC stability could also
have implications for many other cancers
The oncogenic protein MYC drives prostate cancer cells require PHLPP2 to
cell growth and proliferation while survive and proliferate. They discovered
enhancing cell metabolism and survival. that PHLPP2 helps stabilize MYC by
It causes many different types of cancer removing a phosphate group that would
but cannot be targeted by conventional otherwise trigger MYC’s destruction.
drug therapies. “It is estimated that
450,000 Americans are diagnosed The researchers deleted the Phlpp2
each year with a cancer that is driven gene in mice and found that doing so
by MYC,” says Dawid G. Nowak, an prevented prostate cancer cells from
assistant professor at Weill Cornell metastasizing to other organs. This is
Medicine in New York. significant because researchers have
been unable to develop treatments
One type of cancer associated with that directly inhibit MYC, as it does not
elevated MYC levels is metastatic contain any features that can be easily
prostate cancer. Around one in nine targeted with a drug.
men will be diagnosed with prostate
cancer during their lifetime. The disease Trotman and colleagues then turned Red arrows indicate prostate can-
is the second leading cause of cancer to human prostate cancer cells, which cer cells that have metastasized to
death among American men and is they treated with a drug that inhibits the lymph nodes of a genetically
projected to kill over 30,000 people in PHLPP2. This lowered MYC levels engineered mouse. This process is
and caused the cells to stop proliferating blocked in mice lacking the enzyme
2019. The vast majority of these deaths
and die. Phlpp2.
are the result of cancers that spread, or
metastasize, from the prostate to other Credit: Nowak et al., 2019
organs in the body. PHLPP2 does not appear to perform any
essential functions in healthy cells, so
“The five-year survival of metastatic the researchers think that the enzyme
prostate cancer is only 28%, whereas could be an attractive way to indirectly
the five-year survival of prostate- target MYC in metastatic prostate
confined disease is almost 99%,” cancer and possibly other cancers, too.
explains Lloyd C. Trotman, a professor at
Cold Spring Harbor Laboratory. “Our results suggest that targeted
efforts to design pharmacologically
The phosphatase PHLPP2 is also relevant PHLPP2 inhibitors could
elevated in metastatic prostate cancer result in very efficient new drugs
cells, but the role of this protein that suppress MYC-driven cancer,”
was unclear. Nowak, Trotman, and Trotman says.
colleagues found that metastatic
RESEARCHER DETAILS ORIGINAL PAPER
Nowak, D.G., K.C. Katsenelson, K.E. Watrud, M. Chen, G. Mathew, V.D. D’Andrea,
M.F. Lee, M.M. Swamynathan, I. Casanova-Salas, M.C. Jibilian, C.L. Buckholtz,
A.J. Ambrico, C.-H. Pan, J.E. Wilkinson, A.C. Newton, and L.C. Trotman. 2019. The
PHLPP2 phosphatase is a druggable driver of prostate cancer progression. J. Cell
Biol. 218:1943–1957.
https://doi.org/10.1083/jcb.201902048
Lloyd C. Trotman Dawid G. Nowak
Professor Assistant Professor
Cold Spring Harbor Weill Cornell Medicine
Laboratory dgn2001@med.cornell.edu
trotman@cshl.edu
7
CELL DEATH PATHWAY PROVIDES
POSSIBLE ANTI-CANCER TARGETS
Modulating cell stress pathways that regulate levels of the pro-apoptotic protein BIK
could help treat deadly triple-negative breast cancer
When a cell is stressed, a complex net- via a process known as ubiquitination.
work of signals determine whether the Chen and colleagues began searching
cell will survive. Regulating these path- for the protein involved in flagging it
ways can offer anti-cancer strategies. and identified Cul5-ASB11 as the ubiq-
Fei-Yun Chen, Ruey-Hwa Chen, and uitin ligase that modifies BIK and tar-
colleagues at the Academia Sinica in gets it for destruction. The researchers
Taiwan and National Taiwan University found that, in response to endoplasmic
reveal a new understanding of what reticulum stress, ASB11 is transcrip-
drives cell death under different stress tionally activated by an effector of the
conditions and how these pathways stress-sensing protein IRE1α, promot-
can be targeted to reduce tumor size in ing BIK degradation and cell survival.
triple-negative breast cancer (TNBC) However, DNA damage–induced stress In a mouse model of triple-negative
models. caused the tumor suppressor p53 to breast cancer, overexpressing an
active BIK mutant (VISA-BIKDD) in
repress ASB11 through IRE1α, stabiliz-
Cell death regulation is crucial during combination with an IRE1α inhibitor
ing BIK and promoting cell death.
