Evidence map›Paper›PMID 34621019›Full record

ArticleOncogene2021

CRISPR screens identify cholesterol biosynthesis as a therapeutic target on stemness and drug resistance of colon cancer.

Shanshan Gao, Fraser Soares, Shiyan Wang, Chi Chun Wong, Huarong Chen, Zhenjie Yang, Weixin Liu, Minnie Y Y Go, Musaddeque Ahmed, Yong Zeng and 4 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Oncogene, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.

0numbers the graph read from it
0cells of the map it votes in
60citing papers in PubMed
6.2field-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.

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

60 citing papers in PubMed, 91 citations in OpenAlex.

  1. Article
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  8. Biomolecules & biomedicine · 2026
    Article
  9. Article
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  11. Targeting of the mNature communications · 2025
    Article
  12. Article
  13. Review
  14. Review
  15. Review
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  17. Article
  18. Article
  19. Review
  20. Dysregulation of cholesterol homeostasis in cancer pathogenesis.Cellular and molecular life sciences : CMLS · 2025
    Review
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

14 authors at 2 institutions in 3 countries.

Shanshan GaoInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Fraser SoaresPrincess Margaret Cancer Centre, University Health Network, Ontario, ON, Canada.ORCID http://orcid.org/0000-0002-3977-7939
Shiyan WangPrincess Margaret Cancer Centre, University Health Network, Ontario, ON, Canada.ORCID http://orcid.org/0000-0002-8240-7933
Chi Chun WongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.ORCID http://orcid.org/0000-0003-1362-3541
Huarong ChenInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.ORCID http://orcid.org/0000-0003-2192-1864
Zhenjie YangInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Weixin LiuInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Minnie Y Y GoInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Musaddeque AhmedPrincess Margaret Cancer Centre, University Health Network, Ontario, ON, Canada.
Yong ZengPrincess Margaret Cancer Centre, University Health Network, Ontario, ON, Canada.
Catherine Adell O'BrienPrincess Margaret Cancer Centre, University Health Network, Ontario, ON, Canada.
Joseph J Y SungInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Housheng Hansen HePrincess Margaret Cancer Centre, University Health Network, Ontario, ON, Canada. hansenhe@uhnresearch.ca.ORCID http://orcid.org/0000-0003-2898-3363
Jun YuInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. junyu@cuhk.edu.hk.ORCID http://orcid.org/0000-0001-5008-2153
Chinese University of Hong Kong · HKUniversity Health Network · CA

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Cancer stem cells (CSCs) are responsible for tumor progression, recurrence, and drug resistance. To identify genetic vulnerabilities of colon cancer, we performed targeted CRISPR dropout screens comprising 657 Drugbank targets and 317 epigenetic regulators on two patient-derived colon CSC-enriched spheroids. Next-generation sequencing of pooled genomic DNAs isolated from surviving cells yielded therapeutic candidates. We unraveled 44 essential genes for colon CSC-enriched spheroids propagation, including key cholesterol biosynthetic genes (HMGCR, FDPS, and GGPS1). Cholesterol biosynthesis was induced in colon cancer tissues, especially CSC-enriched spheroids. The genetic and pharmacological inhibition of HMGCR/FDPS impaired self-renewal capacity and tumorigenic potential of the spheroid models in vitro and in vivo. Mechanistically, HMGCR or FDPS depletion impaired cancer stemness characteristics by activating TGF-β signaling, which in turn downregulated expression of inhibitors of differentiation (ID) proteins, key regulators of cancer stemness. Cholesterol and geranylgeranyl diphosphate (GGPP) rescued the growth inhibitory and signaling effect of HMGCR/FDPS blockade, implying a direct role of these metabolites in modulating stemness. Finally, cholesterol biosynthesis inhibitors and 5-FU demonstrated antitumor synergy in colon CSC-enriched spheroids, tumor organoids, and xenografts. Taken together, our study unravels novel genetic vulnerabilities of colon CSC-enriched spheroids and suggests cholesterol biosynthesis as a potential target in conjunction with traditional chemotherapy for colon cancer treatment.

Indexed as

CRISPR-Cas SystemsAnimalsAntineoplastic Combined Chemotherapy ProtocolsApoptosisCell ProliferationCholesterolColonic NeoplasmsDimethylallyltranstransferaseDrug Resistance, NeoplasmFarnesyltranstransferaseFluorouracilGeranyltranstransferaseHumansLovastatinMaleMiceCholesterolDimethylallyltranstransferaseFarnesyltranstransferaseFluorouracilGeranyltranstransferaseGGPS1 protein, humanLovastatinZoledronic Acid

Identifiers

PMID34621019
PMCPMC8639446
OpenAlexW3202642825

What OpenQuestion 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 OpenQuestion graph.