Ras-p53 genomic cooperativity as a model to investigate mechanisms of innate immune regulation in gastrointestinal cancers

Austin R. Dosch, Walid K. Chatila, Yuguang Ban, Anna Bianchi, Nilesh U. Deshpande, Iago de Castro Silva, Nipun B. Merchant, Jashodeep Datta

Research output: Contribution to journalReview articlepeer-review

Abstract

Despite increasingly thorough mechanistic understanding of the dominant genetic drivers of gastrointestinal (GI) tumorigenesis (e.g., Ras/Raf, TP53, etc.), only a small proportion of these molecular alterations are therapeutically actionable. In an attempt to address this therapeutic impasse, our group has proposed an innovative extreme outlier model to identify novel cooperative molecular vulnerabilities in high-risk GI cancers which dictate prognosis, correlate with distinct patterns of metastasis, and define therapeutic sensitivity or resistance. Our model also proposes comprehensive investigation of their downstream transcriptomic, immunomic, metabolic, or upstream epigenomic cellular consequences to reveal novel therapeutic targets in previously “undruggable” tumors with high-risk genomic features. Leveraging this methodology, our and others’ data reveal that the genomic cooperativity between Ras and p53 alterations is not only prognostically relevant in GI malignancy, but may also represent the incipient molecular events that initiate and sustain innate immunoregulatory signaling networks within the GI tumor microenvironment, driving T-cell exclusion and therapeutic resistance in these cancers. As such, deciphering the unique transcriptional programs encoded by Ras-p53 cooperativity that promote innate immune trafficking and chronic inflammatory tumor-stromal-immune crosstalk may uncover immunologic vulnerabilities that could be exploited to develop novel therapeutic strategies for these difficult-to-treat malignancies.

Original languageEnglish (US)
Pages (from-to)2104-2110
Number of pages7
JournalOncotarget
Volume12
Issue number20
DOIs
StatePublished - Sep 28 2021

Keywords

  • Gastrointestinal cancer
  • Immune
  • Ras
  • Ras-p53 cooperativity
  • TP53

ASJC Scopus subject areas

  • Oncology

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