LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma

Wenjin Liu; Kimberly B. Monahan; Adam D. Pfefferle; Takeshi Shimamura; Jessica Sorrentino; Keefe T. Chan; David W. Roadcap; David W. Ollila; Nancy E. Thomas; Diego H. Castrillon; C. Ryan Miller; Charles M. Perou; Kwok Kin Wong; James E. Bear; Norman E. Sharpless

doi:10.1016/j.ccr.2012.03.048

LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma

Wenjin Liu, Kimberly B. Monahan, Adam D. Pfefferle, Takeshi Shimamura, Jessica Sorrentino, Keefe T. Chan, David W. Roadcap, David W. Ollila, Nancy E. Thomas, Diego H. Castrillon, C. Ryan Miller, Charles M. Perou, Kwok Kin Wong, James E. Bear, Norman E. Sharpless

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Abstract

Germline mutations in LKB1 (STK11) are associated with the Peutz-Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (±p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC family kinase (SFK) YES, increased expression of WNT target genes, and expansion of a CD24⁺ cell population, which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24^- cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing an SFK-dependent expansion of a prometastatic, CD24⁺ tumor subpopulation.

Original language	English (US)
Pages (from-to)	751-764
Number of pages	14
Journal	Cancer Cell
Volume	21
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2012.03.048
State	Published - Jun 12 2012

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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Liu, W., Monahan, K. B., Pfefferle, A. D., Shimamura, T., Sorrentino, J., Chan, K. T., Roadcap, D. W., Ollila, D. W., Thomas, N. E., Castrillon, D. H., Miller, C. R., Perou, C. M., Wong, K. K., Bear, J. E., & Sharpless, N. E. (2012). LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma. Cancer Cell, 21(6), 751-764. https://doi.org/10.1016/j.ccr.2012.03.048

Liu, W, Monahan, KB, Pfefferle, AD, Shimamura, T, Sorrentino, J, Chan, KT, Roadcap, DW, Ollila, DW, Thomas, NE, Castrillon, DH, Miller, CR, Perou, CM, Wong, KK, Bear, JE & Sharpless, NE 2012, 'LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma', Cancer Cell, vol. 21, no. 6, pp. 751-764. https://doi.org/10.1016/j.ccr.2012.03.048

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title = "LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma",

abstract = "Germline mutations in LKB1 (STK11) are associated with the Peutz-Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (±p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC family kinase (SFK) YES, increased expression of WNT target genes, and expansion of a CD24+ cell population, which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24- cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing an SFK-dependent expansion of a prometastatic, CD24+ tumor subpopulation.",

author = "Wenjin Liu and Monahan, {Kimberly B.} and Pfefferle, {Adam D.} and Takeshi Shimamura and Jessica Sorrentino and Chan, {Keefe T.} and Roadcap, {David W.} and Ollila, {David W.} and Thomas, {Nancy E.} and Castrillon, {Diego H.} and Miller, {C. Ryan} and Perou, {Charles M.} and Wong, {Kwok Kin} and Bear, {James E.} and Sharpless, {Norman E.}",

note = "Funding Information: The authors wish to thank the UNC Lineberger Comprehensive Cancer Center Mouse Phase 1 Unit for assistance with animal handling and tumor assessment. We thank the UNC gastrointestinal histology and flow cytometry core facilities for assistance. This work was supported by the UNC University Cancer Research Fund, and grants from the NCI. ",

year = "2012",

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doi = "10.1016/j.ccr.2012.03.048",

language = "English (US)",

volume = "21",

pages = "751--764",

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T1 - LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma

AU - Liu, Wenjin

AU - Monahan, Kimberly B.

AU - Pfefferle, Adam D.

AU - Shimamura, Takeshi

AU - Sorrentino, Jessica

AU - Chan, Keefe T.

AU - Roadcap, David W.

AU - Ollila, David W.

AU - Thomas, Nancy E.

AU - Castrillon, Diego H.

AU - Miller, C. Ryan

AU - Perou, Charles M.

AU - Wong, Kwok Kin

AU - Bear, James E.

AU - Sharpless, Norman E.

N1 - Funding Information: The authors wish to thank the UNC Lineberger Comprehensive Cancer Center Mouse Phase 1 Unit for assistance with animal handling and tumor assessment. We thank the UNC gastrointestinal histology and flow cytometry core facilities for assistance. This work was supported by the UNC University Cancer Research Fund, and grants from the NCI.

PY - 2012/6/12

Y1 - 2012/6/12

N2 - Germline mutations in LKB1 (STK11) are associated with the Peutz-Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (±p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC family kinase (SFK) YES, increased expression of WNT target genes, and expansion of a CD24+ cell population, which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24- cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing an SFK-dependent expansion of a prometastatic, CD24+ tumor subpopulation.

AB - Germline mutations in LKB1 (STK11) are associated with the Peutz-Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (±p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC family kinase (SFK) YES, increased expression of WNT target genes, and expansion of a CD24+ cell population, which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24- cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing an SFK-dependent expansion of a prometastatic, CD24+ tumor subpopulation.

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LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma

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