Cancer Cell最新文献

In this issue of Cancer Cell, McIntyre et al. show that specific mutations in the KRAS proto-oncogene shape clinical progression of pancreatic ductal adenocarcinoma (PDAC). Importantly, they find that the KRAS^G12R mutation is enriched in early-stage PDAC, and it is characterized by distinctly activated molecular programs.

Precision oncology endeavors to tailor therapies based on individual patient and tumor characteristics. This rapidly evolving field has transformed cancer treatment across all age groups. In this commentary, we review the application of precision oncology across different age groups, specifically in children, adolescents, and young adults, and emphasize that precision medicine is age and tissue agnostic.

Human tumors are intricate ecosystems composed of diverse genetic clones and malignant cell states that evolve in a complex tumor micro-environment. Single-cell RNA-sequencing (scRNA-seq) provides a compelling strategy to dissect this intricate biology and has enabled a revolution in our ability to understand tumor biology over the last ten years. Here we reflect on this first decade of scRNA-seq in human tumors and highlight some of the powerful insights gleaned from these studies. We first focus on computational approaches for robustly defining cancer cell states and their diversity and highlight some of the most common patterns of gene expression intra-tumor heterogeneity (eITH) observed across cancer types. We then discuss ambiguities in the field in defining and naming such eITH programs. Finally, we highlight critical developments that will facilitate future research and the broader implementation of these technologies in clinical settings.

Neoadjuvant chemoradiotherapy has been a mainstay of the treatment of locally advanced rectal cancer. Programmed cell death protein 1 (PD-1) blockade therapy has demonstrated efficacy in combination with radiation. In this issue, Xiao et al. demonstrate promising efficacy with the addition of PD-1 blockade to neoadjuvant therapy for mismatch-repair proficient rectal cancer.

KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRAS^G12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRAS^G12R tumors are associated with decreased distant recurrence and improved survival as compared to KRAS^G12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRAS^G12D and increased nuclear factor κB (NF-κB) signaling in KRAS^G12R tumors. Orthogonal studies of mouse Kras^G12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8⁺ T cells and exhausted CD8⁺ T cell (T_EX) clones. Focused analyses of T_EX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor T_EX, which synergizes with anti-PD-1 to reinvigorate T_EX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.

Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions in colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- and peri-tumor mature TLSs (TLS+) are associated with improved clinical outcomes than TLS− tumors. Using single-cell-RNA-sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we reveal that TLS+ tumors are enriched with IgG⁺ plasma cells (PCs), while TLS− tumors are characterized with IgA⁺ PCs. By generating TLS-associated PC-derived monoclonal antibodies in vitro, we show that TLS-PCs secrete tumor-targeting antibodies. As the proof-of-concept, we demonstrate the anti-tumor activities of TLS-PC-mAb6 antibody in humanized mouse model of colorectal cancer. We identify a fibroblast lineage secreting CCL19 that facilitates lymphocyte trafficking to TLSs. CCL19 treatment promotes TLS neogenesis and prevents tumor growth in mice. Our data uncover the central role of CCL19⁺ fibroblasts in TLS formation, which in turn generates therapeutic antibodies to restrict CRLM.

Changes in plasma and fecal metabolomes in colorectal cancer (CRC) progression (normal-adenoma-CRC) remain unclear. Here, plasma and fecal samples were collected from four independent cohorts of 1,251 individuals (422 CRC, 399 colorectal adenoma [CRA], and 430 normal controls [NC]). By metabolomic profiling, signature plasma and fecal metabolites with consistent shift across NC, CRA, and CRC are identified, including CRC-enriched oleic acid and CRC-depleted allocholic acid. Oleic acid exhibits pro-tumorigenic effects in CRC cells, patient-derived organoids, and two murine CRC models, whereas allocholic acid has opposing effects. By integrative analysis, we found that oleic acid or allocholic acid directly binds to α-enolase or farnesoid X receptor-1 in CRC cells, respectively, to modulate cancer-associated pathways. Clinically, we establish a panel of 17 plasma metabolites that accurately diagnoses CRC in a discovery and three validation cohorts (AUC = 0.848–0.987). Overall, we characterize metabolite signatures, mechanistic significance, and diagnostic potential of plasma and fecal metabolomes in CRC.