A modular master regulator landscape controls cancer transcriptional identity

Paull, Evan O.; Aytés, Álvaro; Jones, Sunny J.; Subramaniam, Prem S.; Giorgi, Federico M.; Douglass, Eugene F.; Tagore, Somnath; Chu, Brennan; Vasciaveo, Alessandro; Zheng, Siyuan; Verhaak, Roel G.W.; Abate‐Shen, Cory; Alvarez, Mariano J.; Califano, Andrea

doi:10.1016/j.cell.2020.11.045

Cited by 103 publications

(138 citation statements)

References 83 publications

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“…As illustrated here for one case of prostate cancer, and in previous papers on cases of papillary thyroid cancer [ 46 , 92 ] and clear cell renal cell carcinoma [ 35 , 93 ], GFP offers a comprehensive personalized alternative to the biomarkers approach to determine the cancer transcriptional identity (e.g., [ 112 ]) and explore gene therapy.…”

Section: Discussionmentioning

confidence: 96%

A Personalized Genomics Approach of the Prostate Cancer

Iacobaş

2021

Cells

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Decades of research identified genomic similarities among prostate cancer patients and proposed general solutions for diagnostic and treatments. However, each human is a dynamic unique with never repeatable transcriptomic topology and no gene therapy is good for everybody. Therefore, we propose the Genomic Fabric Paradigm (GFP) as a personalized alternative to the biomarkers approach. Here, GFP is applied to three (one primary—“A”, and two secondary—“B” & “C”) cancer nodules and the surrounding normal tissue (“N”) from a surgically removed prostate tumor. GFP proved for the first time that, in addition to the expression levels, cancer alters also the cellular control of the gene expression fluctuations and remodels their networking. Substantial differences among the profiled regions were found in the pathways of P53-signaling, apoptosis, prostate cancer, block of differentiation, evading apoptosis, immortality, insensitivity to anti-growth signals, proliferation, resistance to chemotherapy, and sustained angiogenesis. ENTPD2, AP5M1 BAIAP2L1, and TOR1A were identified as the master regulators of the “A”, “B”, “C”, and “N” regions, and potential consequences of ENTPD2 manipulation were analyzed. The study shows that GFP can fully characterize the transcriptomic complexity of a heterogeneous prostate tumor and identify the most influential genes in each cancer nodule.

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Section: Discussionmentioning

confidence: 96%

A Personalized Genomics Approach of the Prostate Cancer

Iacobaş

2021

Cells

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“…1a). In cancer, we have shown that highly coordinated modules comprising between 10 and 50 proteins are necessary to control the state of a malignant cell(10, 19). We thus expect that an equally compact set of MR proteins would regulate the state of the host cells following SARS-CoV-2 infection and that a subset of these proteins would be responsible for implementing and sustaining cellular mechanisms critical for viral hijacking and replication.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that tumor check-points can be pharmacologically switched, either off(11, 15, 20, 55, 56) or on(19), leading to their collapse and loss of viability or gain of associated functional properties, respectively. This observation was instrumental for the development and validation of the NY CLIA certified, VIPER-based methodology OncoTreat, for the prioritization of small molecule compounds that can either inactivate or activate a tumor checkpoint on a sample-by-sample basis, with critical applications in precision oncology(11).…”

Section: Methodsmentioning

confidence: 99%

“…We have shown that VIPER can accurately measure the activity of >70% of regulatory proteins, including in single cells, where we have shown that metaVIPER(16)—a VIPER extension specifically designed for single-cell analyses—can virtually eliminate the gene dropout issue due to low single cell profiling depth(17, 18) and outperform antibody based measurements(17). Both algorithms have been highly effective in elucidating protein-based mechanisms that were virtually undetectable by gene expression-based methods alone(10, 17, 19, 20) (see methods for additional details). Once MR proteins are identified by VIPER analysis, we have shown that the Clinical Laboratory Improvement Amendments (CLIA)-certified On-coTreat algorithm(11) can accurately and efficiently identify small molecule inhibitors that can invert their activity thus collapsing the regulatory programs they control.…”

Section: Introductionmentioning

confidence: 99%

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Network-based identification and pharmacological targeting of host cell master regulators induced by SARS-CoV-2 infection

Laise

Stanifer

Bosker

et al. 2021

Preprint

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Precise characterization and targeting of host cell transcriptional machinery hijacked by SARS-CoV-2 remains challenging. To identify therapeutically targetable mechanisms that are critical for SARS-CoV-2 infection, here we elucidated the Master Regulator (MR) proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2. The analysis revealed coordinated inactivation of MR-proteins linked to regulatory programs potentiating efficiency of viral replication (detrimental host MR-signature) and activation of MR-proteins governing innate immune response programs (beneficial MR-signature). To identify MR-inverting compounds capable of rescuing activity of inactivated host MR-proteins, without adversely affecting the beneficial MR-signature, we developed the ViroTreat algorithm. Overall, >80% of drugs predicted to be effective by this methodology induced significant reduction of SARS-CoV-2 infection, without affecting cell viability. ViroTreat is fully generalizable and can be extended to identify drugs targeting the host cell-based MR signatures induced by virtually any pathogen.

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“…Colorectal adenocarcinoma (COAD) was selected as a relevant tumor context because of lack of effective therapy and recent elucidation of Master Regulator proteins defining 8 molecularly distinct subtypes, including 3 subtypes highly enriched in MSI-high tumors and an aggressive, genomically-stable subtype characterized by very poor outcome (Paull, Aytes et al 2021). Thus, we expected that a high-quality experimentally dissected GRN would be a first step towards the elucidation of critical COAD tumorigenesis and progression mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Interrogation of genome-wide, experimentally dissected gene regulatory networks reveals mechanisms underlying dynamic cellular state control

Tan

Worley

Turunen

et al. 2021

Preprint

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Pooled CRISPRi-mediated silencing of >1,000 transcriptional regulators expressed in single colorectal adenocarcinoma cells, followed by single-cell RNA-seq profiling at two time points, 1D and 4D, allowed reverse engineering the underlying tumor context-specific, causal regulatory network. Furthermore, the availability of experimentally derived, highly multiplexed gene reporter assays for each regulator, as identified by this analysis, allowed accurate assessment of differential protein activity following silencing of each regulator, thus providing proof-of-concept for generating comprehensive, tissue-specific networks of transcriptional and post-translational interactions. Analysis of this causal network allowed elucidation of complex autoregulatory mechanisms that have eluded previous computational approaches and supported systematic elucidation of cooperative mechanisms, where one regulatory protein can modulate the activity of another regulatory protein, as well as transcriptional mimicry, where one regulatory protein can phenocopy others.

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A modular master regulator landscape controls cancer transcriptional identity

Cited by 103 publications

References 83 publications

A Personalized Genomics Approach of the Prostate Cancer

A Personalized Genomics Approach of the Prostate Cancer

Network-based identification and pharmacological targeting of host cell master regulators induced by SARS-CoV-2 infection

Interrogation of genome-wide, experimentally dissected gene regulatory networks reveals mechanisms underlying dynamic cellular state control

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