Extracellular vesicle-mediated drug delivery in breast cancer theranostics.

Breast cancer (BC) continues to be a significant global challenge due to drug resistance and severe side effects. The increasing prevalence is alarming, requiring new therapeutic approaches to address these challenges. At this point, Extracellular vesicles (EVs), specifically small endosome-released nanometer-sized EVs (SEVs) or exosomes, have been explored by literature as potential theranostics. Therefore, this review aims to highlight the therapeutic potential of exosomes in BC, focusing on their advantages in drug delivery and their ability to mitigate metastasis. Following the review, we identified exosomes' potential in combination therapies, serving as miRNA carriers and contributing to improved anti-tumor effects. This is evident in clinical trials investigating exosomes in BC, which have shown their ability to boost chemotherapy efficacy by delivering drugs like paclitaxel (PTX) and doxorubicin (DOX). However, the translation of EVs into BC therapy is hindered by various challenges. These challenges include the heterogeneity of EVs, the selection of the appropriate parent cell, the loading procedures, and determining the optimal administration routes. Despite the promising therapeutic potential of EVs, these obstacles must be addressed to realize their benefits in BC treatment.

FOXM1: A small fox that makes more tracks for cancer progression and metastasis.

Transcription factors (TFs) are indispensable for the modulation of various signaling pathways associated with normal cell homeostasis and disease conditions. Among cancer-related TFs, FOXM1 is a critical molecule that regulates multiple aspects of cancer cells, including growth, metastasis, recurrence, and stem cell features. FOXM1 also impact the outcomes of targeted therapies, chemotherapies, and immune checkpoint inhibitors (ICIs) in various cancer types. Recent advances in cancer research strengthen the cancer-specific role of FOXM1, providing a rationale to target FOXM1 for developing targeted therapies. This review compiles the recent studies describing the pivotal role of FOXM1 in promoting metastasis of various cancer types. It also implicates the contribution of FOXM1 in the modulation of chemotherapeutic resistance, antitumor immune response/immunotherapies, and the potential of small molecule inhibitors of FOXM1.

MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis.

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. METHODS: To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. RESULTS: A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. CONCLUSIONS: Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis.

Emerging role of chemokines in small cell lung cancer: Road signs for metastasis, heterogeneity, and immune response.

Small cell lung cancer (SCLC) is a recalcitrant, relatively immune-cold, and deadly subtype of lung cancer. SCLC has been viewed as a single or homogenous disease that includes deletion or inactivation of the two major tumor suppressor genes (TP53 and RB1) as a key hallmark. However, recent sightings suggest the complexity of SCLC tumors that comprises highly dynamic multiple subtypes contributing to high intratumor heterogeneity. Furthermore, the absence of targeted therapies, the understudied tumor immune microenvironment (TIME), and subtype plasticity are also responsible for therapy resistance. Secretory chemokines play a crucial role in immunomodulation by trafficking immune cells to the tumors. Chemokines and cytokines modulate the anti-tumor immune response and wield a pro-/anti-tumorigenic effect on SCLC cells after binding to cognate receptors. In this review, we summarize and highlight recent findings that establish the role of chemokines in SCLC growth and metastasis, and sophisticated intratumor heterogeneity. We also discuss the chemokine networks that are putative targets or modulators for augmenting the anti-tumor immune responses in targeted or chemo-/immuno-therapeutic strategies, and how these combinations may be utilized to conquer SCLC.