(STF) showed enhanced anti-tumor
development and for maintaining
effects compared to either treatment
healthy tissue. When cell death is sup- “BIK ubiquitination and degrada-
by itself.
pressed, cells can grow out of control, tion are enhanced by ER stress and
Credit: Chen et al., 2019
causing tumors to form. Regulating cell reduced by DNA damage, thereby
death pathways can influence cancer oppositely regulating cell life/death de-
cells’ sensitivity to anti-tumor treat- cisions in the two stressed conditions,”
ments. A family of proteins known as Ruey-Hwa Chen says. This presents inhibitor showed enhanced anti-tumor
Bcl-2 determine whether cells commit “an intriguing crosstalk between differ- effects compared to either treatment
to death, and one of the proteins in ent cellular stress pathways.” by itself.
the family is BIK. BIK is considered a
pro-death protein; its presence signals In TNBC, a highly aggressive disease “Targeting the BIK degradation path-
a cell to die, but how BIK is regulated with limited treatment options, the an- way in combination with the adminis-
and its physiological functions were ti-tumor strategy of expressing an ac- tration of an active BIK mutant could
not well understood, nor was it known tive BIK mutant is ineffective because offer an effective anti-cancer strategy,”
what stressors trigger BIK to promote the mutant is prone to degradation, Chen says.
cell death. which helps keep TNBC cells alive. In
both cell lines and a mouse model of
BIK protein has a short half-life and is TNBC, overexpressing the active BIK
thought to be flagged for destruction mutant in combination with an IRE1α
RESEARCHER DETAILS ORIGINAL PAPER
Chen, F.Y., M.Y. Huang, Y.M. Lin , C.H. Ho , S.Y. Lin , H.Y. Chen , M.C. Hung, and R.H.
Chen. 2019. BIK ubiquitination by the E3 ligase Cul5-ASB11 determines cell fate
during cellular stress. J. Cell Biol. 218:3002–3018.
https://doi.org/10.1083/jcb.201901156
Fei-Yun Chen Ruey-Hwa Chen
Postdoctoral Fellow Associate Professor
Academia Sinica, Taiwan Academia Sinica, Taiwan
National Taiwan University National Taiwan University
rhchen@gate.sinica.edu.tw
8
SRC TARGETS THE TUMOR SUPPRESSOR
DLC1
Interaction between DLC1 and tumor promoting kinase SRC reveals a possible new
treatment route for DLC1-positive tumors
Personalized treatments hold promise To explore a possible mechanistic rela-
for cancers that evade generic chemo- tionship between SRC, RhoA-GTP, and
therapies. Research by Brajendra Trip- DLC1, they treated two DLC1-positive
athi, Douglas Lowy, and colleagues at and two DLC1-negative non–small cell
the National Cancer Institute indicates lung cancer lines with the SRC inhibitor
that it may be possible to target a sub- Saracatinib, which reduced RhoA-GTP
set of cancers that express the tumor in both DLC1-positive lines, but not in
suppressor and focal adhesion protein the DLC1-negative lines. These results
DLC1, a component of focal adhesions indicate SRC kinase can increase RhoA-
that can switch off the active GTPase GTP in DLC1-positive cells, and the SRC
RhoA by acting as a GTPase-activat- inhibitor can reverse the process.
ing protein (GAP). They establish, for Colocalization between DLC1 (red)
the first time, a connection between Using co-immunoprecipitation assays,
and SRC (green) in a DLC1-positive
DLC1 and the tumorigenesis-promoting they found that SRC and DLC1 interact non–small cell lung cancer cell line.
