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Distinct cancer-associated fibroblast states drive clinical outcomes in high-grade serous ovarian cancer and are regulated by TCF21

Ali Hussain, Veronique Voisin, Stephanie Poon, Jalna Meens, Julia Dmytryshyn, 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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Jalna Meens
3Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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Julia Dmytryshyn
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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Abstract

Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes, the roles they play in cancer progression, and molecular mediators of the CAF “state”. Here we identify a novel cell surface pan-CAF marker, CD49e, and demonstrate that two distinct CAF states, distinguished by expression of fibroblast activation protein (FAP), co-exist within the CD49e+ CAF compartment in high grade serous ovarian cancers. We show for the first time that CAF state influences patient outcomes, and that this is mediated by the ability FAP-high (FH) but not FAP-low (FL) CAFs to aggressively promote proliferation, invasion and therapy resistance of cancer cells. Overexpression of the FL-specific transcription factor TCF21 in FH CAFs decreases their ability to promote invasion, chemoresistance and in vivo tumor growth, indicating that it acts as a master regulator of the CAF state. Understanding CAF states in more detail could lead to better patient stratification and novel therapeutic strategies.

One sentence summary In this study we demonstrate that cancer-associated fibroblasts (CAFs) in high-grade serous ovarian cancer are heterogeneous, that CAF state drives cancer aggressiveness and patient outcomes, and that TCF21 is a master regulator of CAF state.

Footnotes

  • Figure 7 revised

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Posted May 10, 2019.
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Distinct cancer-associated fibroblast states drive clinical outcomes in high-grade serous ovarian cancer and are regulated by TCF21
Ali Hussain, Veronique Voisin, Stephanie Poon, Jalna Meens, Julia Dmytryshyn, 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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Distinct cancer-associated fibroblast states drive clinical outcomes in high-grade serous ovarian cancer and are regulated by TCF21
Ali Hussain, Veronique Voisin, Stephanie Poon, Jalna Meens, Julia Dmytryshyn, 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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