BICC1 drives pancreatic cancer stemness and chemoresistance by facilitating tryptophan metabolism.

Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells. However, the mechanisms sustaining stemness and chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we demonstrate that Bicaudal C homolog 1 (BICC1), an RNA binding protein regulating numerous cytoplasmic mRNAs, facilitates chemoresistance and stemness in PDAC. Mechanistically, BICC1 activated tryptophan catabolism in PDAC by up-regulating indoleamine 2,3-dioxygenase-1 (IDO1) expression, a tryptophan-catabolizing enzyme. Increased levels of tryptophan metabolites contribute to NAD+ synthesis and oxidative phosphorylation, leading to a stem cell-like phenotype. Blocking BICC1/IDO1/tryptophan metabolism signaling greatly improves the gemcitabine (GEM) efficacy in several PDAC models with high BICC1 level. These findings indicate that BICC1 is a critical tryptophan metabolism regulator that drives the stemness and chemoresistance of PDAC and thus a potential target for combinatorial therapeutic strategy against chemoresistance.

CD73/NT5E is a Potential Biomarker for Cancer Prognosis and Immunotherapy for Multiple Types of Cancers.

Cluster of Differentiations 73 (CD73)/ecto-5'-nucleotidase (NT5E) is a novel type of immune molecular marker expressed on many tumor cells and involved in regulating the essential immune functions and affecting the prognosis of cancer patients. However, it is not clear how the NT5E is linked to the infiltration levels of the immune cells in pan-cancer patients and their final prognosis. This study explores the role of NT5E in 33 tumor types using GEPIA, TIMER, Oncomine, BioGPS databases, and several bioinformatic tools. The findings reveal that the NT5E is abnormally expressed in a majority of the types of cancers and can be used for determining the prognosis prediction ability of different cancers. Moreover, NT5E is significantly related to the infiltration status of numerous immune cells, immune-activated pathways, and immunoregulator expressions. Last, specific inhibitor molecules, like NORNICOTINE, AS-703026, and FOSTAMATINIB, which inhibit the expression of NT5E in various types of cancers, are screened with the CMap. Thus, it is proposed that NT5E can be utilized as a potential biomarker for predicting the prognosis of cancer patients and determining the infiltration of various immune cells in different types of cancers.

CD73, a Promising Therapeutic Target of Diclofenac, Promotes Metastasis of Pancreatic Cancer through a Nucleotidase Independent Mechanism.

CD73, a cell surface-bound nucleotidase, facilitates extracellular adenosine formation by hydrolyzing 5'-AMP to adenosine. Several studies have shown that CD73 plays an essential role in immune escape, cell proliferation and tumor angiogenesis, making it an attractive target for cancer therapies. However, there are limited clinical benefits associated with the mainstream enzymatic inhibitors of CD73, suggesting that the mechanism underlying the role of CD73 in tumor progression is more complex than anticipated, and further investigation is necessary. In this study, CD73 is found to overexpress in the cytoplasm of pancreatic ductal adenocarcinoma (PDAC) cells and promotes metastasis in a nucleotidase-independent manner, which cannot be restrained by the CD73 monoclonal antibodies or small-molecule enzymatic inhibitors. Furthermore, CD73 promotes the metastasis of PDAC by binding to the E3 ligase TRIM21, competing with the Snail for its binding site. Additionally, a CD73 transcriptional inhibitor, diclofenac, a non-steroidal anti-inflammatory drug, is more effective than the CD73 blocking antibody for the treatment of PDAC metastasis. Diclofenac also enhances the therapeutic efficacy of gemcitabine in the spontaneous KPC (LSL-KrasG12D/+ , LSL-Trp53R172H/+ , and Pdx-1-Cre) pancreatic cancer model. Therefore, diclofenac may be an effective anti-CD73 therapy, when used alone or in combination with gemcitabine-based chemotherapy regimen, for metastatic PDAC.

Genome-wide CRISPR screen identifies MTA3 as an inducer of gemcitabine resistance in pancreatic ductal adenocarcinoma.

Gemcitabine (GEM) resistance is one of the major causes of treatment failure in pancreatic ductal adenocarcinoma (PDAC) in clinic. Here, through CRISPR/Cas9 activation library screen, we found that MTA3 mediates the GEM resistance of PDAC and thus might be a potential therapeutic target for combination chemotherapy. The CRISPR library screening showed that MTA3 is the most enriched gene in the surviving GEM-treated cells, and bioinformatic and histology analysis implied its high correlation with GEM resistance. MTA3 promoted GEM resistance of PDAC cells in in vitro and in vivo experiments. Mechanistically, as a component of the Mi-2/nucleosome remodeling and deacetylase transcriptional repression complex, MTA3 transcriptionally represses CRIP2, a transcriptional repressor of NF-κB/p65, activating NF-κB signaling and consequently leading to GEM resistance. Furthermore, the treatment of GEM increases MTA3 expression in PDAC cells via activating STAT3 signaling, thereby inducing the acquired chemoresistance of PDAC to GEM. In patients derived xenografts (PDX) mouse model, Colchicine suppresses the expression of MTA3 and increases the sensitivity of tumor cells to GEM. Based on these findings, MTA3 plays a key role in GEM resistance in pancreatic cancer and is a promising therapeutic target for reversing GEM chemotherapy resistance.