Predictive Outcomes for HER2-enriched Cancer Using Growth and Metastasis Signatures Driven By SPARC

Abstract

Understanding the mechanism of metastatic dissemination is crucial for the rational design of novel therapeutics. The secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein which has been extensively associated with human breast cancer aggressiveness although the underlying mechanisms are still unclear. Here, shRNA-mediated SPARC knockdown greatly reduced primary tumor growth and completely abolished lung colonization of murine 4T1 and LM3 breast malignant cells implanted in syngeneic BALB/c mice. A comprehensive study including global transcriptomic analysis followed by biological validations confirmed that SPARC induces primary tumor growth by enhancing cell cycle and by promoting a COX-2-mediated expansion of myeloid-derived suppressor cells (MDSC). The role of SPARC in metastasis involved a COX-2-independent enhancement of cell disengagement from the primary tumor and adherence to the lungs that fostered metastasis implantation. Interestingly, SPARC-driven gene expression signatures obtained from these murine models predicted the clinical outcome of patients with HER2-enriched breast cancer subtypes. In total, the results reveal that SPARC and its downstream effectors are attractive targets for antimetastatic therapies in breast cancer. These findings shed light on the prometastatic role of SPARC, a key protein expressed by breast cancer cells and surrounding stroma, with important consequences for disease outcome. .

Genetic trajectory and immune microenvironment of lung-specific oligometastatic colorectal cancer

“…Another study suggested that the Ala variant increased the risk of lung cancer, indicating that it may promote ERBB2 activity 25 . However, Minn et al 26 and Guttlein et al 27 showed that, in ERBB2 overexpressing breast cancer cell lines, lung colonization is predominant and mediated by SPARC (secreted protein acidic and rich in cysteine).…”

Common extracellular matrix regulation of myeloid cell activity in the bone marrow and tumor microenvironments

“…A similar ECM gene cluster, comprising COL1A1, FN1, LOX, SPARC, TIMP3, and COL1A2 has been associated with the resistance to tamoxifen when administered as a first-line therapy inpatients with metastatic breast cancer [11]. More recently, a SPARC-driven gene expression signature obtained from murine models predicted the clinical outcome of patients with HER2-enriched breast cancer subtypes [12]. Notably, signatures enriched in collagen genes together with LOX, THBS2, TIMP3, and SPARC have also been associated with poor survival after adjuvant chemotherapy and with a high hazard of death in ovarian cancer [13,14].…”

Modulating secreted components of tumor microenvironment: A masterstroke in tumor therapeutics

“…These include cytokines, growth factors, ligands, small RNAs, DNA, soluble factors, metabolite, and the non-cellular solid-state extracellular matrix (ECM) that make the TME more amiable for the progression of the tumor. 8,42,52,72,92,99,101 The cellular interactions with the non-cellular microenvironment also play a role in governing the tumor metastasis. 23 Tumor-stromal cell crosstalk intensifies the production of chemokines, growth factors, cytokines, matrix metalloproteinases (MMPs) which facilitate the tumor growth and angiogenesis.…”

“…Among a class of matricellular proteins in TEM, a secreted protein acidic and rich in cysteine (SPARC) has been shown to be linked to aggressiveness of human breast cancer. G€ uttlein et al 42 revealed the clinical evidence of SPARC in breast carcinoma and highlighted its importance in therapeutics and biomarker study. Recently, Hu et al 49 showed the presence of several secreted proteins, namely SULT2B1, CEACAM5, SPRR3, AGR2, S100P, and S100A14, which can potentially be used as therapeutic targets and biomarkers in non-small cell lung cancer (NSCLC).…”