Cancer research最新文献

In most solid tumors, cellular energy metabolism is primarily dominated by aerobic glycolysis, which fulfills the high demand for biomacromolecules at the expense of reduced ATP production efficiency. Elucidation of the mechanisms by which rapidly proliferating malignant cells acquire sufficient energy in this state of inefficient ATP production from glycolysis could enable development of metabolism targeted therapeutic strategies. In this study, we observed a significant association between elevated expression levels of the long non-coding RNA (lncRNA) SNHG17 and unfavorable prognosis in breast cancer (BCa). SNHG17 promoted BCa cell proliferation by augmenting mitochondrial ATP production. Mechanistically, SNHG17 directly interacted with the p65 subunit of NF-κB and phosphorylated p65 at the threonine 505 site. SNHG17 bound to p65 at its truncated loop2 site, recruited p65 to mitochondria, and co-regulated the transcriptional activation of mitochondrial DNA to promote ATP production. Accordingly, targeting SNHG17 with an anti-sense oligonucleotide (ASO) significantly reduced BCa tumor growth both in vitro and in vivo. Overall, these results established a role for SNHG17 in promoting BCa progression by increasing ATP production and provided insight into the reprogramming of energy metabolism in solid tumors.

Immunotherapy has elicited significant improvements in outcomes for patients with several tumor types. However, the immunosuppressive microenvironment in glioblastoma restricts the therapeutic efficacy of immune checkpoint blockade (ICB). In this study, we investigated which components of the immune microenvironment contribute to ICB failure in glioblastoma to elucidate the underlying causes of immunotherapeutic resistance. Macrophages were identified as a main contributor to ICB resistance. Expression of ARPC1B, a regulatory subunit of the Arp2/3 complex, was elevated in glioblastoma and correlated with macrophage enrichment and prognosis. ARPC1B in tumor cells increased STAT1 expression and subsequent IL10 production, which induced a pro-tumorigenic macrophage state. Mechanistically, ARPC1B inhibited the ubiquitination and degradation of STAT1 by preventing the E3 ubiquitin ligase NEDD4L from binding to STAT1 and by supporting the interaction between STAT1 and the deubiquitinase USP7. Inhibiting ARPC1B reshaped the immunosuppressive microenvironment and increased the efficacy of ICB in glioblastoma models. This study highlights the important role of ARPC1B in macrophage-mediated immunosuppression and proposes a combination treatment regimen for glioblastoma immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on pre-clinical models driven by KrasG12D and mutant Trp53. Elucidation of the contribution of additional known oncogenic drivers, including KrasG12V mutation and Smad4 loss, is needed to increase understanding of malignant cell-stroma crosstalk in PDAC. Here, we used single-cell RNA-sequencing to analyze the cellular landscape of Trp53-mutant mouse models driven by KrasG12D or KrasG12V in which Smad4 was wild-type or deleted. KrasG12D Smad4-deleted PDAC developed a fibro-inflammatory rich stroma with increased malignant JAK/STAT cell signaling and enhanced therapeutic response to JAK/STAT inhibition. SMAD4 loss in KrasG12V PDAC differently altered the tumor microenvironment compared to KrasG12D PDAC, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype impacts cancer cell and stromal cell phenotypes in PDAC, directly affecting therapeutic efficacy.