kinase SRC, revealing SRC inhibition and that the localization of SRC to focal
Credit: Tripathi et al., 2019
can be an effective part of the tumor adhesions depends on the presence of
treatment in a DLC1-positive cancer DLC1 protein. Their results show that
model and that reactivation of the tumor SRC binds directly to DLC1 and phos-
suppressor can be a potent anti-tumor phorylates it at residues Y451 and Y701. activity,” Tripathi, Lowy, and colleagues
approach. Phosphorylation analysis indicated that said. A SRC inhibitor by itself reduced
DLC1 can also be phosphorylated on the size of DLC1-expressing tumors in
SRC is a kinase that controls many S129 by the kinase ERK, which increas- mice by 64%, and combining it with an
tumor-promoting processes, including es both the binding of SRC to DLC1 and inhibitor of AKT, which also phosphory-
regulating the cytoskeleton and a cell’s SRC-dependent phosphorylation of lates and attenuates the tumor suppres-
ability to move and attach, by changing DLC1. Phosphorylation of DLC1 by SRC sor activity of DLC1, reduced tumor size
the expression of oncogenic and tumor attenuates DLC1’s Rho-GAP activity, the by 89%.
suppressor genes. SRC also regulates researchers discovered. Cells with DLC1
the RhoA GTPase, a protein that is fre- mutations that are deficient for SRC “One possible way to increase the
quently activated in advanced cancer. phosphorylation lacked well-formed proportion of tumors for which the
While surveying protein expression in stress fibers, like those found in cells therapeutic targeting of DLC1 could be
cancer-derived cell lines, Tripathi, Lowy, with an active DLC1. clinically beneficial might be to use a
and colleagues found a strong and un- suitable inhibitor to reverse an epigene-
expected correlation between the levels “Given the reversibility of the SRC-de- tic change that has resulted in reduced
of RhoA-GTP, total SRC protein, and pendent DLC1 phosphorylation, we or silenced DLC1 expression... and to
SRC activity and an inverse correlation evaluated whether SRC inhibitors combine this treatment with inhibition
with DLC1 protein levels. might have therapeutic efficacy in a of SRC and/or AKT kinase activities,”
DLC1-positive tumor that had high SRC Tripathi, Lowy, and colleagues say.
RESEARCHER DETAILS ORIGINAL PAPER
Tripathi, B.K., M.F. Anderman, X. Qian, M. Zhou, D. Wang, A.G. Papageorge, and D.R.
Lowy. 2019. SRC and ERK cooperatively phosphorylate DLC1 and attenuate its Rho-
GAP and tumor suppressor functions. J. Cell Biol. 218:3060–3076.
https://doi.org/10.1083/jcb.201810098
Brajendra K. Tripathi Douglas R. Lowy
Senior Scientist Chief, Laboratory of Cellular Oncology
Center for Cancer Research Center for Cancer Research
National Cancer Institute National Cancer Institute
tripathib@mail.nih.gov lowyd@mail.nih.gov
9
HAIR FOLLICLES RESTRICT CANCER
GROWTH
Normal skin corrals cancer-causing mutations and reveals how tissue can subvert
tumorigenesis
Normal aged skin contains cancer-caus-
ing mutations, recent research has
shown, but how these mutations are
prevented from forming tumors was a
mystery. Christiana M. Pineda, Valentina
Greco, and colleagues at Yale University
used unique live-tissue imaging to track
mouse skin cells after inducing can-
cer-causing mutations. They found that
protection against skin cancer comes
from a surprising place: hair follicles.
