Ras-p53 genomic cooperativity as a model to investigate mechanisms of innate immune regulation in gastrointestinal cancers
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Austin R. Dosch1,2, Walid K. Chatila3, Yuguang Ban4, Anna Bianchi1, Nilesh U. Deshpande1, Iago De Castro Silva1, Nipun B. Merchant1,2 and Jashodeep Datta1,2
1 Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
2 Sylvester Comprehensive Cancer Center, Miami, FL, USA
3 Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
4 Department of Public Health Sciences; University of Miami Miller School of Medicine, Miami, FL, USA
|Jashodeep Datta,||email:||[email protected]|
Keywords: Ras-p53 cooperativity; Ras; TP53; immune; gastrointestinal cancer
Received: May 20, 2021 Accepted: May 26, 2021 Published: September 28, 2021
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.
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