Colorectal carcinoma (CRC) progression is associated with an increase in PROX1+ tumor cells, which exhibit features of CRC stem cells and contribute to metastasis. Here, we aimed to provide a better understanding to the function of PROX1+ cells in CRC, investigating their progeny and their role in therapy resistance. PROX1+ cells in intestinal adenomas of ApcMin/+ mice expressed intestinal epithelial and CRC stem cell markers, and cells with high PROX1 expression could both self-renew tumor stem/progenitor cells and contribute to differentiated tumor cells. Most PROX1-lineage traced tumor cells were stem/progenitor cells, which can supply cells to multiple intestinal tumor cell lineages, whereas most lineage-traced LGR5+ tumor cells were enterocytes, indicating that PROX1+ and LGR5+ tumor stem cells have distinct differentiation programs. Although the PROX1+ tumor cells proliferated slower than PROX1- cells, irradiation increased the proportion of PROX1+ cells in human CRC cell lines, patient-derived organoids, and tumor xenografts. Furthermore, transcripts related to DNA damage repair (DDR) were enriched in PROX1+ vs. PROX1- cells in adenomas and in CRC tumor cells from patients. Experiments with PROX1 silencing and overexpression indicated that PROX1 expression enhances CRC cell colony formation following irradiation. PROX1 interacted with DDR proteins, including components of non-homologous end-joining (NHEJ) and base excision repair, and inhibition of NHEJ repair led to a decreased proportion of PROX1+ cells following irradiation. In conclusion, PROX1+ cells are irradiation-resistant tumor stem/progenitor cells capable of self-renewal and differentiation. DDR inhibitors could represent a strategy to target the treatment-resistant PROX1+ tumor stem cells.

The batch effect is a nonbiological variation that arises from technical differences across different batches of data during the data generation process for acquisition-related reasons, such as collection of images at different sites or using different scanners. This phenomenon can affect the robustness and generalizability of computational pathology- or radiology-based cancer diagnostic models, especially in multicenter studies. To address this issue, we developed an open-source platform, Batch Effect Explorer (BEEx), that is designed to qualitatively and quantitatively determine whether batch effects exist among medical image datasets from different sites. A suite of tools was incorporated into BEEx that provide visualization and quantitative metrics based on intensity, gradient, and texture features to allow users to determine whether there are any image variables or combinations of variables that can distinguish datasets from different sites in an unsupervised manner. BEEx was designed to support various medical imaging techniques, including microscopy and radiology. Four use cases clearly demonstrated the ability of BEEx to identify batch effects and validated the effectiveness of rectification methods for batch effect reduction. Overall, BEEx is a scalable and versatile framework designed to read, process, and analyze a wide range of medical images to facilitate the identification and mitigation of batch effects, which can enhance the reliability and validity of image-based studies. Significance: BEEx is a prescreening tool for image-based analyses that allows researchers to evaluate batch effects in multicenter studies and determine their origin and magnitude to facilitate development of accurate AI-based cancer models.

Antibody-based therapies have emerged as a powerful strategy for the management of diverse cancers. Unfortunately, tumor-specific antigens remain challenging to identify and target. Recent work established that inhibitor-modified peptide adducts derived from KRAS G12C are competent for antigen presentation via MHC I and can be targeted by antibody-based therapeutics, offering a means to directly target an intracellular oncoprotein at the cell surface with combination therapies. Here, we validated the antigen display of "haptenated" KRAS G12C peptide fragments on tumors in mouse models treated with the FDA-approved KRAS G12C covalent inhibitor sotorasib using PET/CT imaging of an 89Zr-labeled P1B7 IgG antibody, which selectively binds sotorasib-modified KRAS G12C-MHC I complexes. Targeting this peptide-MHC I complex with radioligand therapy using 225Ac- or 177Lu-P1B7 IgG effectively inhibited tumor growth in combination with sotorasib. Elucidation of the 3.1 Å cryo-EM structure of P1B7 bound to a haptenated KRAS G12C peptide-MHC I complex confirmed that the sotorasib-modified KRAS G12C peptide is presented via a canonical binding pose and showed that P1B7 binds the complex in a T-cell receptor-like manner. Together, these findings demonstrate the potential value of targeting unique oncoprotein-derived, haptenated MHC I complexes with radioligand therapeutics and provide a structural framework for developing next generation antibodies. Significance: Radioligand therapy using an antibody targeting KRAS-derived, sotorasib-modified MHC I complexes elicits antitumor effects superior to those of sotorasib alone and provides a potential strategy to repurpose sotorasib as a hapten to overcome resistance.