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

Gao, Shanshan ; Soares, Fraser ; Wang, Shiyan ; Wong, Chi Chun ; Chen, Huarong ; Yang, Zhenjie ; Liu, Weixin ; Go, Minnie Y Y ; Ahmed, Musaddeque ; Zeng, Yong ; O'Brien, Catherine Adell ; Sung, Joseph J Y ; He, Housheng Hansen ; Yu, Jun

Oncogene, 2021-12, Vol.40 (48), p.6601-6613 [Periódico revisado por pares]

England: Nature Publishing Group

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CRISPR screens identify cholesterol biosynthesis as a therapeutic target on stemness and drug resistance of colon cancer
Autor: Gao, Shanshan ; Soares, Fraser ; Wang, Shiyan ; Wong, Chi Chun ; Chen, Huarong ; Yang, Zhenjie ; Liu, Weixin ; Go, Minnie Y Y ; Ahmed, Musaddeque ; Zeng, Yong ; O'Brien, Catherine Adell ; Sung, Joseph J Y ; He, Housheng Hansen ; Yu, Jun
Assuntos: Adjuvant treatment ; Animals ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Apoptosis ; Biosynthesis ; Cancer ; Care and treatment ; Cell Proliferation ; Cell self-renewal ; Chemotherapy ; Cholesterol ; Cholesterol - biosynthesis ; Cholesterol - chemistry ; Cholesterol metabolism ; Colon cancer ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - genetics ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; Colorectal cancer ; Complications and side effects ; CRISPR ; CRISPR-Cas Systems ; Diagnosis ; Dimethylallyltranstransferase - antagonists & inhibitors ; Drug resistance ; Drug Resistance, Neoplasm - drug effects ; Epigenetics ; Farnesyltranstransferase - antagonists & inhibitors ; Fluorouracil - administration & dosage ; Geranyltranstransferase - antagonists & inhibitors ; Health aspects ; Humans ; Lovastatin - administration & dosage ; Male ; Mice ; Mice, Nude ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Next-generation sequencing ; Observations ; Organoids ; Patient outcomes ; Risk factors ; Spheroids ; Stem cells ; Therapeutic targets ; Tumor Cells, Cultured ; Tumors ; Xenograft Model Antitumor Assays ; Xenografts ; Zoledronic Acid - administration & dosage
É parte de: Oncogene, 2021-12, Vol.40 (48), p.6601-6613
Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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

Gao, Shanshan ; Soares, Fraser ; Wang, Shiyan ; Wong, Chi Chun ; Chen, Huarong ; Yang, Zhenjie ; Liu, Weixin ; Go, Minnie Y Y ; Ahmed, Musaddeque ; Zeng, Yong ; O'Brien, Catherine Adell ; Sung, Joseph J Y ; He, Housheng Hansen ; Yu, Jun

England: Nature Publishing Group

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