Mohamed Bentires-Alj

San Antonio Breast Cancer Symposium, December 6-10, 2016 Mohamed Bentires-Alj Professor of experimental surgical oncology Department of Biomedicine University of Basel University Hospital Basel m.bentires-alj@unibas.ch This presenta,on is the intellectual property of the author/presenter. Contact them at (m.ben,res-alj@unibas.ch) for permission to reprint and/or distribute

This presenta,on is the intellectual property of the author/presenter. Contact them at (m.ben,res-alj@unibas.ch) for permission to reprint and/or distribute Normal and neoplastic stem cells Genomic/proteomic landscape of breast cancer and novel targets Mechanisms of metastasis

This presenta,on is the intellectual property of the author/presenter. Contact them at (m.ben,res-alj@unibas.ch) for permission to reprint and/or distribute Normal and neoplastic stem cells Questions How is the mammary cell hierarchy organized? What mechanisms are involved in cell fate determination? What are the effects of the tumor cell-of-origin on heterogeneity, subtype, and aggressiveness of breast cancer? What are the therapeutic implications?

Normal mammary gland hierarchy This presenta,on is the intellectual property of the author/presenter. Contact them at (m.ben,res-alj@unibas.ch) for permission to reprint and/or distribute

Two methods: 1- Statistical analysis of multicolor lineage tracing 2- Lineage tracing at saturation to assess the fate of ALL SCs within a given lineage and the flux of cells between different lineages GENES & DEVELOPMENT 30:1261 1277 (2016)

This presenta,on is the intellectual property of the author/presenter. Contact them at (m.ben,res-alj@unibas.ch) for permission to reprint and/or distribute Normal mammary gland hierarchy Therapeutic implications

NATURE MEDICINE VOLUME 22 NUMBER 8 AUGUST 2016

Model of RANKL activation of progenitor cells MaSC (BRCA1 mut/+ ) Luminal progenitor cells Basal-like tumour HR+ RANK HR RANK+ Responder cell Hormone sensor cell RANKL RANKL inhibitor Progesterone Myoepithelial cell Alveolar cell HR HR+ Ductal cells Nolan et al Nature Med 2016

RANK is expressed in luminal progenitors cells **** 3 2 10 10 Stroma Basal/MS 102 Stroma Basal/MS 102 103 104 105 102 CD49f 103 104 105 LP ML LP EpCAM EpCAM ML 5 4 1043 10 103 102 10 2 Stroma Basal/MS 10 10 Basal/MS 104 105 Stroma CD49f 3 102 10 104 105 CD49f 2 3 80 60 60 40 40 20 40 20 20 20 102 103 104 105 RANK 102 103 104 105 RANK LP BRCA1 100 A1mut/+5 10 LP 100 80 80 60 RANK Isotype RANK Isotype 102 103 104 105 RANK 102 103 104 105 RANK mut/+ Basal/MS 100 Basal/MS 100 80 80 60 60 40 60 40 40 20 40 20 20 20 2 10 102 3 4 5 10 10 10 RANK 103 104 105 RANK p < 0.0001 100 80 60 40 CD49f A1mut/+ 10 10 80 60 Basal/MS 60 50 40 30 20 10 0 WT BRCA1 (n = 33) (n = 22) 102 103 104 105 RANK 102 103 104 105 RANK Prominent RANK expression in progenitors from BRCA1 mutation carriers B R C A 2m ut at ed LP 1043 10 100 B R C A 1m ut at ed ML 100 80 RANK Isotype RANK Isotype W ild -t yp e LP LP Basal/MS % RANK positive LP cells 100 ML % of%max of Max 1054 10 LP % of%max of Max EpCAM EpCAM -type5 10 (p < 0.0001) Normal (wildtype) -type