About 30% of all cancers contain a Ras
mutation, but these same mutations
have been found in non-cancerous
skin epithelia. Pineda and colleagues
induced Ras mutations in mouse hair
follicle cells along with a glowing red
reporter to track the mutant stem cells Two-photon images of the ear skin from the same mouse at day 0 and 4 months
and their progeny. The cells persisted in after Ras activation reveal normal follicular architecture despite the persistent pres-
the epithelium, revealing that the body ence of mutant cells (red).
doesn’t just eliminate mutant cells. Credit: Pineda et al., 2019
Pineda and colleagues found that when
they induced mutations in hair follicle “Our results indicate that the hair
induce some tumors, typically at sites
stem cells, they outcompeted wild-type follicle has a unique ability to cope with
of high grooming or scratching. Imag-
neighboring cells. They still responded Ras-activated cells. This organ is able
ing revealed that those tumors arose
to normal tissue constraints, such as to integrate the mutant epithelial cells
after an injury caused them to exit the
resting phase cues, however. Even after while remaining clinically normal,” Pine-
follicular niche. To test whether injury
a year, the transformed cells did not de- da says. There’s still much to learn about
can promote tumorigenesis within the
velop into tumors. In contrast, targeting what’s going on in the skin that could be
follicle, they ablated hair follicle bulbs
the Ras mutation to the upper non-cy- applied to other cancers. “Manipulation
and the double mutant cells showed
cling region of the skin epithelium led to of certain cell types or signaling path-
rapid, and normal, regeneration. “Once
benign outgrowths. ways may enable and/or enhance the
out of the follicular niche, Hras mutant
cells can no longer be controlled and ability of other epithelial tissues to also
Introducing a second mutation that
contained through hair regeneration suppress oncogenic growth.”
results in the loss of TGFβ signaling into
programs,” Pineda says.
Ras-mutant hair follicle stem cells did
RESEARCHER DETAILS ORIGINAL PAPER
Pineda, C.M., D.G. Gonzalez, C. Matte-Martone , J. Boucher , E. Lathrop , S. Gallini ,
N.R. Fons, T. Xin , K. Tai, E. Marsh , D. X. Nguyen , K.C. Suozzi , S. Beronja , and V.
Greco. 2019. Hair follicle regeneration suppresses Ras-driven oncogenic growth. J.
Cell Biol. 218:3212-3222.
https://doi.org/10.1083/jcb.201907178
Cristiana M. Pineda Valentina Greco
Graduate Student Professor
Yale University Yale University
valentina.greco@yale.edu
10PROTEIN INVOLVED IN CANCER
METASTASIS HIJACKS ANOTHER FOR
TRANSPORT
A critical protease for metastasis uses a protein involved in intracellular transport to
get to the cell surface
Metastasis is often a death sentence is localized in a unique organelle and
for cancer patients. When a cancer forms specific complexes with cognate
cell begins to invade surrounding SNAREs to ensure membrane fusion
tissue, it forms a protrusion called an specificity,” Miyagawa says. The team
invadopodium. Matrix metalloprotein- identified Bet1 as the SNARE that is
ases (MMPs) are critical regulators of required for extracellular matrix degra-
this process. Takuya Miyagawa, Kana dation. Bet1 was previously shown to be
Hasegawa, Yoko Aoki, Takuya Wata- involved in transport from the ER to the
nabe, Hiroki Inoue, and colleagues at Golgi apparatus. Bet1 (green) colocalizes with MT1-
Tokyo University of Pharmacy and Life MMP (red) in invasive breast cancer
They found Bet1 colocalized with the cells.
Sciences reveal a novel mechanism for
how one of those MMPs, membrane Golgi, but surprisingly also with MT1- Credit: Miyagawa et al., 2019
type 1–MMP (MT1-MMP), is delivered to MMP in late endosomes. In invasive
invadopodia. cells, the team found that Bet1 was
able to reach the cell membrane, but in Bet1 function for its own transport,”
Many MMPs involved in cancer cell non-invasive cells, it stayed in the Golgi. Miyagawa says. Also, the team showed
invasion are secreted, soluble enzymes, Bet1 appears to be involved in MT1- that in invasive cells Bet1 is localized in
but MT1-MMP is membrane bound. MMP delivery to the cell surface, as MT1-MMP–positive endosomes as well
MT1-MMP is synthesized in the endo- Bet1 knockdown decreased the amount as the Golgi apparatus, and it forms a
plasmic reticulum (ER) and transported of MT1-MMP that reached the mem- novel SNARE complex with syntaxin 4
in vesicles to invadopodia, which are brane, whereas Bet1 overexpression and endosomal SNAREs.
