Triple-negative breast cancer (TNBC) is among the most aggressive breast cancer subtypes. Despite being initially responsive to chemotherapy, patients develop drug-resistant and metastatic tumors. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a secreted protein with a tumor suppressor function due to its anti-proteolytic activity. Nevertheless, evidence indicates that TIMP-1 binds to the CD63 receptor and activates noncanonical oncogenic signaling in several cancers, but its role in mediating TNBC chemoresistance is still largely unexplored. Here, we show that mesenchymal-like TNBC cells express TIMP-1, whose levels are further increased in cells generated to be resistant to cisplatin (Cis-Pt-R) and doxorubicin (Dox-R). Moreover, public dataset analyses indicate that high TIMP-1 levels are associated with a worse prognosis in TNBC subjected to chemotherapy. Knock-down of TIMP-1 in both Cis-Pt-R and Dox-R cells reverses their resistance by inhibiting AKT activation. Consistently, TNBC cells exposed to recombinant TIMP-1 or TIMP-1-enriched media from chemoresistant cells, acquire resistance to both cisplatin and doxorubicin. Importantly, released TIMP-1 reassociates with plasma membrane by binding to CD63 and, in the absence of CD63 expression, TIMP-1-mediated chemoresistance is blocked. Thus, our results identify TIMP-1 as a new biomarker of TNBC chemoresistance and lay the groundwork for evaluating whether blockade of TIMP-1 signal is a viable treatment strategy.

The limitations of current diagnostic imaging techniques and therapies for bladder cancer are associated with and responsible for the recurrence and progression of residual disease, with an impact on social costs and quality of life of patients. This study delivers a cost‐effective solution for the detection of bladder cancer residual disease, which is represented by the early detection of bladder cancer lesions < 1 mm. Urine‐stable 34‐mer SH‐terminated 2′F‐Py‐RNA aptamer that recognizes the integrin α5β1, expressed by 81% of human high‐grade non‐muscle invasive bladder cancer, is developed. The intravesical instillation of aptamer‐conjugated gold nanorods as contrast agent for photoacoustic imaging is validated in a preclinical model of orthotopic bladder cancer expressing the integrin α5β1. The photoacoustic signal of gold nanorods remains on the tumor surface for 3 h and allows early detection of cancer lesions < 1 mm. The aptamer is internalized into lysosomes, an opportunity that paves the way for lysosomal‐mediated drug release in tumor cells. This study highlights the potential of urine‐stable aptamer for the delivery of a solution to target the residual high‐grade bladder cancer disease.

Triple-negative breast cancer (TNBC) represents a significant therapeutic challenge owing to the scarcity of targeted medicines and elevated recurrence rates. We previously reported the development of the nuclease-resistant RNA sTN58 aptamer, which selectively targets TNBC cells. Here, sTN58 aptamer was employed to capture and purify its binding target from the membrane protein fraction of cisplatin-resistant mesenchymal stem-like TNBC cells. Mass spectrometry in conjunction with aptamer binding assays across various cancer cell lines identified CD44 as the cellular target of sTN58. By binding to CD44, sTN58 inhibits the invasive growth and hyaluronic acid-dependent tube formation in chemoresistant TNBC cells, where CD44 serves as a key driver of tumor cell aggressiveness and stem-like plasticity. Moreover, in vivo studies demonstrated the aptamer's high tumor targeting efficacy and its capacity to significantly inhibit tumor growth and lung metastases following intravenous administration in mice with orthotopic TNBC. Overall, our findings reveal the striking potential of sTN58 as a targeting reagent for the recognition and therapy of cancers overexpressing CD44.

Red-emitting carbon dot–alginate–aptamer systems afforded the targeted detection and bioimaging of triple-negative breast cancer cells.