AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer

Agnete S.T. Engelsen; Katarzyna Wnuk-Lipinska; Sebastien Bougnaud; Fanny A. Pelissier Vatter; Crina Tiron; René Villadsen; Masaru Miyano; Maria L. Lotsberg; Noëlly Madeleine; Pouda Panahandeh; Sushil Dhakal; Tuan Zea Tan; Stacey D.mello Peters; Sturla Grøndal; Sura M. Aziz; Silje Nord; Lars Herfindal; Martha R. Stampfer; Therese Sørlie; Rolf A. Brekken; Oddbjørn Straume; Nils Halberg; Gro Gausdal; Jean Paul Thiery; Lars A. Akslen; Ole W. Petersen; Mark A. LaBarge; James B. Lorens

doi:10.1016/j.isci.2020.101649

AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer

Agnete S.T. Engelsen, Katarzyna Wnuk-Lipinska, Sebastien Bougnaud, Fanny A. Pelissier Vatter, Crina Tiron, René Villadsen, Masaru Miyano, Maria L. Lotsberg, Noëlly Madeleine, Pouda Panahandeh, Sushil Dhakal, Tuan Zea Tan, Stacey D.mello Peters, Sturla Grøndal, Sura M. Aziz, Silje Nord, Lars Herfindal, Martha R. Stampfer, Therese Sørlie, Rolf A. BrekkenOddbjørn Straume, Nils Halberg, Gro Gausdal, Jean Paul Thiery, Lars A. Akslen, Ole W. Petersen, Mark A. LaBarge, James B. Lorens

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

15 Scopus citations

Abstract

The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl⁺ cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells.

Original language	English (US)
Article number	101649
Journal	iScience
Volume	23
Issue number	11
DOIs	https://doi.org/10.1016/j.isci.2020.101649
State	Published - Nov 20 2020

Keywords

Cancer
Cell Biology
Stem Cells Research

ASJC Scopus subject areas

General

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10.1016/j.isci.2020.101649

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Engelsen, A. S. T., Wnuk-Lipinska, K., Bougnaud, S., Pelissier Vatter, F. A., Tiron, C., Villadsen, R., Miyano, M., Lotsberg, M. L., Madeleine, N., Panahandeh, P., Dhakal, S., Tan, T. Z., Peters, S. D. M., Grøndal, S., Aziz, S. M., Nord, S., Herfindal, L., Stampfer, M. R., Sørlie, T., ... Lorens, J. B. (2020). AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer. iScience, 23(11), Article 101649. https://doi.org/10.1016/j.isci.2020.101649

Engelsen, AST, Wnuk-Lipinska, K, Bougnaud, S, Pelissier Vatter, FA, Tiron, C, Villadsen, R, Miyano, M, Lotsberg, ML, Madeleine, N, Panahandeh, P, Dhakal, S, Tan, TZ, Peters, SDM, Grøndal, S, Aziz, SM, Nord, S, Herfindal, L, Stampfer, MR, Sørlie, T, Brekken, RA, Straume, O, Halberg, N, Gausdal, G, Thiery, JP, Akslen, LA, Petersen, OW, LaBarge, MA & Lorens, JB 2020, 'AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer', iScience, vol. 23, no. 11, 101649. https://doi.org/10.1016/j.isci.2020.101649

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title = "AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer",

abstract = "The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl+ cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells.",

keywords = "Cancer, Cell Biology, Stem Cells Research",

author = "Engelsen, {Agnete S.T.} and Katarzyna Wnuk-Lipinska and Sebastien Bougnaud and {Pelissier Vatter}, {Fanny A.} and Crina Tiron and Ren{\'e} Villadsen and Masaru Miyano and Lotsberg, {Maria L.} and No{\"e}lly Madeleine and Pouda Panahandeh and Sushil Dhakal and Tan, {Tuan Zea} and Peters, {Stacey D.mello} and Sturla Gr{\o}ndal and Aziz, {Sura M.} and Silje Nord and Lars Herfindal and Stampfer, {Martha R.} and Therese S{\o}rlie and Brekken, {Rolf A.} and Oddbj{\o}rn Straume and Nils Halberg and Gro Gausdal and Thiery, {Jean Paul} and Akslen, {Lars A.} and Petersen, {Ole W.} and LaBarge, {Mark A.} and Lorens, {James B.}",

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year = "2020",

month = nov,

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doi = "10.1016/j.isci.2020.101649",

language = "English (US)",

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AU - Engelsen, Agnete S.T.

AU - Wnuk-Lipinska, Katarzyna

AU - Bougnaud, Sebastien

AU - Pelissier Vatter, Fanny A.

AU - Tiron, Crina

AU - Villadsen, René

AU - Miyano, Masaru

AU - Lotsberg, Maria L.

AU - Madeleine, Noëlly

AU - Panahandeh, Pouda

AU - Dhakal, Sushil

AU - Tan, Tuan Zea

AU - Peters, Stacey D.mello

AU - Grøndal, Sturla

AU - Aziz, Sura M.

AU - Nord, Silje

AU - Herfindal, Lars

AU - Stampfer, Martha R.

AU - Sørlie, Therese

AU - Brekken, Rolf A.

AU - Straume, Oddbjørn

AU - Halberg, Nils

AU - Gausdal, Gro

AU - Thiery, Jean Paul

AU - Akslen, Lars A.

AU - Petersen, Ole W.

AU - LaBarge, Mark A.

AU - Lorens, James B.

PY - 2020/11/20

Y1 - 2020/11/20

N2 - The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl+ cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells.

AB - The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl+ cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells.

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KW - Cell Biology

KW - Stem Cells Research

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M1 - 101649

ER -

AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer

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