structures with the ability to degrade increased MT1-MMP delivery. Addi-
the extracellular matrix, but the molecu- tionally, in invasive cells, Bet1-GFP was “MT1-MMP changes the function of Bet1
lar mechanism underlying this intracel- found in areas associated with invado- for its efficient transport to invadopodia.
lular transport was not fully understood. podia maturation. Bet1 is critical for the formation of func-
tional invadopodia that degrade ECM,
One crucial family of proteins involved Together, the team’s data indicates that and therefore could be a novel target
in vesicle trafficking specificity are MT1-MMP diverts Bet1 from its function for diagnosis, treatment, and prognosis
SNAREs, which act like twist ties when in ER to Golgi transport, to promote prediction of the disease,” Miyagawa
they meet on opposing membranes, MT1-MMP trafficking to the cell surface, says.
driving the fusion of a vesicle with its including to invadopodia in invasive
destination membrane. “Each SNARE breast cancer cells. “MT1-MMP hijacks
RESEARCHER DETAILS ORIGINAL PAPER
Takuya Miyagawa Miyagawa, T., K. Hasegawa, Y. Aoki , T. Watanabe, Y. Otagiri , K. Arasaki, Y. Wakana, K.
Kana Hasegawa Asano, M. Tanaka, H. Yamaguchi , M. Tagaya, and H. Inoue. 2019. MT1-MMP recruits
Yoko Aoki the ER-Golgi SNARE Bet1 for efficient MT1-MMP transport to the plasma membrane.
Takuya Watanabe
J. Cell Biol. 218: 3355-3371.
Graduate students https://doi.org/10.1083/jcb.201808149
Tokyo University of Pharmacy and Life Sciences
Hiroki Inoue
Assistant Professor
Tokyo University of Pharmacy
and Life Sciences
hirokii@toyaku.ac.jp
11CANCER CELLS TURN TO CANNIBALISM
TO SURVIVE CHEMOTHERAPY
Senescent cancer cells can engulf and digest their neighbors, allowing them to stay
alive and initiate tumor relapse
Chemotherapy drugs like doxorubicin bicin or other chemotherapy agents,
kill cancer cells by damaging their DNA, breast cancer cells that become senes-
but cells that survive initial treatment cent often engulf neighboring cancer
can soon give rise to new tumors. This cells. The researchers observed this
is a particular problem in breast cancers surprising behavior not only in cancer
that retain a normal copy of the TP53 cells in vitro, but also in orthotopic
gene. Instead of dying in response to tumors growing in mice. Lung and bone
chemotherapy-induced DNA damage, cancer cells are also capable of en-
these cancer cells generally just stop gulfing their neighbors after becoming
proliferating and enter a dormant but senescent, the researchers discovered.
metabolically active state known as
senescence. In addition to surviving Tonnessen-Murray and colleagues
chemotherapy, these senescent cancer found that senescent cancer cells
cells produce large amounts of inflam- upregulate a group of genes that are in-
matory molecules and other factors that volved in phagocytosis and are normal-
A breast tumor formed in mice and
can promote tumor regrowth. Chemo- ly active in macrophages. After “eating”
treated with doxorubicin contains
therapy-treated breast cancer patients their neighbors, senescent cancer cells some cancer cells (red nuclei) that
with normal TP53 genes are therefore digest them by delivering them to lyso- have been engulfed by other cancer
prone to relapse and have poor survival somes, degradative organelles that are cells (green cell membrane).
rates. also highly active in senescent cells.
Credit: Tonnessen-Murray et al., 2019
“Understanding the properties of these Importantly, the researchers deter-
senescent cancer cells that allow their mined that this process helps senes-
survival after chemotherapy treatment cent cancer cells stay alive. Senescent “Inhibiting this process may provide
is extremely important,” says Crystal cancer cells that engulfed a neighboring new therapeutic opportunities, because
A. Tonnessen-Murray, a postdoctoral cell survived in culture for longer than we know that it is the breast cancer
research fellow in James G. Jackson’s senescent cancer cells that didn’t. The patients with tumors that undergo
laboratory at the Tulane University researchers suspect that consuming TP53-mediated senescence in response
School of Medicine. their neighbors may provide senescent to chemotherapy that have poor re-
cancer cells with the energy and mate- sponse and poor survival rates,” Jackson
Tonnessen-Murray and colleagues rials they need to survive and produce says.
found that, after exposure to doxoru- the factors that drive tumor relapse.
