Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer

被引：329

作者：

Cazet, Aurelie S. ^{[1
,2
,3
]}

Hui, Mun N. ^{[1
,2
,4
,5
]}

Elsworth, Benjamin L. ^{[6
]}

Wu, Sunny Z. ^{[1
,2
,3
]}

Roden, Daniel ^{[1
,2
,3
]}

Chan, Chia-Ling ^{[1
,2
]}

Skhinas, Joanna N. ^{[1
,2
]}

Collot, Raphael ^{[1
,2
]}

Yang, Jessica ^{[1
,2
]}

Harvey, Kate ^{[1
,2
]}

Johan, M. Zahied ^{[7
,8
,9
]}

Cooper, Caroline ^{[10
,11
]}

Nair, Radhika ^{[12
]}

Herrmann, David ^{[1
,2
,3
]}

McFarland, Andrea ^{[1
,2
]}

Deng, Niantao ^{[1
,2
,3
]}

Ruiz-Borrego, Manuel ^{[13
]}

Rojo, Federico ^{[14
]}

Trigo, Jose M. ^{[15
]}

Bezares, Susana ^{[16
]}

Caballero, Rosalia ^{[16
]}

Lim, Elgene ^{[3
,14
,17
]}

Timpson, Paul ^{[1
,2
,3
]}

O'Toole, Sandra ^{[1
,2
,5
]}

Watkins, D. Neil ^{[1
,2
,3
,17
]}

Cox, Thomas R. ^{[1
,2
,3
]}

Samuel, Michael S. ^{[7
,8
,9
]}

Martin, Miguel ^{[18
]}

Swarbrick, Alexander ^{[1
,2
,3
]}

机构：

[1] Garvan Inst Med Res, Darlinghurst, NSW 2010, Australia

[2] Kinghorn Canc Ctr, Darlinghurst, NSW 2010, Australia

[3] UNSW Sydney, St Vincents Clin Sch, Fac Med, Darlinghurst, NSW 2010, Australia

[4] Chris OBrien Lifehouse, Camperdown, NSW 2050, Australia

[5] Royal Prince Alfred Hosp, Camperdown, NSW 2050, Australia

[6] Univ Bristol, MRC, Integrat Epidemiol Unit, Oakfield House, Bristol BS8 2BN, Avon, England

[7] SA Pathol, Ctr Canc Biol, Adelaide, SA 5000, Australia

[8] Univ South Australia, Adelaide, SA 5000, Australia

[9] Univ Adelaide, Fac Hlth Sci, Sch Med, Adelaide, SA 5000, Australia

[10] Univ Queensland, Pathol Queensland, St Lucia, Qld 4006, Australia

[11] Univ Queensland, Sch Med, St Lucia, Qld 4006, Australia

[12] Raj Gandhi Ctr Biotechnol, Thiruvananthapuram 695014, Kerala, India

[13] Hosp Univ Virgen Rock, Dept Med Oncol, Seville 41013, Spain

[14] Hosp Univ Fdn Jimenez Diaz, Dept Pathol, Madrid 28040, Spain

[15] Hosp Clin Univ Virgen de la Victoria, Dept Med Oncol, IBIMA, Malaga 29010, Spain

[16] Spanish Breast Canc Grp, GEICAM, Madrid 28703, Spain

[17] St Vincents Hosp, Darlinghurst, NSW 2010, Australia

[18] Univ Complutense, Ctr Invest Biomed Red Oncol, Inst Invest Sanitaria Gregorio Maranon, Dept Med Oncol,CIBERONC ISCIII, E-28040 Madrid, Spain

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

MAMMARY-GLAND DEVELOPMENT; BRANCHING MORPHOGENESIS; MAMMOGRAPHIC DENSITY; TISSUE STIFFNESS; ANALYSIS REVEALS; FIBROBLASTS; GROWTH; EXPRESSION; COLLAGEN; CHEMOTHERAPY;

D O I：

10.1038/s41467-018-05220-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xeno-grafts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC.

引用

页数：18

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