CXCL3/TGF-ß-mediated crosstalk between CAFs and tumor cells augments RCC progression and sunitinib resistance.

Cancer-associated fibroblasts (CAFs) play a significant role in tumor development and treatment failure, yet the precise mechanisms underlying their contribution to renal cell carcinoma (RCC) remains underexplored. This study explored the interaction between CAFs and tumor cells, and related mechanisms. CAFs isolated from tumor tissues promoted the tumor progression and drugs resistance both in vivo and in vitro. Mechanistically, chemokine (C-X-C motif) ligand (CXCL) 3 secreted from CAFs mediated its effects. CXCL3 activated its receptor CXCR2 to active the downstream ERK1/2 signaling pathway, subsequently promoting epithelial-mesenchymal transition and cell stemness. Blocking the crosstalk between CAFs and tumor cells by CXCR2 inhibitor SB225002 attenuated the functions of CAFs. Furthermore, Renca cells facilitated the transformation of normal interstitial fibroblasts (NFs) into CAFs and the expression of CXCL3 through TGF-ß-Smad2/3 signaling pathway. In turn, transformed NFs promoted the tumor progression and drug resistance of RCC. These findings may constitute potential therapeutic strategies for RCC treatment.

IL-23 inhibitor enhances the effects of PTEN DNA-loaded lipid nanoparticles for metastatic CRPC therapy.

Introduction: Metastatic castration-resistant prostate cancer (mCRPC) patients face challenges due to limited treatment options. About 50% of patients with mCRPC have a functional loss of phosphatase and tensin homology deleted on chromosome 10 (PTEN), leading to tumor progression, metastasis, and immune suppression. Moreover, elevated IL-23 produced by myeloid-derived suppressor cells (MDSCs) is found in CRPC patients, driving tumor progression. Therefore, a combination strategy based on PTEN restoration and IL-23 inhibition may block CRPC progression and metastasis. Methods: The antitumor effect of restoring PTEN expression combined with the IL-23 inhibitor Apilimod was studied in a mouse model of bone metastasis CRPC and mouse prostate cancer RM-1 cells. To verify the targeting ability of PTEN DNA coated with lipid nanoparticles (LNP@PTEN) in vitro and in vivo. In addition, RT-qPCR and flow cytometry were used to investigate the related mechanisms of the antitumor effect of LNP@PTEN combined with Apilimod. Results: LNPs exhibited significant tumor-targeting and tumor accumulation capabilities both in vitro and in vivo, enhancing PTEN expression and therapeutic efficacy. Additionally, the combination of LNP@PTEN with the IL-23 inhibitor Apilimod demonstrated enhanced inhibition of tumor growth, invasion, and metastasis (particularly secondary organ metastasis) compared to other groups, and extended the survival of mice to 41 days, providing a degree of bone protection. These effects may be attributed to the PTEN function restoration combined with IL-23 inhibition, which help reverse immune suppression in the tumor microenvironment by reducing MDSCs recruitment and increasing the CD8+/CD4+ T cell ratio. Discussion: In summary, these findings highlight the potential of LNPs for delivering gene therapeutic agents. And the combination of LNP@PTEN with Apilimod could achieve anti-tumor effects and improve tumor microenvironment. This combinational strategy opens new avenues for the treatment of mCRPC.

MiR26a reverses enzalutamide resistance in a bone-tumor targeted system with an enhanced effect on bone metastatic CRPC.

Resistance to androgen receptor (AR) inhibitors, including enzalutamide (Enz), as well as bone metastasis, are major challenges for castration-resistant prostate cancer (CRPC) treatment. In this study, we identified that miR26a can restore Enz sensitivity and inhibit bone metastatic CRPC. To achieve the highest combination effect of miR26a and Enz, we developed a cancer-targeted nano-system (Bm@PT/Enz-miR26a) using bone marrow mesenchymal stem cell (BMSC) membrane and T140 peptide to co-deliver Enz and miR26a. The in vitro/in vivo results demonstrated that miR26a can reverse Enz resistance and synergistically shrink tumor growth, invasion, and metastasis (especially secondary metastasis) in both subcutaneous and bone metastatic CRPC mouse models. We also found that the EZH2/SFRP1/WNT5A axis may be involved in this role. These findings open new avenues for treating bone metastatic and Enz-resistant CRPC.

Mechanisms of sunitinib resistance in renal cell carcinoma and associated opportunities for therapeutics.

Sunitinib is the first-line drug for renal cell carcinoma (RCC) treatment. However, patients who received sunitinib treatment will ultimately develop drug resistance after 6-15 months, creating a huge obstacle to the current treatment of renal cell carcinoma. Therefore, it is urgent to clarify the mechanisms of sunitinib resistance and develop new strategies to overcome it. In this review, the mechanisms of sunitinib resistance in renal cell carcinoma have been summarized based on five topics: activation of bypass or alternative pathway, inadequate drug accumulation, tumour microenvironment, metabolic reprogramming and epigenetic regulation. Furthermore, present and potential biomarkers, as well as potential treatment strategies for overcoming sunitinib resistance in renal cell carcinoma, are also covered.

Harnessing the native type I-B CRISPR-Cas for genome editing in a polyploid archaeon.

Research on CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR associated protein) systems has led to the revolutionary CRISPR/Cas9 genome editing technique. However, for most archaea and half of bacteria, exploitation of their native CRISPR-Cas machineries may be more straightforward and convenient. In this study, we harnessed the native type I-B CRISPR-Cas system for precise genome editing in the polyploid haloarchaeon Haloarcula hispanica. After testing different designs, the editing tool was optimized to be a single plasmid that carries both the self-targeting mini-CRISPR and a 600-800 bp donor. Significantly, chromosomal modifications, such as gene deletion, gene tagging or single nucleotide substitution, were precisely introduced into the vast majority of the transformants. Moreover, we showed that simultaneous editing of two genomic loci could also be readily achieved by one step. In summary, our data demonstrate that the haloarchaeal CRISPR-Cas system can be harnessed for genome editing in this polyploid archaeon, and highlight the convenience and efficiency of the native CRISPR-based genome editing strategy.