RESEARCHER DETAILS ORIGINAL PAPER
Tonnessen-Murray, C.A., W.D. Frey, S.G. Rao, A. Shahbandi, N.A. Ungerleider, J.O.
Olayiwola, L.B. Murray, B.T. Vinson, D.B. Chrisey, C.J. Lord, and J.G. Jackson. 2019.
Chemotherapy-induced senescent cancer cells engulf other cells to enhance their
survival. J. Cell Biol. 218:3827–3844.
Jackson (back left) and Tonnes- https://doi.org/10.1083/jcb.201904051
sen-Murray (back right) pictured
with co-authors Joy Olayiwola (front
left) and Sonia Rao (front right).
James G. Jackson Crystal A. Tonnessen-
Assistant professor Murray
Tulane School of Medicine Postdoctoral fellow
jjacks8@tulane.edu Tulane School of Medicine
12IMPORTIN-11 MEDIATES NUCLEAR
IMPORT OF βCATENIN
Targeting this transport step may block the growth of colorectal cancers caused by
mutations in APC
Around 80% of colorectal cancers are manner. Due to their high βcatenin
associated with mutations in the APC levels, most cells die in response to
gene that stabilize the transcription Caspase-9 induction. But cells will sur-
factor βcatenin and lead to the protein’s vive if they lack genes required to main-
accumulation in the cell nucleus, where tain βcatenin transcriptional activity.
it can activate numerous genes that “The DEADPOOL platform constitutes
drive cell proliferation and promote the a robust system to conduct genetic
growth and maintenance of colorectal suppressor screens for the identification
tumors. But how βcatenin enters the of genes involved in signaling systems,”
cell nucleus after its levels rise is poorly Mis says.
understood.
One of the top hits in a CRISPR-based
“Because the molecular mechanisms screen of the DEADPOOL cells was
underlying βcatenin nuclear transport IPO11, which encodes a protein called
remain unclear, we set out to identify Importin-11 that is known to be involved
genes required for continuous βcatenin in nuclear import. Angers and col-
activity in colorectal cancer cells har- leagues found that Importin-11 binds to
Compared with a control (top left),
boring APC mutations,” says Stephane βcatenin and escorts it into the nucleus
removal of βcatenin (top right) or
Angers, a professor in the Department of colorectal cancer cells with muta- Importin-11 (bottom left and bottom
of Pharmaceutical Sciences at the Uni- tions in APC. Removing Importin-11 from right) reduces the growth of colorec-
versity of Toronto’s Leslie Dan Faculty of these cells prevented βcatenin from tal cancer cells carrying a mutation
Pharmacy. entering the nucleus and activating its in APC.
target genes. Credit: Mis et al., 2019
Angers and colleagues, including first
author Monika Mis, developed a new The researchers discovered that Impor-
technique that allowed them to screen tin-11 levels are often elevated in human
the human genome for genes that sup- colorectal cancers. Moreover, remov- more about how Importin-11 transports
port βcatenin’s activity in APC-mutant ing Importin-11 inhibited the growth of βcatenin into the nucleus may help
colorectal cancer cells. The DEADPOOL tumor organoids formed by APC mutant researchers develop new therapies
technique uses a colon cancer cell line cancer cells isolated from patients. that block this process and reduce the
engineered to express an inducible growth of colorectal cancers caused by
form of the apoptosis-inducing protease “We conclude that Importin-11 is mutations in APC.
