CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression

Huiqiang Cai; Bin Zhang; Johanne Ahrenfeldt; Justin V. Joseph; Maria Riedel; Zongliang Gao; Sofie K. Thomsen; Ditte S. Christensen; Rasmus O. Bak; Henrik Hager; Mikkel H. Vendelbo; Xin Gao; Nicolai Birkbak; Martin K. Thomsen

doi:10.1038/s41467-024-46370-0

CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression

Huiqiang Cai, Bin Zhang, Johanne Ahrenfeldt, Justin V. Joseph, Maria Riedel, Zongliang Gao, Sofie K. Thomsen, Ditte S. Christensen, Rasmus O. Bak, Henrik Hager, Mikkel H. Vendelbo, Xin Gao, Nicolai Birkbak, Martin K. Thomsen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Metastatic prostate cancer (PCa) poses a significant therapeutic challenge with high mortality rates. Utilizing CRISPR-Cas9 in vivo, we target five potential tumor suppressor genes (Pten, Trp53, Rb1, Stk11, and RnaseL) in the mouse prostate, reaching humane endpoint after eight weeks without metastasis. By further depleting three epigenetic factors (Kmt2c, Kmt2d, and Zbtb16), lung metastases are present in all mice. While whole genome sequencing reveals few mutations in coding sequence, RNA sequencing shows significant dysregulation, especially in a conserved genomic region at chr5qE1 regulated by KMT2C. Depleting Odam and Cabs1 in this region prevents metastasis. Notably, the gene expression signatures, resulting from our study, predict progression-free and overall survival and distinguish primary and metastatic human prostate cancer. This study emphasizes positive genetic interactions between classical tumor suppressor genes and epigenetic modulators in metastatic PCa progression, offering insights into potential treatments.

Original language	English (US)
Article number	2088
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-46370-0
State	Published - Dec 2024

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-024-46370-0

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Cai, H., Zhang, B., Ahrenfeldt, J., Joseph, J. V., Riedel, M., Gao, Z., Thomsen, S. K., Christensen, D. S., Bak, R. O., Hager, H., Vendelbo, M. H., Gao, X., Birkbak, N., & Thomsen, M. K. (2024). CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression. Nature Communications, 15(1), Article 2088. https://doi.org/10.1038/s41467-024-46370-0

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title = "CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression",

abstract = "Metastatic prostate cancer (PCa) poses a significant therapeutic challenge with high mortality rates. Utilizing CRISPR-Cas9 in vivo, we target five potential tumor suppressor genes (Pten, Trp53, Rb1, Stk11, and RnaseL) in the mouse prostate, reaching humane endpoint after eight weeks without metastasis. By further depleting three epigenetic factors (Kmt2c, Kmt2d, and Zbtb16), lung metastases are present in all mice. While whole genome sequencing reveals few mutations in coding sequence, RNA sequencing shows significant dysregulation, especially in a conserved genomic region at chr5qE1 regulated by KMT2C. Depleting Odam and Cabs1 in this region prevents metastasis. Notably, the gene expression signatures, resulting from our study, predict progression-free and overall survival and distinguish primary and metastatic human prostate cancer. This study emphasizes positive genetic interactions between classical tumor suppressor genes and epigenetic modulators in metastatic PCa progression, offering insights into potential treatments.",

author = "Huiqiang Cai and Bin Zhang and Johanne Ahrenfeldt and Joseph, {Justin V.} and Maria Riedel and Zongliang Gao and Thomsen, {Sofie K.} and Christensen, {Ditte S.} and Bak, {Rasmus O.} and Henrik Hager and Vendelbo, {Mikkel H.} and Xin Gao and Nicolai Birkbak and Thomsen, {Martin K.}",

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year = "2024",

month = dec,

doi = "10.1038/s41467-024-46370-0",

language = "English (US)",

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Cai, H, Zhang, B, Ahrenfeldt, J, Joseph, JV, Riedel, M, Gao, Z, Thomsen, SK, Christensen, DS, Bak, RO, Hager, H, Vendelbo, MH, Gao, X, Birkbak, N & Thomsen, MK 2024, 'CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression', Nature Communications, vol. 15, no. 1, 2088. https://doi.org/10.1038/s41467-024-46370-0

TY - JOUR

T1 - CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression

AU - Cai, Huiqiang

AU - Zhang, Bin

AU - Ahrenfeldt, Johanne

AU - Joseph, Justin V.

AU - Riedel, Maria

AU - Gao, Zongliang

AU - Thomsen, Sofie K.

AU - Christensen, Ditte S.

AU - Bak, Rasmus O.

AU - Hager, Henrik

AU - Vendelbo, Mikkel H.

AU - Gao, Xin

AU - Birkbak, Nicolai

AU - Thomsen, Martin K.

PY - 2024/12

Y1 - 2024/12

N2 - Metastatic prostate cancer (PCa) poses a significant therapeutic challenge with high mortality rates. Utilizing CRISPR-Cas9 in vivo, we target five potential tumor suppressor genes (Pten, Trp53, Rb1, Stk11, and RnaseL) in the mouse prostate, reaching humane endpoint after eight weeks without metastasis. By further depleting three epigenetic factors (Kmt2c, Kmt2d, and Zbtb16), lung metastases are present in all mice. While whole genome sequencing reveals few mutations in coding sequence, RNA sequencing shows significant dysregulation, especially in a conserved genomic region at chr5qE1 regulated by KMT2C. Depleting Odam and Cabs1 in this region prevents metastasis. Notably, the gene expression signatures, resulting from our study, predict progression-free and overall survival and distinguish primary and metastatic human prostate cancer. This study emphasizes positive genetic interactions between classical tumor suppressor genes and epigenetic modulators in metastatic PCa progression, offering insights into potential treatments.

AB - Metastatic prostate cancer (PCa) poses a significant therapeutic challenge with high mortality rates. Utilizing CRISPR-Cas9 in vivo, we target five potential tumor suppressor genes (Pten, Trp53, Rb1, Stk11, and RnaseL) in the mouse prostate, reaching humane endpoint after eight weeks without metastasis. By further depleting three epigenetic factors (Kmt2c, Kmt2d, and Zbtb16), lung metastases are present in all mice. While whole genome sequencing reveals few mutations in coding sequence, RNA sequencing shows significant dysregulation, especially in a conserved genomic region at chr5qE1 regulated by KMT2C. Depleting Odam and Cabs1 in this region prevents metastasis. Notably, the gene expression signatures, resulting from our study, predict progression-free and overall survival and distinguish primary and metastatic human prostate cancer. This study emphasizes positive genetic interactions between classical tumor suppressor genes and epigenetic modulators in metastatic PCa progression, offering insights into potential treatments.

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ER -

CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression

Abstract

ASJC Scopus subject areas

UN SDGs

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