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ExoCanCell: Targeting exosomes-mediated communication in pancreatic cancer

ExoCanCell: Targeting exosomes-mediated communication in pancreatic cancer. Nuno Bastos Sonia Melo´s Lab. PDAC Epidemiology. PDAC is the twelfth most frequent cancer worldwide. Overall 5-year survival rate is in the range of 6%-10%.

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ExoCanCell: Targeting exosomes-mediated communication in pancreatic cancer

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  1. ExoCanCell: Targeting exosomes-mediated communication in pancreatic cancer Nuno Bastos Sonia Melo´s Lab

  2. PDAC Epidemiology • PDAC is the twelfth most frequent cancer worldwide. • Overall 5-year survival rate is in the range of 6%-10%. • PDAC the most lethal cancer type being the seventh leading cause of cancer death in both genders. Poor screening and limited treatment options

  3. Exosomes in Cancer Tickner et al. 2014

  4. Exosomes biogenesis RabGTPases • Vesicle budding • Mobility • Docking and fusion with plasma membrane

  5. How important are Rabs in exosomes biogenesis and function?

  6. How we target cancer exosomes in vivo? Cell line injection Treatment Exosomes biogenesis proteins knockdown GW4869 Pitfalls Pitfalls • Not replicate full tumor development • Lack of an immune system • Non-exosomes specific • Non-tumor targeted Genetically engineered mouse models are the answer!

  7. Main question How do exosomes-mediated communication impacts pancreatic cancer progression? 1) Understand the dynamics of exosomes biogenesis during pancreatic cancer progression and how it supports tumor growth and metastasis. 2) Assess exosomes biogenesis as a new therapeutic target for pancreatic cancer.

  8. MIA PaCa-2 MIA PaCa-2 Capan-1 Capan-1 PANC-1 PANC-1 BxPC-3 BxPC-3 Rab5 Rab7 25kDa 23kDa Rab27a protein shows the higher correlation with exosomes release in PDAC β-actin β-actin 42kDa 42kDa MIA PaCa-2 MIA PaCa-2 Capan-1 Capan-1 PANC-1 PANC-1 BxPC-3 BxPC-3 Rab27a Rab27b 26kDa 26kDa β-actin β-actin 42kDa 42kDa

  9. Gemcitabine treatment leads to deregulation of Rabs expression pattern in PDAC

  10. Gemcitabine treatment leads to an increase in exosomes release in PDAC

  11. Gemcitabine treatment leads to an increase in exosomes release in PDAC Control Vehicle DAPI Phalloidin CD63-GFP DAPI Phalloidin CD63-GFP 40X 40X Gemcitabine DAPI Phalloidin CD63-GFP 40X

  12. First GEMM to evaluate the impact of exosomes-mediated communication in PDAC progression. Rab27aKO-KPC inducible and conditional mouse model Rab27a allele Legend: Rab27aFRT/FRT ROSA26LSL-FLPo/ERT2 Frt site Exon 4 cKO region Rab27aFRT/+ ROSA26LSL-FLPo/ERT2 Cre-Driven Model Rab27aFRT/+ ROSA26LSL-FLPo/ERT2 Cre-driven model

  13. Rab27aKO-KPC inducible and conditional mouse model First GEMM to evaluate the impact of exosomes-mediated communication in PDAC progression. SLOW PROGRESSION PDAC MODEL • KPC • PDX-1Cre/+ • KRASLSLG12D/+ • TP53R172H/+ KPC progression PanINs “Normal” PDAC weeks 12 0 16 4 8

  14. Rab27aKO-KPC inducible and conditional mouse model First GEMM to evaluate the impact of exosomes-mediated communication in PDAC progression. KPC progression PanINs “Normal” PDAC weeks 12 0 16 4 8 Tamoxifen – IP 75 mg/Kg Once every 24 h for 5 days Ultrasound Blood collection Rab27aFRT/FRT ROSA26LSL-FLPo/ERT2 KPC PDX-1Cre/+ Kras+/LSLG12D TP53R172H/+ Euthanasia Gemcitabine IV 20 mg/Kg, every 4 days Exosomes treatment (complementary group) IP injection of exosomes derived from KPC689 cell line 1x1010 p/g every 72h until euthanasia

  15. Take home message Novel therapeutic target Improve patient survival

  16. Acknowledgements i3S Instituto de Investigação e Inovação em Saúde Sonia Melo, PhD Bárbara Adem, MSc Carolina Ruivo, MSc Nuno Bastos, MSc Tiago Gama, MD Soraia Silva, MSc José Carlos Machado, PhD Collaborators MD Anderson Cancer Center University of Texas Raghu Kalluri, MD, PhD Roswell Park Cancer Institute David Goodrich, PhD Medical University of Viena Paola Martinelli, PhD Clinical University Carl Gustav Carus Dresden Christopher Kalhert, MD Hospital São João Pedro Moutinho, MD Guilherme Macedo, MD PTDC/BIM-ONC/2754/2014 IF/00543/2013

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