克拉斯
生物
癌症研究
先天免疫系统
癌症
转录组
胰腺癌
肿瘤微环境
髓样
免疫系统
免疫学
结直肠癌
遗传学
基因
基因表达
作者
Jashodeep Datta,Anna Bianchi,Iago De Castro Silva,Nilesh Deshpande,Long Long Cao,Siddharth Mehra,Samara Singh,Christine I. Rafie,Xiaodian Sun,Xi Chen,Xizi Dai,Antonio Colaprico,Prateek Sharma,Austin R. Dosch,Asha Pillai,Peter J. Hosein,Nagaraj S. Nagathihalli,Krishna V. Komanduri,Julie M. Wilson,Yuguang Ban,Nipun B. Merchant
出处
期刊:Oncogene
[Springer Nature]
日期:2022-06-14
卷期号:41 (28): 3640-3654
被引量:16
标识
DOI:10.1038/s41388-022-02368-w
摘要
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/TP53WT 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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