Research Perspectives:

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 and Jashodeep Datta _

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Oncotarget. 2021; 12:2104-2110. https://doi.org/10.18632/oncotarget.27983

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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

Correspondence to:

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

Copyright: © 2021 Dosch et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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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