Evidence map›Paper›PMID 33197448›Full record

ArticleGastroenterology2021

The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis.

Hiroki Kobayashi, Krystyna A Gieniec, Josephine A Wright, Tongtong Wang, Naoya Asai, Yasuyuki Mizutani, Tadashi Lida, Ryota Ando, Nobumi Suzuki, Tamsin R M Lannagan and 26 more

Erratum issued Registry-linked trialOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Gastroenterology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT05064618 (Phase I/II Investigator-initiated Clinical Trial of MIKE-1 With Gemcitabine and Nab-paclitaxel Combination Therapy for Unresectable Pancreatic Cancer), which is not on this map. Cited by 111 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
111citing papers in PubMed, 2 pooled it
6.6field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT05064618 phase1 / phase2unknown statusnot on this map

Phase I/II Investigator-initiated Clinical Trial of MIKE-1 With Gemcitabine and Nab-paclitaxel Combination Therapy for Unresectable Pancreatic Cancer

TypeinterventionalSponsorNagoya UniversityRan2021 to 2025Enrolled55ConditionsPancreatic CancerArmsAm80, Gemcitabine, nab-Paclitaxel
3 · Its place in the literature

Who cites it

111 citing papers in PubMed, 2 syntheses or guidelines pooled it, 159 citations in OpenAlex.

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51 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

36 authors at 12 institutions in 5 countries.

Hiroki KobayashiAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Krystyna A GieniecAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.
Josephine A WrightSouth Australian Health and Medical Research Institute, Adelaide, Australia.
Tongtong WangAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.
Naoya AsaiDepartment of Molecular Pathology, Graduate School of Medicine, Fujita Health University, Toyoake, Japan.
Yasuyuki MizutaniDepartment of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Tadashi LidaDepartment of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Ryota AndoDepartment of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Nobumi SuzukiAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Tamsin R M LannaganAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.
Jia Q NgAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.
Akitoshi HaraDepartment of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yukihiro ShirakiDepartment of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Shinji MiiDepartment of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Mari IchinoseAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.
Laura VrbanacAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.
Matthew J LawrenceColorectal Unit, Department of Surgery, Royal Adelaide Hospital, Adelaide, Australia.
Tarik SammourAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia; Colorectal Unit, Department of Surgery, Royal Adelaide Hospital, Adelaide, Australia.
Kay UeharaDivision of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Gareth DaviesUCB Pharma, Slough, Berkshire, United Kingdom.
Leszek LisowskiTranslational Vectorology Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Vector and Genome Engineering Facility, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, Australia; Military Institute of Hygiene and Epidemiology, The Biological Threats Identification and Countermeasure Centre, Puławy, Poland.
Ian E AlexanderGene Therapy Research Unit, Sydney Children's Hospitals Network and Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Australia.
Yoku HayakawaDepartment of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Lisa M ButlerAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.
Andrew C W ZannettinoAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.
M Omar DinGenCirq, Inc, San Diego, California.
Jeff HastyDepartment of Bioengineering, University of California, San Diego, La Jolla, California.
Alastair D BurtAdelaide Medical School, University of Adelaide, Adelaide, Australia; Precision and Molecular Pathology, Newcastle University, Newcastle Upon Tyne, United Kingdom.
Simon J LeedhamIntestinal Stem Cell Biology Lab, Wellcome Trust Centre Human Genetics, University of Oxford, Oxford, United Kingdom.
Anil K RustgiHerbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York.
Siddhartha MukherjeeDepartment of Medicine and Irving Cancer Research Center, Columbia University, New York, New York.
Timothy C WangDepartment of Medicine and Irving Cancer Research Center, Columbia University, New York, New York.
Atsushi EnomotoDepartment of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: enomoto@iar.nagoya-u.ac.jp.
Masahide TakahashiDepartment of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan. Electronic address: mtakaha@med.nagoya-u.ac.jp.
Daniel L WorthleySouth Australian Health and Medical Research Institute, Adelaide, Australia. Electronic address: Dan.Worthley@sahmri.com.
Susan L WoodsAdelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia. Electronic address: susan.woods@adelaide.edu.au.
South Australian Health and Medical Research Institute · AUNagoya University · JPColumbia University Irving Medical Center · USFujita Health University · JPRoyal Adelaide Hospital · AUThe University of Sydney · AUCentre for Human Genetics · GBNagoya City University · JPThe University of Adelaide · AUThe University of Tokyo · JPUCB Pharma (United Kingdom) · GBUniversity of California San Diego · US

Funding

Understanding stem cell heterogeneity and niche function in intestinal regeneration after irradiationU01DK103155 · NIDDK · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GUHA, CHANDAN, WANG, TIMOTHY CRAGIN · 2014 to 2023
$4.4M
NIDDK NIH HHS U01 DK103155Wellcome Trust 206314Wellcome Trust 206314/Z/17/Z
6 · The paper itself

Abstract

BACKGROUND &

aimsCancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored.

methodsUsing human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC.

resultsWe identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor β and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5

conclusionsStromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.

Indexed as

AdultAgedAged, 80 and overAnimalsBone Morphogenetic ProteinsCancer-Associated FibroblastsCarcinogenesisCell DifferentiationCell Line, TumorColorectal NeoplasmsDisease ProgressionFemaleHepatocytesHumansImmunoglobulinsIntercellular Signaling Peptides and ProteinsBone Morphogenetic ProteinsGREM1 protein, humanImmunoglobulinsIntercellular Signaling Peptides and ProteinsISLR protein, humanBone Morphogenetic ProteinCancer-Associated FibroblastsColorectal CancerTumor Microenvironment

Identifiers

PMID33197448
PMCPMC7617122
OpenAlexW3103125459

What Socratic holds

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LicenceCC BY
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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.