miR200-regulated CXCL12β promotes ﬁbroblast
heterogeneity and immunosuppression in ovarian
, Yann Kieffer
, Alix Scholer-Dahirel
, Philemon Sirven
, Melissa Cardon
, Ilaria Magagna
, Géraldine Gentric
, Ana Costa
, Claire Bonneau
, Virginie Mieulet
& Fatima Mechta-Grigoriou
High-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes.
The mesenchymal HGSOC subgroup, deﬁned by stromal-related gene signatures, is invari-
ably associated with poor patient survival. We demonstrate that stroma exerts a key function
in mesenchymal HGSOC. We highlight stromal heterogeneity in HGSOC by identifying four
subsets of carcinoma-associated ﬁbroblasts (CAF-S1-4). Mesenchymal HGSOC show high
content in CAF-S1 ﬁbroblasts, which exhibit immunosuppressive functions by increasing
attraction, survival, and differentiation of CD25
T lymphocytes. The beta isoform of
the CXCL12 chemokine (CXCL12β) speciﬁcally accumulates in the immunosuppressive CAF-
S1 subset through a miR-141/200a dependent-mechanism. Moreover, CXCL12β expression in
CAF-S1 cells plays a crucial role in CAF-S1 immunosuppressive activity and is a reliable
prognosis factor in HGSOC, in contrast to CXCL12α. Thus, our data highlight the differential
regulation of the CXCL12α and CXCL12β isoforms in HGSOC, and reveal a CXCL12β-
associated stromal heterogeneity and immunosuppressive environment in mesenchymal
Institut Curie, Stress and Cancer Laboratory, Equipe labelisée Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d’Ulm, 75005 Paris, France.
U830, Inserm, 75005 Paris, France.
Institut Curie, Integrative Biology of Human Dendritic Cells and T Cells Laboratory, PSL Research University, U932,
Inserm, 26, rue d’Ulm, 75005 Paris, France.
Department of Pathology, Institut Curie Hospital Group, 26, rue d’Ulm, 75248 Paris, France. Correspondence
and requests for materials should be addressed to F.M-G. (email: firstname.lastname@example.org)