期刊
ONCOGENE
卷 41, 期 28, 页码 3640-3654出版社
SPRINGERNATURE
DOI: 10.1038/s41388-022-02368-w
关键词
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资金
- Miami CTSI under NIH Award [UL1TR002736]
- Stanley Glaser Foundation
- American College of Surgeons Franklin Martin Career Development Award
- Association for Academic Surgery Joel J. Roslyn Faculty Award
- NIH [R01 CA161976]
- NCI/NIH Award [P30CA240139]
Co-occurrent KRAS and TP53 mutations are common in patients with pancreatic ductal adenocarcinoma (PDAC) and are associated with worse survival. These mutations lead to innate immune enrichment and CD8(+) T-cell exclusion, as well as affecting transcriptomes and cell migration in the tumor microenvironment. These molecular characteristics can predict chemoresistance and overall survival in patients with metastatic PDAC.
Co-occurrent KRAS and TP53 mutations define a majority of patients with pancreatic ductal adenocarcinoma (PDAC) and define its pro-metastatic proclivity. Here, we demonstrate that KRAS-TP53 co-alteration is associated with worse survival compared with either KRAS-alone or TP53-alone altered PDAC in 245 patients with metastatic disease treated at a tertiary referral cancer center, and validate this observation in two independent molecularly annotated datasets. Compared with non-TP53 mutated KRAS-altered tumors, KRAS-TP53 co-alteration engenders disproportionately innate immune-enriched and CD8(+) T-cell-excluded immune signatures. Leveraging in silico, in vitro, and in vivo models of human and murine PDAC, we discover a novel intersection between KRAS-TP53 co-altered transcriptomes, TP63-defined squamous trans-differentiation, and myeloid-cell migration into the tumor microenvironment. Comparison of single-cell transcriptomes between KRAS-TP53 co-altered and KRAS-altered/TP53(WT) tumors revealed cancer cell-autonomous transcriptional programs that orchestrate innate immune trafficking and function. Moreover, we uncover granulocyte-derived inflammasome activation and TNF signaling as putative paracrine mediators of innate immunoregulatory transcriptional programs in KRAS-TP53 co-altered PDAC. Immune subtyping of KRAS-TP53 co-altered PDAC reveals conflation of intratumor heterogeneity with progenitor-like stemness properties. Coalescing these distinct molecular characteristics into a KRAS-TP53 co-altered immunoregulatory program predicts chemoresistance in metastatic PDAC patients enrolled in the COMPASS trial, as well as worse overall survival.
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