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

Abstract

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.

Context Matters: Response Heterogeneity to Collagen-Targeting Approaches in Desmoplastic Cancers

“…Nevertheless, this report was substantiated by Fatherree et al [84], who recently demonstrated that chemotherapy-mediated upregulation of collagen IV in the mammary carcinoma ECM enhanced cancer cell motility in a Src-and focal-adhesion kinase (FAK)-dependent manner [84]. Inhibition of Src/FAK signaling downstream of collagen IV attenuated chemotherapy-induced cancer cell migration, providing insights into mechanisms by which cytotoxic treatments may augment the metastatic potential of residual disease [84]. In contrast to the full-length molecule, collagen IV matrikines including arrestin, canstatin, and pentastatin (cleavage products of Col4a1, Col4a2, and Col4a5, respectively) inhibited tumor growth in xenograft models of prostate, mammary, and pancreatic carcinoma [85][86][87][88].…”

“…However, the authors did not evaluate whether this phenotype also led to increased cancer cell migratory and/or invasive capacity [83]. Nevertheless, this report was substantiated by Fatherree et al [84], who recently demonstrated that chemotherapy-mediated upregulation of collagen IV in the mammary carcinoma ECM enhanced cancer cell motility in a Src-and focal-adhesion kinase (FAK)-dependent manner [84]. Inhibition of Src/FAK signaling downstream of collagen IV attenuated chemotherapy-induced cancer cell migration, providing insights into mechanisms by which cytotoxic treatments may augment the metastatic potential of residual disease [84].…”

Mammary Tissue-Derived Extracellular Matrix Hydrogels Reveal the Role of Irradiation in Driving a Pro-Tumor and Immunosuppressive Microenvironment

“…A major function of collagen I, IV and VI in the local ECM environment is to provide structural support for cells and enrich the cell surface with growth factors and cytokines that are important in tumor progression. Increased collagen IV after chemotherapy has been shown to drive TNBC cell invasion [42]. Collagen VI is secreted by adipocytes and is known to regulate breast tumor development and facilitate TNBC cell migration [43,44].…”

FAK-SFK Signaling Integrates ECM Rigidity Sensing and Engagement of ERBB2 to Activate YAP and Promote Invasive Growth and Metastasis in Breast Cancer

“…A recent study in triple negative MDA-MB-231 cells shows that EZH2-upregulated integrin β1 activates FAK, which phosphorylates TGFβ receptor type I (TGFβRI) at Y182 to increases its binding to TGFβ receptor type II (TGFβRII), thus activating TGFβ signaling and bone metastatic potential (29). ECM deposition and remodeling promotes chemoresistance by inducing FAK activation through integrin α1/α2/α5 (11, 30). These studies shed light on FAK activation by upstream integrin and RTKs.…”

“…In HER2 positive breast cancer, ECM rigidity drives resistance to HER2 inhibitor lapatinib (10). In Triple Negative breast cancer, chemotherapy induces Collagen IV upregulation in the ECM, which in turn leads to drug resistance and promotes cell invasion (11).…”