Dissecting Effects of Anti-cancer Drugs and Cancer-Associated Fibroblasts by On-Chip Reconstitution of Immunocompetent Tumor Microenvironments

N'guyen, M. J.; Ninno, Adele De; Mencattini, Arianna; Mermet-Meillon, Fanny; Fornabaio, Giulia; Evans, Sophia S.; Cossutta, Mélissande; Khira, Yasmine; Han, Weijing; Sirven, Philémon; Pelon, Floriane; Giuseppe, Davide Di; Bertani, Francesca Romana; Gerardino, Annamaria; Yamada, Ayako; Descroix, Stéphanie; Soumelis, Vassili; Mechta‐Grigoriou, Fatima; Zalcman, Gérard; Camonis, Jacques; Martinelli, Eugenio; Businaro, Luca; Parrini, Maria Carla

doi:10.1016/j.celrep.2018.12.015

Cited by 146 publications

(132 citation statements)

References 43 publications

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“…Therefore, if TILs indicate the presence of an immune response, it may be possible that the role of immune surveillance for tumor control is relatively ineffective when using trastuzumab due to stromal reactivity which exerts immune suppression . In support of this possibility are the findings of several recent preclinical studies that demonstrated that CAFs have immunosuppressive effects which may affect the response to trastuzumab . The application of data from a prospective, rigorously conducted randomized clinical trial strengthens the relevance of our observation and highlights the importance of the role of the tumor microenvironment in the efficacy of trastuzumab.…”

Section: Discussionsupporting

confidence: 71%

“…S1). Given that preclinical data suggested that reactive stroma may decrease trastuzumab efficacy, we investigated this hypothesis in HER2‐positive breast cancer.…”

Section: Resultsmentioning

confidence: 99%

“…Given the increasing evidence of the significant contribution of tumor‐associated stroma to trastuzumab efficacy, we decided to evaluate biomarkers capable of identifying the patients who are resistant to trastuzumab in the context of a large Phase III adjuvant clinical trial in which patients were randomly assigned to anti‐HER2 treatments.…”

Section: Introductionmentioning

confidence: 99%

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Reactive stroma and trastuzumab resistance in HER2‐positive early breast cancer

Sonnenblick

Salmon‐Divon

Salgado

et al. 2020

Intl Journal of Cancer

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We investigated the value of reactive stroma as a predictor for trastuzumab resistance in patients with early HER2-positive breast cancer receiving adjuvant therapy. The pathological reactive stroma and the mRNA gene signatures that reflect reactive stroma in 209 HER2-positive breast cancer samples from the FinHer adjuvant trial were evaluated. Levels of stromal gene signatures were determined as a continuous parameter, and pathological reactive stromal findings were defined as stromal predominant breast cancer (SPBC; ≥50% stromal) and correlated with distant disease-free survival. Gene signatures associated with reactive stroma in HER2-positive early breast cancer (N = 209) were significantly associated with trastuzumab resistance in estrogen receptor (ER)-negative tumors (hazard ratio [HR] = 1.27 p interaction = 0.014 [DCN], HR = 1.58, p interaction = 0.027 [PLAU], HR = 1.71, p interaction = 0.019 [HER2STROMA, novel HER2 stromal signature]), but not in ERpositive tumors (HR = 0.73 p interaction = 0.47 [DCN], HR = 0.71, p interaction = 0.73 [PLAU], HR = 0.84; p interaction = 0.36 [HER2STROMA]). Pathological evaluation of HER2-positive/ER-negative tumors suggested an association between SPBC and trastuzumab resistance. Reactive stroma did not correlate with tumor-infiltrating lymphocytes (TILs), and the expected benefit from trastuzumab in patients with high levels of TILs was pronounced only in tumors with low stromal reactivity (SPBC <50%). In conclusion, reactive stroma in HER2-positive/ER-negative early breast cancer tumors may predict resistance to adjuvant trastuzumab therapy. † A.S., M.S.-D. and R.S. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

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Section: Discussionsupporting

confidence: 71%

“…S1). Given that preclinical data suggested that reactive stroma may decrease trastuzumab efficacy, we investigated this hypothesis in HER2‐positive breast cancer.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Reactive stroma and trastuzumab resistance in HER2‐positive early breast cancer

