TY - JOUR
T1 - Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL6-Mediated Therapy Resistance in Pancreatic Cancer
AU - McAndrews, Kathleen M.
AU - Chen, Yang
AU - Darpolor, J. Kebbeh
AU - Zheng, Xiaofeng
AU - Yang, Sujuan
AU - Carstens, Julienne L.
AU - Li, Bingrui
AU - Wang, Huamin
AU - Miyake, Toru
AU - De Sampaio, Pedro Correa
AU - Kirtley, Michelle L.
AU - Natale, Mariangela
AU - Wu, Chia Chin
AU - Sugimoto, Hikaru
AU - Lebleu, Valerie S.
AU - Kalluri, Raghu
N1 - Publisher Copyright:
© 2022 The Authors; Published by the American Association for Cancer Research.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of fibroblasts as part of the host response to cancer. Using single-cell RNA sequencing, multiplex immunostaining, and several genetic mouse models, we identify carcinoma-associated fibroblasts (CAF) with opposing functions in PDAC progression. Depletion of fibroblast activation protein (FAP)+ CAFs results in increased survival, in contrast to depletion of alpha smooth muscle actin (αSMA)+ CAFs, which leads to decreased survival. Tumor-promoting FAP+ CAFs (TP-CAF) and tumor-restraining αSMA+ CAFs (TR-CAF) differentially regulate cancer-associated pathways and accumulation of regulatory T cells. Improved efficacy of gemcitabine is observed when IL6 is deleted from αSMA+ CAFs but not from FAP+ CAFs using dual-recombinase genetic PDAC models. Improved gemcitabine efficacy due to lack of IL6 synergizes with anti-PD-1 immunotherapy to significantly improve survival of PDAC mice. Our study identifies functional heterogeneity of CAFs in PDAC progression and their different roles in therapy response.
AB - The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of fibroblasts as part of the host response to cancer. Using single-cell RNA sequencing, multiplex immunostaining, and several genetic mouse models, we identify carcinoma-associated fibroblasts (CAF) with opposing functions in PDAC progression. Depletion of fibroblast activation protein (FAP)+ CAFs results in increased survival, in contrast to depletion of alpha smooth muscle actin (αSMA)+ CAFs, which leads to decreased survival. Tumor-promoting FAP+ CAFs (TP-CAF) and tumor-restraining αSMA+ CAFs (TR-CAF) differentially regulate cancer-associated pathways and accumulation of regulatory T cells. Improved efficacy of gemcitabine is observed when IL6 is deleted from αSMA+ CAFs but not from FAP+ CAFs using dual-recombinase genetic PDAC models. Improved gemcitabine efficacy due to lack of IL6 synergizes with anti-PD-1 immunotherapy to significantly improve survival of PDAC mice. Our study identifies functional heterogeneity of CAFs in PDAC progression and their different roles in therapy response.
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U2 - 10.1158/2159-8290.CD-20-1484
DO - 10.1158/2159-8290.CD-20-1484
M3 - Article
C2 - 35348629
AN - SCOPUS:85131268451
SN - 2159-8274
VL - 12
SP - 1580
EP - 1597
JO - Cancer discovery
JF - Cancer discovery
IS - 6
ER -