Cancer discovery最新文献

We performed whole exome sequencing of 250 unique tumor tissues from 30 multi-region sampled pancreatic cancer research autopsies from patients diagnosed with advanced-stage disease. Convergent evolution within the TGF-β pathway is a common feature of advanced-stage disease. However, SMAD4 inactivation is more common among de novo metastatic PDACs, whereas inactivation of TGF-β surface receptors is more common among locally advanced non-metastatic cancers. These differences in metastatic propensity were orthogonally validated in mice by orthotopic injections of PDAC organoids with SMAD4 versus TGFBR2 inactivation. No functionally deleterious driver gene mutations were identified that were attributed to treatment, although radiated PDACs had significantly greater genomic complexity and distinct mutational signatures compared to PDACs managed by chemotherapy. These findings provide a high-level profile of the genetic features distinguishing locally advanced from metastatic PDAC, potentially serving as a biomarker of borderline resectable or locally advanced PDACs most likely to benefit from neoadjuvant chemoradiation.

Pancreatic ductal adenocarcinoma (PDAC) co-opts the peripheral nervous system through nerve hypertrophy, axonogenesis and perineural invasion, and these processes correlate with patient morbidity and mortality. Prior work has shown that autonomic nerves directly modulate neoplastic cells in PDAC, but whether cancer-associated fibroblasts (CAFs) participate in neural remodeling is unknown. Using thick tissue sections, we identified dense neo-innervation near myofibroblastic CAFs (myCAFs) in preinvasive Pancreatic Intraepithelial Neoplasms (PanINs). Mechanistically, TGF-β produced during inflammation and neoplasia triggers myofibroblast formation, and myCAFs produce axon guidance molecules that recruit sympathetic nerves. Norepinephrine released by sympathetic nerves activates myofibroblast cultures in vitro, and sympathetic nerve depletion impairs stromal activation and PDAC growth in vivo. A chemogenetic model confirmed that fibroblast-specific α1-adrenergic signaling exacerbated pancreatic inflammation and neoplasia. Therefore, beyond direct epithelial effects, sympathetic nerves promote pancreatitis and PDAC by co-opting myofibroblasts and myCAFs as disease amplifiers, highlighting CAF subtype-specific stromal interactions as putative therapeutic targets.

The tumor microenvironment in high-grade serous ovarian carcinoma (HGSC) is a complex network of malignant-host cell interactions, yet its orchestration remains poorly understood. We present a single-cell spatial atlas of metastatic HGSC from 280 patients, integrating high-dimensional imaging and molecular profiling. Analyzing 929 single-cell maps, we identify spatial domains with diverse cell compositions and show that immune cell co-infiltration at the tumor-stroma interface impacts clinical outcomes. Using CEFIIRA, we find that tumor cell MHCII expression is a key predictor of prolonged survival. Validation with deconvoluted, single-cell, and two distinct spatial transcriptomic datasets, along with immunopeptidomic analysis, confirms that MHCII expression correlates with immune activation, antigen presentation, and TCR clonality. Using a patient-derived immuno-oncology platform, we demonstrate that tumor MHCII expression associates with increased CD8+ T cell cytotoxicity after PD-1 blockade, while blocking MHCII inhibits this activation. Our atlas offers new insights into immune activation, potentially improving patient stratification in HGSC.

Earnshaw and colleagues discover a tumor-intrinsic mechanism driven by glucocorticoid receptor (GR) activation, in which GR downregulates glycoprotein A repetitions predominant (GARP), thereby inhibiting TGFβ signaling and releasing CD8+ T cells to exert their antitumor activity. This mechanistic insight significantly advances our understanding of how GR shapes tumor immunity and highlights new avenues for overcoming immune checkpoint blockade resistance in melanoma and other cancers. See related article by Earnshaw et al., p. 345.

In this issue of Cancer Discovery, Chen and colleagues demonstrate that, in preclinical models, HER2 expression level directly affects trastuzumab deruxtecan internalization and cytotoxicity, with clinical data revealing divergent target dynamics depending on whether HER2 functions as an oncogenic driver or a dispensable antigen. Together with prior preclinical and clinical evidence, these findings support a context-dependent model in which target downregulation predominates in HER2-low disease, whereas payload resistance or rare binding-site mutations may dominate resistance in HER2-addicted tumors, with important implications for antibody-drug conjugate selection and sequencing. See related article by Chen et al., p. 235.

Gut microbiota has emerged as a determinant of cancer therapy efficacy, shaping immune responses both systemically and locally within the tumor microenvironment. In this piece, we discuss current insights into the mechanistic basis of these interactions, with a focus on type I interferon as a central mediator of microbiota-driven immune modulation.

Aneuploidy is prevalent across human cancers, yet its specific contributions to tumor evolution remain poorly understood. In this issue, Cross, Nowinski, Cresswell, Mossner, and colleagues present a longitudinal analysis of 755 samples from 167 patients with colorectal cancer, uncovering the temporal dynamics of karyotype evolution in this tumor type. See related article by Cross et al., p. 218.

Centonze and colleagues demonstrate that KRASG12D inhibition in metastatic colorectal cancer triggers rapid transcriptional reprogramming from a metastasis-associated EMP1+ state to a WNT-driven LGR5+ stem cell-like state, a plastic adaptation captured through real-time live cell imaging, revealing cell state conversion as a mechanism of therapeutic resistance that can be exploited through combinatorial targeting. See related article by Centonze et al., p. 320.