Transcript MDM2 and Soft Tissue Sarcomas

Cancer: The complex seeds of metastasis
•Michael M. Shen
Analyses of prostate-cancer metastases reveal a complex cellular architecture, and
show that secondary sites can be seeded by multiple cell populations derived from both
the primary tumour and other metastases. See Letter p.353
The evolutionary history of lethal metastatic prostate cancer
•Gunes Gundem, Peter Van Loo, Barbara Kremeyer, et al.
Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones
within a single primary tumour1, 2, 3, 4. This evolutionary process culminates in the formation of metastases, which
is the cause of 90% of cancer-related deaths5. However, despite its clinical importance, little is known about the
principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each
metastasis originates from a single tumour cell is generally supported6, 7, 8, recent studies using mouse models of
cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple
subclones9, 10. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy
and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic
prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate
tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in
unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de
novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones
between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas
mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in
different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our
understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.
Cancer: An extravascular route for
tumour
cells
•Mary J. C.
Hendrix
Molecular tracing of populations of breast-cancer cells in a primary tumour in mice
reveals that two proteins, Serpine2 and Slpi, enable tumour cells to form vascular-like
networks, facilitating perfusion and metastasis. See Letter p.358
A model of breast cancer heterogeneity reveals vascular mimicry as a
driver of metastasis
•Elvin Wagenblast, Mar Soto, Sara Gutiérrez-Ángel, et al.
Cancer metastasis requires that primary tumour cells evolve the capacity to intravasate into the lymphatic system
or vasculature, and extravasate into and colonize secondary sites1. Others have demonstrated that individual cells
within complex populations show heterogeneity in their capacity to form secondary lesions2, 3, 4, 5. Here we develop
a polyclonal mouse model of breast tumour heterogeneity, and show that distinct clones within a mixed population
display specialization, for example, dominating the primary tumour, contributing to metastatic populations, or
showing tropism for entering the lymphatic or vasculature systems. We correlate these stable properties to distinct
gene expression profiles. Those clones that efficiently enter the vasculature express two secreted proteins,
Serpine2 and Slpi, which were necessary and sufficient to program these cells for vascular mimicry. Our data
indicate that these proteins not only drive the formation of extravascular networks but also ensure their perfusion
by acting as anticoagulants. We propose that vascular mimicry drives the ability of some breast tumour cells to
contribute to distant metastases while simultaneously satisfying a critical need of the primary tumour to be fed by
the vasculature. Enforced expression of SERPINE2 and SLPI in human breast cancer cell lines also programmed
them for vascular mimicry, and SERPINE2 and SLPI were overexpressed preferentially in human patients that had
lung-metastatic relapse. Thus, these two secreted proteins, and the phenotype they promote, may be broadly
relevant as drivers of metastatic progression in human cancer.
A resource for cell line authentication, annotation and
quality control
•Mamie Yu, Suresh K. Selvaraj, May M. Y. Liang-Chu, et al.
Genentech Inc.
Cell line misidentification, contamination and poor annotation affect scientific
reproducibility. Here we outline simple measures to detect or avoid cross-contamination,
present a framework for cell line annotation linked to short tandem repeat and single
nucleotide polymorphism profiles, and provide a catalogue of synonymous cell lines.
This resource will enable our community to eradicate the use of misidentified lines and
generate credible cell-based data.
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Scientific Reports
Oncogene
mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5
induction on 4E-BP1 dephosphorylation.
He K1, Zheng X1, Li M1, Zhang L2, Yu J1.
Author information
11] Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA,
USA Abstract
The mammalian target of rapamycin (mTOR) is commonly activated in colon cancer.
mTOR complex 1 (mTORC1) is a major downstream target of the PI3K/ATK pathway
and activates protein synthesis by phosphorylating key regulators of messenger RNA
translation and ribosome synthesis. Rapamycin analogs Everolimus and Temsirolimus
are non-ATP-competitive mTORC1 inhibitors, and suppress proliferation and tumor
angiogenesis and invasion. We now show that apoptosis plays a key role in their antitumor activities in colon cancer cells and xenografts through the DR5, FADD and
caspase-8 axis, and is strongly enhanced by tumor necrosis factor-related apoptosisinducing ligand (TRAIL) and 5-fluorouracil. The induction of DR5 by rapalogs is
mediated by the ER stress regulator and transcription factor CHOP, but not the tumor
suppressor p53, on rapid and sustained inhibition of 4E-BP1 phosphorylation, and
attenuated by eIF4E expression. ATP-competitive mTOR/PI3K inhibitors also promote
DR5 induction and FADD-dependent apoptosis in colon cancer cells. These results
establish activation of ER stress and the death receptor pathway as a novel anticancer
mechanism of mTOR inhibitors.
MicroRNAs as mediators and communicators between
cancer cells and the tumor microenvironment.
Kohlhapp FJ1, Mitra AK2, Lengyel E3, Peter ME1.
Author information
•1Division of Hematology/Oncology, Northwestern University,
Feinberg School of Medicine, Chicago, IL, USA.
•2Medical Sciences Program, Indiana University School of
Medicine, Indiana University, Bloomington, IN, USA.
Negative regulation of the p300-p53 interplay by
DDX24.
Shi D1, Dai C1, Qin J2, Gu W1.
Author information
•1Institute for Cancer Genetics, Department of
Pathology and Cell Biology, Herbert Irving
Comprehensive Cancer Center, College of Physicians
& Surgeons, Columbia University, New York, NY, USA
Hyperthermic intraperitoneal chemotherapy leads to an
anticancer immune response via exposure of cell surface
heat shock protein 90.
Zunino B1, Rubio-Patiño C2, Villa E2, Meynet O2, Proics E2,
Cornille A2, Pommier S1, Mondragón L2, Chiche J2, Bereder JM3,
Carles M1, Ricci JE1.
Author information
•11] Inserm, U1065, Centre Méditerranéen de Médecine
Moléculaire (C3M), équipe "contrôle métabolique des morts
cellulaires", Nice, France
Oncogene
The NEDD8 inhibitor MLN4924 increases the size of the
nucleolus and activates p53 through the ribosomal-Mdm2
pathway.
Bailly A1, Perrin A1, Bou Malhab LJ1, Pion E1, Larance M2,
Nagala M2, Smith P3, O'Donohue MF4, Gleizes PE4, Zomerdijk J2,
Lamond AI2, Xirodimas DP1.
Author information
•1Centre de Recherche de Biochimie Macromoléculaire-UMR
5237, CNRS, Montpellier, France
Fer tyrosine kinase oligomer mediates and amplifies Srcinduced tumor progression.
Oneyama C1, Yoshikawa Y1, Ninomiya Y1, Iino T1, Tsukita S2,
Okada M1.
Author information
•1Department of Oncogene Research, Research Institute for
Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Activation of mechanosensitive ion channel TRPV4
normalizes tumor vasculature and improves cancer therapy.
Adapala RK1, Thoppil RJ1, Ghosh K2, Cappelli HC1, Dudley AC3,
Paruchuri S4, Keshamouni V5, Klagsbrun M6, Meszaros JG1,
Chilian WM1, Ingber DE7, Thodeti CK8.
Author information
•11] Department of Integrative Medical Sciences, Northeast Ohio
Medical University, Rootstown, OH, USA [2] School of
Biomedical Sciences, Kent State University, Kent, OH, USA