Sonnenblick

Salmon‐Divon

Salgado

et al. 2020

Intl Journal of Cancer

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“…4e, right). To go deeper in the characterization of BC cell motility in 3D, we took advantage of the tumor-on-chip system 42 , a microfluidic device where cancer cells and CAF subsets were co-cultured in 3D and followed by time-lapse video microscopy. In this system, we reproduced the intrinsic CAF subset motility, CAF-S1 being more motile than CAF-S4 ( Supplementary Fig.…”

Section: Caf-s1mentioning

confidence: 99%

Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms

et al. 2020

Self Cite

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Although fibroblast heterogeneity is recognized in primary tumors, both its characterization in and its impact on metastases remain unknown. Here, combining flow cytometry, immunohistochemistry and RNA-sequencing on breast cancer samples, we identify four Cancer-Associated Fibroblast (CAF) subpopulations in metastatic lymph nodes (LN). Two myofibroblastic subsets, CAF-S1 and CAF-S4, accumulate in LN and correlate with cancer cell invasion. By developing functional assays on primary cultures, we demonstrate that these subsets promote metastasis through distinct functions. While CAF-S1 stimulate cancer cell migration and initiate an epithelial-to-mesenchymal transition through CXCL12 and TGFβ pathways, highly contractile CAF-S4 induce cancer cell invasion in 3-dimensions via NOTCH signaling. Patients with high levels of CAFs, particularly CAF-S4, in LN at diagnosis are prone to develop late distant metastases. Our findings suggest that CAF subset accumulation in LN is a prognostic marker, suggesting that CAF subsets could be examined in axillary LN at diagnosis.

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“…Most cancer cells utilize the extracellular matrix (ECM), which acts as a physical constraint, to mediate communication signals, promote interactions with other cells and establish the cancer microenvironment [5][6][7][8]. Cancer microenvironments are mainly constituted by cancer-associated fibroblasts (CAFs), macrophages, mesenchymal stem cells and cancer-specific ECM [9].…”

Section: Introductionmentioning

confidence: 99%

Cancer-Associated Fibroblasts Differentiated by Exosomes Isolated from Cancer Cells Promote Cancer Cell Invasion

Kim

Sohn

Lee

et al. 2020

IJMS

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Cancer-associated fibroblasts (CAFs) in the cancer microenvironment play an essential role in metastasis. Differentiation of endothelial cells into CAFs is induced by cancer cell-derived exosomes secreted from cancer cells that transfer molecular signals to surrounding cells. Differentiated CAFs facilitate migration of cancer cells to different regions through promoting extracellular matrix (ECM) modifications. However, in vitro models in which endothelial cells exposed to cancer cell-derived exosomes secreted from various cancer cell types differentiate into CAFs or a microenvironmentally controlled model for investigating cancer cell invasion by CAFs have not yet been studied. In this study, we propose a three-dimensional in vitro cancer cell invasion model for real-time monitoring of the process of forming a cancer invasion site through CAFs induced by exosomes isolated from three types of cancer cell lines. The invasiveness of cancer cells with CAFs induced by cancer cell-derived exosomes (eCAFs) was significantly higher than that of CAFs induced by cancer cells (cCAFs) through physiological and genetic manner. In addition, different genetic tendencies of the invasion process were observed in the process of invading cancer cells according to CAFs. Our 3D microfluidic platform helps to identify specific interactions among multiple factors within the cancer microenvironment and provides a model for cancer drug development.

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Dissecting Effects of Anti-cancer Drugs and Cancer-Associated Fibroblasts by On-Chip Reconstitution of Immunocompetent Tumor Microenvironments

Cited by 146 publications

References 43 publications

Reactive stroma and trastuzumab resistance in HER2‐positive early breast cancer

Reactive stroma and trastuzumab resistance in HER2‐positive early breast cancer

Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms

Cancer-Associated Fibroblasts Differentiated by Exosomes Isolated from Cancer Cells Promote Cancer Cell Invasion

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