Evidence map›Paper›PMID 34031411›Full record

ArticleNature communications2021

In vivo genome-wide CRISPR screen reveals breast cancer vulnerabilities and synergistic mTOR/Hippo targeted combination therapy.

Meiou Dai, Gang Yan, Ni Wang, Girija Daliah, Ashlin M Edick, Sophie Poulet, Julien Boudreault, Suhad Ali, Sergio A Burgos, Jean-Jacques Lebrun

Open access · goldAbstract read
In one paragraph

Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
72citing papers in PubMed, 1 pooled it
11.8field-weighted citation impact, top 1% 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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

72 citing papers in PubMed, 1 synthesis or guideline pooled it, 130 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. Article
  4. Review
  5. Article
  6. Article
  7. Article
  8. Article
  9. Article
  10. Article
  11. Article
  12. Review
  13. Article
  14. Article
  15. Article
  16. Review
  17. Review
  18. Review
  19. Article
  20. Article

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

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 2 institutions in 1 country.

Meiou DaiDepartment of Medicine, McGill University Health Center, Cancer Research Program, Montreal, QC, Canada.
Gang YanDepartment of Medicine, McGill University Health Center, Cancer Research Program, Montreal, QC, Canada.
Ni WangDepartment of Medicine, McGill University Health Center, Cancer Research Program, Montreal, QC, Canada.
Girija DaliahDepartment of Medicine, McGill University Health Center, Cancer Research Program, Montreal, QC, Canada.ORCID 0000-0002-5508-5457
Ashlin M EdickDepartment of Animal Science, McGill University, Sainte-Anne-de-Bellevue, QC, Canada.ORCID 0000-0003-2146-4798
Sophie PouletDepartment of Medicine, McGill University Health Center, Cancer Research Program, Montreal, QC, Canada.
Julien BoudreaultDepartment of Medicine, McGill University Health Center, Cancer Research Program, Montreal, QC, Canada.
Suhad AliDepartment of Medicine, McGill University Health Center, Cancer Research Program, Montreal, QC, Canada.
Sergio A BurgosDepartment of Animal Science, McGill University, Sainte-Anne-de-Bellevue, QC, Canada.ORCID 0000-0003-0569-4307
Jean-Jacques LebrunDepartment of Medicine, McGill University Health Center, Cancer Research Program, Montreal, QC, Canada. JJ.Lebrun@mcgill.ca.ORCID 0000-0001-5809-1409
McGill University Health Centre · CAMcGill University · CA

Funding

CIHR 8117
6 · The paper itself

Abstract

Triple negative breast cancer (TNBC) patients exhibit poor survival outcomes and lack effective targeted therapies. Using unbiased in vivo genome-wide CRISPR screening, we interrogated cancer vulnerabilities in TNBC and identified an interplay between oncogenic and tumor suppressor pathways. This study reveals tumor regulatory functions for essential components of the mTOR and Hippo pathways in TNBC. Using in vitro drug matrix synergy models and in vivo patient-derived xenografts, we further establish the therapeutic relevance of our findings and show that pharmacological inhibition of mTORC1/2 and oncoprotein YAP efficiently reduces tumorigenesis in TNBC. At the molecular level, we find that while verteporfin-induced YAP inhibition leads to apoptosis, torin1-mediated mTORC1/2 inhibition promotes macropinocytosis. Torin1-induced macropinocytosis further facilitates verteporfin uptake, thereby greatly enhancing its pro-apoptotic effects in cancer cells. Overall, our study underscores the power and robustness of in vivo CRISPR genome-wide screens in identifying clinically relevant and innovative therapeutic modalities in cancer.

Indexed as

Clustered Regularly Interspaced Short Palindromic RepeatsAnimalsCarcinogenesisCell Line, TumorCombined Modality TherapyCRISPR-Cas SystemsGene Expression Regulation, NeoplasticGene Knockout TechniquesHEK293 CellsHippo Signaling PathwayHumansMechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2MiceProtein Serine-Threonine KinasesTOR Serine-Threonine KinasesMechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2MTOR protein, humanProtein Serine-Threonine KinasesTOR Serine-Threonine KinasesVerteporfin

Identifiers

PMID34031411
PMCPMC8144221
OpenAlexW3164322129

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.