Caspase-9 in a βcatenin-dependent required for the growth of colorectal
cancer cells,” Angers says. Learning
RESEARCHER DETAILS ORIGINAL PAPER
Mis, M., S. O’Brien, Z. Steinhart, S. Lin, T. Hart, J. Moffat, and S. Angers. 2020. IPO11
mediates βcatenin nuclear import in a subset of colorectal cancers. J. Cell Biol.
219:27–39.
https://doi.org/10.1083/jcb.201903017
Monika Mis Stephane Angers
Graduate student Professor
University of Toronto University of Toronto
stephane.angers@utoronto.ca
13CHROMOSOMES ARE A BARRIER TO
NORMAL CELL DIVISION IN POLYPLOID
CELLS
Duplicated chromosome sets is common in cancer but the extra chromosomes act as a
barrier to typical “bipolar” cell division
Polyploidy, when an entire duplicated clusters at each side of the cell. But
chromosome set is maintained within a things get even more complicated when
cell, is common in human tumors. How there are extra chromosomes as well as
cells maintain this unwieldy extra DNA, extra centrosomes.
especially when it comes time to divide,
was not well understood. Alix Goupil, Goupil and colleagues focused on cells
Maddalena Nano, Renata Basto, and with polyploidy and extra centrosomes
colleagues at the Institut Curie in Paris, due to errors in cytokinesis. They in-
France studied how polyploid cells duced cytokinesis failure in Drosophila
divide and found that the chromosomes neural stem cells and found that the
act as a barrier to typical “bipolar” cell extra centrosomes clustered in more Computer simulations with variable
than two groups, while the chromo- amounts of DNA (red) show that
division, but microtubule stability pro-
somes adopted a multilobed arrange- increase in DNA promote multipolar
motes bipolar cell division.
spindle arrangements.
ment within a multipolar spindle. Most
Though polyploidy is associated with polyploid anaphases were multipolar Credit: Goupil et al., 2020
poor prognosis in cancer, it is also a and generated several nuclei at mitotic
programmed and regulated process exit. The extra chromosomes of poly-
that normally occurs in early mamma- ploid cells seemed to prevent spindle tion of a bipolar spindle, the researchers
lian development. Paradoxically, cells bipolarity. looked at ovarian cancer cells lacking
that acquire an extra set of chromo- the microtubule-depolymerizing kinesin
somes through normal regulation have Similarly, in an in silico program de- MCAK. “This microtubule stabilization
a hard time proliferating, but tumors signed to simulate cell division with resulted in a considerable improve-
can form when polyploid cells arise various numbers and arrangements of ment in spindle bipolarity, and a large
from errors in cell division. In a normal centrosomes and DNA, bipolar spindle majority of polyploid cells divided in a
“bipolar” arrangement before cell divi- assembly was inhibited by the presence bipolar manner,” says Goupil. “In light
sion, two centrosomes line up and serve of extra DNA. In an ovarian cancer cell of our findings and knowing that whole
as microtubule-organizing centers at line with polyploidy induced by cytoki- genome duplications are frequent in
either side of the cell. The microtubules netic failure, the researchers confirmed cancer, it is possible that clonal expan-
then attach to the chromosome’s kine- that chromosomes acted as a barrier to sion of polyploid cancer cells is favored
tochores, pull the chromosomes apart, spindle pole coalescence. in conditions of increased microtubule
and the cell splits in two, in a process stability.”
known as cytokinesis. Cells with more Because their simulations also showed
than two centrosomes can still form a that stabilizing microtubules improved
bipolar spindle by forming centrosome centrosome clustering and the forma-
RESEARCHER DETAILS ORIGINAL PAPER
Goupil, A., M. Nano, G. Letort, S. Gemble, F. Edwards, O. Goundiam, D. Gogendeau,
C. Pennetier, and R. Basto. 2020. Chromosomes function as a barrier to mitotic
spindle bipolarity in polyploid cells. J. Cell Biol. 219:1824–1838.
https://doi.org/10.1083/jcb.201908006
Alix Goupil Maddalena Nano Renata Basto
PhD Student Postdoctoral Fellow Team Leader
Institut Curie, Paris, France University of California, Institut Curie
Santa Barbara renata.basto@curie.fr
mnano@ucsb.edu
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