RANKL is required for progesterone-induced proliferation b BRCA1mut/+ Prog + Dmab Ki67 12 10 % KI67+ cells within ducts Prog % KI67+ cells within ducts Vehicle 10 6 8 4 6 0 b 12 8 2 * * * EtOH Prog Prog + EtOH Dmab Prog Prog + * 4 2 mut/+ BRCA1 0 WT BRCA1mut/+ WT Data represents mean ± s.e.m for n = 5 patient samples. *p < 0.05 c within ducts 12 * * Treatment with the RANKL inhibitor Denosumab in 3D breast organoids from prevehicle 10 neoplastic BRCA1mut/+ tissue Prog attenuated progesterone-evoked proliferation 8 Prog + Dmab

RANKL inhibition delays tumor development in mouse models Tumour-free survival (%) *** 100 Vehicle OPG-Fc 80 60 40 20 0 0 120 140 160 180 200 220 240 260 Days (post-surgery) Vehicle OPG-Fc H & E Tumor onset delayed in mice treated with the RANKL inhibitor OPG-Fc (p = 0.0002) Median tumor onset not reached in OPG-Fc group, 6/17 (35%) mice had tumors at experimental endpoint Dramatically reduced hyperplasia in OPG-Fc treated mice at endpoint Nolan et al Nature Med 2016

A targetable pathway in the putative cell-of-origin population in BRCA1-mutation carriers MaSC (BRCA1 mut/+ ) Luminal progenitor cells Basal-like tumour HR+ RANK HR RANK+ Responder cell Hormone sensor cell RANKL RANKL inhibitor Progesterone Myoepithelial cell Alveolar cell HR HR+ Ductal cells Nolan et al Nature Med 2016

Cell Stem Cell 19, 52 65, July 7, 2016

Normal and neoplastic stem cells This presenta,on is the intellectual property of the author/presenter. Contact them at (m.ben,res-alj@unibas.ch) for permission to reprint and/or distribute

Science 30 SEPTEMBER 2016 VOL 353 ISSUE 6307

Science 4 MARCH 2016 VOL 351 ISSUE 6277

This presenta,on is the intellectual property of the author/presenter. Contact them at (m.ben,res-alj@unibas.ch) for permission to reprint and/or distribute Genomic/proteomic landscape of BC and novel targets Questions What are the functional genomic landscape and the repertoire of cancer genes in breast cancer (primary and metastases)? What is the effect of genetic alterations on the proteomic landscape of breast cancer? What are breast cancer vulnerabilities? Can one target epigenome regulating factors (BRD4?) and how does resistance develop? How one can target TNBC?

Nature 2 JUNE 2016 VOL 534

Cell 164, 293 309, January 14, 2016

N&V J. Settleman 21 JANUARY 2016 VOL 529 NATURE 289

Cell 164, 293 309, January 14, 2016

Nature 21 JANUARY 2016 VOL 52 N&V J. Settleman 21 JANUARY 2016 VOL 529 NATURE 289

Potent inhibitory effects of BET bromodomain inhibitors in TNBC

Development of specific resistance to BBI in TNBC

BBI-resistance is associated with increased binding of BRD4 to MED1, independently of the bromodomains (resistant to JQ1) pbrd4 binds MED1 more efficiently than BRD4

Nature 21 JANUARY 2016 VOL 52 N&V J. Settleman 21 JANUARY 2016 VOL 529 NATURE 289

Nature Medicine VOLUME 22 NUMBER 11 NOVEMBER 2016 Nature Medicine VOLUME 22 NUMBER 11 NOVEMBER 2016

Mechanisms of metastasis Questions What are the cell autonomous mechanisms of metastasis? What regulates prometasta,c proteins? What mediates mul,-organ site metasta,c reac,va,on? How do metasta,c cells evade innate immunity? What are the non-cell autonomous mechanisms of metastasis? How do neutrophils contribute to cancer metastasis? This presenta,on is the intellectual property of the author/presenter. Contact them at (m.ben,res-alj@unibas.ch) for permission to reprint and/or distribute

Cell 165, 1416 1427, June 2, 2016

Cell 165, 45 60, March 24, 2016

Nature 17 DECEMBER 2015 VO L 5 Cancer Discov; 6(6); 630 49 (2016)

Cell 166, 47 62, June 30, 2016

Nature 26 MAY 2016 VOL 533