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Molecular and functional heterogeneity of cancer associated fibroblasts in high-grade serous ovarian cancer

Ali Hussain, Veronique Voisin, Stephanie Poon, Julia Dmytryshyn, Cory Richman, Jalna Meens, Victor W Ho, Kwan Ho Tang, Joshua Paterson, Blaise Clarke, Marcus Q Bernardini, Gary D Bader, Benjamin G Neel, Laurie E Ailles
doi: https://doi.org/10.1101/519728
Ali Hussain
1Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
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Veronique Voisin
2The Donnelly Centre, University of Toronto, Toronto, ON, Canada
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Stephanie Poon
1Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
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Julia Dmytryshyn
3Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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Cory Richman
1Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
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Jalna Meens
3Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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Victor W Ho
3Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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Kwan Ho Tang
4Laura and Isaac Perlmutter Cancer Center, New York Langone Health, New York, NY
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Joshua Paterson
3Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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Blaise Clarke
5Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, University Health Network, Toronto, ON, Canada
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Marcus Q Bernardini
6Division of Gynaecologic Oncology, University Health Network, Toronto, Ontario, Canada
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Gary D Bader
2The Donnelly Centre, University of Toronto, Toronto, ON, Canada
7Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
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Benjamin G Neel
1Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
3Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
4Laura and Isaac Perlmutter Cancer Center, New York Langone Health, New York, NY
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Laurie E Ailles
1Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
3Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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  • For correspondence: lailles@uhnresearch.ca
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SUMMARY

Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes and the roles they play in cancer progression. Here we identify and characterize two CAF subtypes that coexist within high grade serous ovarian cancers: Fibroblast activation protein (FAP)-high (FH) CAFs resemble the classical myofibroblast-type CAF, whereas FAP-low (FL) CAFs possesses a preadipocyte-like molecular signature. Patients with predominantly FH CAFs have significantly worse outcomes than patients with predominantly FL CAFs. FH CAFs contract collagen gels and aggressively promote proliferation, invasion and therapy resistance of cancer cells, whereas FL CAFs do not. Overexpression of the FL-specific transcription factor TCF21 in FH CAFs decreases their ability to promote gel contraction, invasion, and in vivo tumor growth. Understanding CAF subtypes in more detail could lead to better patient stratification and novel therapeutic strategies.

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Posted February 07, 2019.
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Molecular and functional heterogeneity of cancer associated fibroblasts in high-grade serous ovarian cancer
Ali Hussain, Veronique Voisin, Stephanie Poon, Julia Dmytryshyn, Cory Richman, Jalna Meens, Victor W Ho, Kwan Ho Tang, Joshua Paterson, Blaise Clarke, Marcus Q Bernardini, Gary D Bader, Benjamin G Neel, Laurie E Ailles
bioRxiv 519728; doi: https://doi.org/10.1101/519728
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Molecular and functional heterogeneity of cancer associated fibroblasts in high-grade serous ovarian cancer
Ali Hussain, Veronique Voisin, Stephanie Poon, Julia Dmytryshyn, Cory Richman, Jalna Meens, Victor W Ho, Kwan Ho Tang, Joshua Paterson, Blaise Clarke, Marcus Q Bernardini, Gary D Bader, Benjamin G Neel, Laurie E Ailles
bioRxiv 519728; doi: https://doi.org/10.1101/519728

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