A RAC-GEF network critical for early intestinal tumourigenesis

K A Pickering; K Gilroy; J W Cassidy; S K Fey; A K Najumudeen; L B Zeiger; D F Vincent; D M Gay; J Johansson; R P Fordham; B Miller; W Clark; A Hedley; E B Unal; C Kiel; E McGhee; L M Machesky; C Nixon; A E Johnsson; M Bain; D Strathdee; S R van Hoof; J P Medema; K I Anderson; S M Brachmann; V M Stucke; A Malliri; M Drysdale; M Turner; L Serrano; K Myant; A D Campbell; O J Sansom

doi:10.1038/s41467-020-20255-4

A RAC-GEF network critical for early intestinal tumourigenesis

K A Pickering, K Gilroy, J W Cassidy, S K Fey, A K Najumudeen, L B Zeiger, D F Vincent, D M Gay, J Johansson, R P Fordham, B Miller, W Clark, A Hedley, E B Unal, C Kiel, E McGhee, L M Machesky, C Nixon, A E Johnsson, M BainD Strathdee, S R van Hoof, J P Medema, K I Anderson, S M Brachmann, V M Stucke, A Malliri, M Drysdale, M Turner, L Serrano, K Myant, A D Campbell, O J Sansom

Cancer Research UK Manchester Institute

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

Abstract

RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2-/- Vav3-/- Tiam1-/-), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.

Original language	English
Pages (from-to)	56
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20255-4
Publication status	Published - 4 Jan 2021

Keywords

Adenomatous Polyposis Coli Protein/metabolism
Animals
Carcinogenesis/genetics
Guanine Nucleotide Exchange Factors/metabolism
Homeostasis
Intestines/pathology
Mice, Knockout
Mutation/genetics
Organ Specificity
Phenotype
Proto-Oncogene Proteins c-vav/metabolism
Proto-Oncogene Proteins p21(ras)/genetics
Signal Transduction
T-Lymphoma Invasion and Metastasis-inducing Protein 1/metabolism
Up-Regulation
Wnt Signaling Pathway
rac1 GTP-Binding Protein/metabolism
Mice

UN SDGs

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

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10.1038/s41467-020-20255-4

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Pickering, K. A., Gilroy, K., Cassidy, J. W., Fey, S. K., Najumudeen, A. K., Zeiger, L. B., Vincent, D. F., Gay, D. M., Johansson, J., Fordham, R. P., Miller, B., Clark, W., Hedley, A., Unal, E. B., Kiel, C., McGhee, E., Machesky, L. M., Nixon, C., Johnsson, A. E., ... Sansom, O. J. (2021). A RAC-GEF network critical for early intestinal tumourigenesis. Nature Communications, 12(1), 56. https://doi.org/10.1038/s41467-020-20255-4

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abstract = "RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2-/- Vav3-/- Tiam1-/-), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.",

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author = "Pickering, {K A} and K Gilroy and Cassidy, {J W} and Fey, {S K} and Najumudeen, {A K} and Zeiger, {L B} and Vincent, {D F} and Gay, {D M} and J Johansson and Fordham, {R P} and B Miller and W Clark and A Hedley and Unal, {E B} and C Kiel and E McGhee and Machesky, {L M} and C Nixon and Johnsson, {A E} and M Bain and D Strathdee and {van Hoof}, {S R} and Medema, {J P} and Anderson, {K I} and Brachmann, {S M} and Stucke, {V M} and A Malliri and M Drysdale and M Turner and L Serrano and K Myant and Campbell, {A D} and Sansom, {O J}",

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doi = "10.1038/s41467-020-20255-4",

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Pickering, KA, Gilroy, K, Cassidy, JW, Fey, SK, Najumudeen, AK, Zeiger, LB, Vincent, DF, Gay, DM, Johansson, J, Fordham, RP, Miller, B, Clark, W, Hedley, A, Unal, EB, Kiel, C, McGhee, E, Machesky, LM, Nixon, C, Johnsson, AE, Bain, M, Strathdee, D, van Hoof, SR, Medema, JP, Anderson, KI, Brachmann, SM, Stucke, VM, Malliri, A, Drysdale, M, Turner, M, Serrano, L, Myant, K, Campbell, AD & Sansom, OJ 2021, 'A RAC-GEF network critical for early intestinal tumourigenesis', Nature Communications, vol. 12, no. 1, pp. 56. https://doi.org/10.1038/s41467-020-20255-4

TY - JOUR

T1 - A RAC-GEF network critical for early intestinal tumourigenesis

AU - Pickering, K A

AU - Gilroy, K

AU - Cassidy, J W

AU - Fey, S K

AU - Najumudeen, A K

AU - Zeiger, L B

AU - Vincent, D F

AU - Gay, D M

AU - Johansson, J

AU - Fordham, R P

AU - Miller, B

AU - Clark, W

AU - Hedley, A

AU - Unal, E B

AU - Kiel, C

AU - McGhee, E

AU - Machesky, L M

AU - Nixon, C

AU - Johnsson, A E

AU - Bain, M

AU - Strathdee, D

AU - van Hoof, S R

AU - Medema, J P

AU - Anderson, K I

AU - Brachmann, S M

AU - Stucke, V M

AU - Malliri, A

AU - Drysdale, M

AU - Turner, M

AU - Serrano, L

AU - Myant, K

AU - Campbell, A D

AU - Sansom, O J

PY - 2021/1/4

Y1 - 2021/1/4

N2 - RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2-/- Vav3-/- Tiam1-/-), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.

AB - RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2-/- Vav3-/- Tiam1-/-), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.

KW - Adenomatous Polyposis Coli Protein/metabolism

KW - Animals

KW - Carcinogenesis/genetics

KW - Guanine Nucleotide Exchange Factors/metabolism

KW - Homeostasis

KW - Intestines/pathology

KW - Mice, Knockout

KW - Mutation/genetics

KW - Organ Specificity

KW - Phenotype

KW - Proto-Oncogene Proteins c-vav/metabolism

KW - Proto-Oncogene Proteins p21(ras)/genetics

KW - Signal Transduction

KW - T-Lymphoma Invasion and Metastasis-inducing Protein 1/metabolism

KW - Up-Regulation

KW - Wnt Signaling Pathway

KW - rac1 GTP-Binding Protein/metabolism

KW - Mice

U2 - 10.1038/s41467-020-20255-4

DO - 10.1038/s41467-020-20255-4

M3 - Article

C2 - 33397922

SN - 2041-1723

VL - 12

SP - 56

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

A RAC-GEF network critical for early intestinal tumourigenesis

Abstract

Keywords

UN SDGs

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