IFNβ1 secreted by breast cancer cells undergoing chemotherapy reprograms stromal fibroblasts to support tumour growth after treatment

Maia, Ana Luiza Silva; Gu, Zuguang; Koch, Andrè; Berdiel-Acer, Mireia; Will, Rainer; Schlesner, Matthias; Wiemann, Stefan

doi:10.1002/1878-0261.12905

Cited by 10 publications

(8 citation statements)

References 64 publications

(77 reference statements)

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“…The apparent disparity between our proteomics and immunostaining data in doxorubicin-treated tumors may help us to understand potential mechanisms. It is well established that chemotherapy stimulates secretion of tumor-derived soluble signals leading to paracrine cross-talk between tumor and stromal cells ( 49 ). In this case, chemotherapy-induced production of ECM regulating enzymes may promote collagen IV trimerization without altering overall abundance of individual collagen IV chains.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy-Induced Collagen IV Drives Cancer Cell Motility through Activation of Src and Focal Adhesion Kinase

et al. 2022

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Triple-negative breast cancer (TNBC) is the most aggressive and deadly subtype of breast cancer, accounting for 30,000 cases annually in the US. While there are several clinical trials ongoing to identify new agents to treat TNBC, the majority of TNBC patients are treated with anthracycline- or taxane-based chemotherapies in the neoadjuvant setting, followed by surgical resection and adjuvant chemotherapy. While many patients respond well to this approach, as many as 25% will suffer local or metastatic recurrence within five years. Understanding the mechanisms that drive recurrence after chemotherapy treatment is critical to improving survival for patients with TNBC. It is well-established that the extracellular matrix, which provides structure and support to tissues, is a major driver of tumor growth, local invasion and dissemination of cancer cells to distant metastatic sites. In the present study, we show that decellularized extracellular matrix (dECM) obtained from chemotherapy-treated mice increases motility of treatment-naïve breast cancer cells compared to vehicle-treated dECM. Tandem-mass-tag proteomics revealed that anthracycline- and taxane-based chemotherapies induce drug-specific changes in tumor ECM composition. The basement membrane protein collagen IV was significantly upregulated in the ECM of chemotherapy-treated mice and patients treated with neoadjuvant chemotherapy. Collagen IV drove invasion via activation of Src and focal adhesion kinase signaling downstream of integrin α1 and α2, and inhibition of collagen IV-driven signaling decreased motility in chemotherapy-treated dECM. These studies provide a novel mechanism by which chemotherapy may induce metastasis via its effects on ECM composition.

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Section: Discussionmentioning

confidence: 99%

Chemotherapy-Induced Collagen IV Drives Cancer Cell Motility through Activation of Src and Focal Adhesion Kinase

et al. 2022

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“…On the other hand, under chemotherapy pressure, interferon β1 (IFNβ1) secretion by cancer cells stimulates the transcription of pro-inflammatory cytokine genes in stromal fibroblasts, by which CAFs acquire an anti-viral state, essential for the recovery and resistance acquisition of BrCa cells after chemotherapy. Indeed, high expression of tumor IFNβ1 in TNBrCa patients correlated with an aggressiveness signature [54]. Another interesting paracrine relationship between cancer cells expressing platelet derived growth factor (PDGF) and CAFs positive for PDGF-receptors was described in basal-like BrCa patients.…”

Section: Cafs and Chemotherapy Resistance In Triple Negative Brcamentioning

confidence: 99%

Cancer-Associated Fibroblasts in Breast Cancer Treatment Response and Metastasis

Fernández‐Nogueira

Fuster

Gutiérrez-Uzquiza

et al. 2021

Cancers

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Breast cancer (BrCa) is the leading cause of death among women worldwide, with about one million new cases diagnosed each year. In spite of the improvements in diagnosis, early detection and treatment, there is still a high incidence of mortality and failure to respond to current therapies. With the use of several well-established biomarkers, such as hormone receptors and human epidermal growth factor receptor-2 (HER2), as well as genetic analysis, BrCa patients can be categorized into multiple subgroups: Luminal A, Luminal B, HER2-enriched, and Basal-like, with specific treatment strategies. Although chemotherapy and targeted therapies have greatly improved the survival of patients with BrCa, there is still a large number of patients who relapse or who fail to respond. The role of the tumor microenvironment in BrCa progression is becoming increasingly understood. Cancer-associated fibroblasts (CAFs) are the principal population of stromal cells in breast tumors. In this review, we discuss the current understanding of CAFs’ role in altering the tumor response to therapeutic agents as well as in fostering metastasis in BrCa. In addition, we also review the available CAFs-directed molecular therapies and their potential implications for BrCa management.

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“…In the same way that cytotoxic agents can drive the senescence of fibroblasts, the cancer cells exposed to these agents can also undergo therapy-induced senescence and acquire the aforementioned senescence-associated secretory phenotype (SASP) [ 175 ], which then modulates the phenotype of fibroblasts. We have recently shown that cancer cells exposed to high doses of chemotherapy upregulate the expression of IFNβ1, which acted in a paracrine manner to drive a pro-tumorigenic state of fibroblasts that then drove the recovery of cancer cells after treatment [ 176 ]. This upregulation of IFNβ1 after treatment with cytotoxic agents goes in line with previous studies that have shown that high levels of damage in cancer cells after treatment results in the activation of the STING/IRF3 pathway and drives IFNβ1 expression [ 177 , 178 , 179 ].…”

Section: Fibroblastsmentioning

confidence: 99%

Cancer-Associated Fibroblasts: Implications for Cancer Therapy

Maia

Wiemann

2021

Cancers

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Tumour cells do not exist as an isolated entity. Instead, they are surrounded by and closely interact with cells of the environment they are emerged in. The tumour microenvironment (TME) is not static and several factors, including cancer cells and therapies, have been described to modulate several of its components. Fibroblasts are key elements of the TME with the capacity to influence tumour progression, invasion and response to therapy, which makes them attractive targets in cancer treatment. In this review, we focus on fibroblasts and their numerous roles in the TME with a special attention to recent findings describing their heterogeneity and role in therapy response. Furthermore, we explore how different therapies can impact these cells and their communication with cancer cells. Finally, we highlight potential strategies targeting this cell type that can be employed for improving patient outcome.

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IFNβ1 secreted by breast cancer cells undergoing chemotherapy reprograms stromal fibroblasts to support tumour growth after treatment

Abstract: IFN1 secreted by breast cancer cells undergoing chemotherapy reprogramsstromal fibroblasts to support tumour growth after treatment.

Cited by 10 publications

References 64 publications

Chemotherapy-Induced Collagen IV Drives Cancer Cell Motility through Activation of Src and Focal Adhesion Kinase

Chemotherapy-Induced Collagen IV Drives Cancer Cell Motility through Activation of Src and Focal Adhesion Kinase

Cancer-Associated Fibroblasts in Breast Cancer Treatment Response and Metastasis

Cancer-Associated Fibroblasts: Implications for Cancer Therapy

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