Cancer research最新文献

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor survival rate. This is largely due to patients being diagnosed when the disease has already metastasized to other organs, most commonly the liver and lungs. For these patients, no effective treatment exists, and the 5-year survival rate is less than 5%. Despite its highly metastatic nature, the timing and mechanisms of metastasis formation in PDAC remain largely unknown. In this issue of Cancer Research, Lasse Opsahl and colleagues identify a role for premalignant pancreatic intraepithelial neoplasia (PanIN) lesions in lung premetastatic niche formation. By performing histology and single-cell RNA sequencing analyses of a KRASG12D inducible mouse model of PDAC, the authors identify pSTAT3+ fibroblasts in the lungs, but not the liver, upon PanIN formation. Notably, pSTAT3+ fibroblasts in the lungs are required for metastasis formation. Mechanistically, KRAS activation in the pancreatic epithelium and consequential IL6 release activate STAT3 in lung fibroblasts. Altogether, Lasse Opsahl and colleagues demonstrate that PanIN lesions prime the lungs to favor future malignant cell outgrowth before the development of a pancreatic tumor and that blocking the formation of this lung premetastatic niche impairs metastasis in mice. See related article by Lasse Opsahl et al., p. 22.

In cells, highly coordinated multivalent interactions give rise to discrete functional assemblies-commonly referred to as biomolecular condensates-that compartmentalize the molecular components required for specific biological reactions. These condensates are increasingly recognized as organizational entities with central roles in normal cellular regulation and in the pathogenesis of human cancers. In a recent issue of Cell, Datar and colleagues investigated the condensation of NPM1c, a common gene mutation in acute myeloid leukemias (AMLs). They demonstrated the necessity and sufficiency of NPM1c in forming nuclear condensates termed coordinating bodies (C-bodies), which show co-partitioning of a suite of transcriptional coactivators such as NUP98, KMT2A/MLL1, Menin and XPO1/CRM1. While C-bodies are necessary for driving NPM1c-mutant AMLs, blockade of the co-partitioned component within C-bodies, such as the XPO1/CRM1 or Menin interaction by inhibitors, significantly alters the condensate composition and functionality. Likewise, a systematic deletion study of various regions within NPM1c pointed to a role for the coordinated multivalent interaction in establishing the functional condensates, as previously reported in studies of the Wilms tumor-causing ENL mutants and AML-causing NUP98 onco-fusions. Co-mixing of C-bodies and condensates formed by the onco-fusion of NUP98 or KMT2A/MLL1 in cells suggested them to be biophysically indistinguishable, indicative of a shared pathogenic mechanism. Altogether, recent studies of multiple genetic drivers in human cancers have revealed a type of chromatin-bound multi-component onco-condensates, which shall motivate the development of onco-condensate disruptors that could potentially be used as the broad treatments for cancer.

Pediatric sarcomas present diagnostic challenges due to their rarity and diverse subtypes, often requiring specialized pathology expertise and costly genetic tests. To overcome these barriers, we developed a computational pipeline leveraging deep learning methods to accurately classify pediatric sarcoma subtypes from digitized histology slides. To ensure classifier generalizability and minimize center-specific artifacts, a dataset comprising 867 whole slide images (WSIs) from three medical centers and the Children's Oncology Group (COG) was collected and harmonized. Multiple convolutional neural network (CNN) and vision transformer (ViT) architectures were systematically evaluated as feature extractors for SAMPLER-based WSI representations, and input parameters, such as tile size combinations and resolutions, were tested and optimized. The analysis showed that advanced ViT foundation models (UNI, CONCH) significantly outperformed earlier approaches, and incorporating multiscale features enhanced classification accuracy. The optimized models achieved high performance, distinguishing rhabdomyosarcoma (RMS) from non-rhabdomyosarcoma (NRSTS) with an AUC of 0.969 and differentiating RMS subtypes (alveolar vs. embryonal) with an AUC of 0.961. Additionally, a two-stage pipeline effectively identified scarce Ewing sarcoma images from other NRSTS (AUC 0.929). Compared to conventional transformer encoder architectures used for WSI representations, these SAMPLER based classifiers were three orders of magnitude faster to train, despite operating entirely without a GPU. This study highlights that digital histopathology paired with rigorous image harmonization provides a powerful solution for pediatric sarcoma classification.

Nerves can regulate tumorigenesis and cancer progression. However, clarification of the role of axon guidance molecules in tumorigenesis, innervation, and metastasis is required to better understand the tumor-promoting functions of nerves. Using murine KrasG12D-mutant pancreatic organoids, we screened axon guidance molecules and identified netrin-1 upregulation. Netrin-1 was also upregulated in vivo during pancreatic tumorigenesis in humans and mice. Mutant KRAS and β-adrenergic signaling upregulated netrin-1 and its receptor NEO1 in epithelial cells in part through the MAPK pathway. Ex vivo culture of celiac ganglia showed that netrin-1 promoted the axonogenesis of sympathetic neurons through nerve NEO1. In the Pdx1-Cre;LSL-KrasG12D/+ model, knockout of Ntn1, which encodes netrin-1, decreased sympathetic innervation and the development of pancreatic intraepithelial neoplasia. Treatment of pancreatic tumor organoids with recombinant netrin-1 enhanced cell growth, epithelial-mesenchymal transition (EMT), and cancer stemness with the upregulation of ZEB1 and SOX9 through NEO1-mediated activation of focal adhesion kinase (FAK). In Pdx1-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+ mice, Ntn1 knockout reduced innervation, FAK phosphorylation, and the features of EMT and stemness to extend mouse survival. In a liver metastasis model of pancreatic ductal adenocarcinoma (PDAC), treatment with a netrin-1-neutralizing antibody or tumoral knockout of Neo1 reduced ZEB1 and SOX9 and decreased tumor progression. In contrast, netrin-1 overexpression promoted innervation and the progression of PDAC liver metastasis. These data suggest that the netrin-1/NEO1 axis is a key regulator of PDAC progression, directly influencing cancer cell stemness and EMT, while indirectly promoting tumor growth through nerves. Inhibiting the netrin-1 pathway could represent a potential therapeutic approach for PDAC.

Basal cell carcinoma (BCC), the most common human cancer, is driven by hyperactivation of the Hedgehog pathway mediated by Smoothened (SMO) signaling and GLI transcription. Gαs and protein kinase A (PKA) negatively regulate Hedgehog signaling, offering a potential alternative BCC development and treatment pathway. Here, using histology alongside bulk and single-cell RNA sequencing, we found that mouse BCC-like tumors that originate from Gαs pathway inactivation are highly similar to those driven by canonical Hedgehog signaling induced by constitutive SMO activation. Both pathways led to expansion of basal stem cells in the skin, with tumor cells clustering in two distinct populations with markers for touch-dome and isthmus stem cell-like cells. Interestingly, mutations that reduce Gαs and PKA activity were present in human BCC. Tumors from Gαs pathway inactivation were independent of the canonical Hedgehog regulators SMO and GPR161, establishing them as SMO-independent oncogenic Hedgehog signaling models. Finally, activation of the Gαs-coupled adenosine 2B receptor with BAY60-6583 counteracted oncogenic SMO, reducing Hedgehog signaling and tumor growth. Together, these findings offer a potential therapeutic strategy for BCC.