Version:1.0.0
Introduction
InFlo is a novel systems biology approach for characterizing the activities of complex signaling networks using a unique multidimensional framework integrating transcriptomic, genomic and/or epigenomic profiles for any given biological sample.
Salient features and merits of InFlo methodology
- InFlo integrates diverse sources of molecular profiles and robustly characterizes tissue-specific differences in activities of signaling networks on a genome scale using unique probabilistic models of molecular interactions on a per-sample basis.
- A unique feature of InFlo is that it specifically accounts for potential inconsistencies between curated signaling network definitions and the wiring of the pathway in the specific tissue context
- We pressure-tested InFlo’s robustness in identifying pathways discriminative of cancer phenotypes by using gene expression and copy-number profiles of over 300 TCGA breast cancer samples, with InFlo consistently exhibiting higher sensitivity and specificity when compared to other pathway modeling approaches.
- Using multi-omics molecular profiles of over 350 high-grade serous ovarian cancer samples from the TCGA, InFlo uniquely revealed, for the first time, that activation of the cAMP-CREB1 axis is significantly associated with (P ≤ 0.001) resistance to platinum-based therapy. The role of cAMP activity in driving platinum-resistance was experimentally validated in vitro using a small molecule inhibitor of CREB1 phosphorylation that sensitized platinum- resistant primary HGSOC cells.
- Taken together, our findings strongly support InFlo as a robust systems biology approach for integrative analysis of multi-omics data to characterize complex biological signaling network activities in any given biological sample.
We expect InFlo to be widely applicable to reliably delineate key molecular determinants of disease progression, thus enabling the discovery of evidence-based biomarkers and therapeutic targets, as well as for facilitating selection of tailored therapies in individual patients.
Reference
InFlo: a novel systems biology framework identifies cAMP-CREB1 axis as a key modulator of platinum resistance in ovarian cancer
N Dimitrova(1), A B Nagaraj(2), A Razi(2), S Singh(2), S Kamalakaran(1), N Banerjee(1), P Joseph(2), A Mankovich(1), P Mittal(3,4), A DiFeo(2,4) and V Varadan(2,4)
Oncogene advance online publication 7 November 2016;doi: 10.1038/onc.2016.398