Hybrid computational modeling highlights reverse warburg effect in breast cancer-associated fibroblasts

Abstract

Cancer-associated fibroblasts (CAFs) are amongst the key players of the tumor microenvironment (TME) and are involved in cancer initiation, progression, and resistance to therapy. They exhibit aggressive phenotypes affecting extracellular matrix remodeling, angiogenesis, immune system modulation, tumor growth, and proliferation. CAFs phenotypic changes appear to be associated with metabolic alterations, notably a reverse Warburg effect that may drive fibroblasts transformation. However, its precise molecular mechanisms and regulatory drivers are still under investigation. Deciphering the reverse Warburg effect in breast CAFs may contribute to a better understanding of the interplay between TME and tumor cells, leading to new treatment strategies. In this regard, dynamic modeling approaches able to span multiple biological layers are essential to capture the emergent properties of various biological entities when complex and intertwined pathways are involved. This work presents the first hybrid large-scale computational model for breast CAFs covering major cellular signaling, gene regulation, and metabolic processes. It was generated by combining a cell- and disease-specific asynchronous Boolean model with a generic core metabolic network leveraging both data-driven and manual curation approaches. This model reproduces the experimentally observed reverse Warburg effect in breast CAFs and further identifies Hypoxia-Inducible Factor 1 (HIF-1) as its key molecular driver. Targeting HIF-1 as part of a TME-centered therapeutic strategy may prove beneficial in the treatment of breast cancer by addressing the reverse Warburg effect. Such findings in CAFs, in light of our previously published results in rheumatoid arthritis synovial fibroblasts, point to a common HIF-1-driven metabolic reprogramming of fibroblasts in breast cancer and rheumatoid arthritis.

Keywords: Breast cancer; Cancer-associated fibroblasts; Hybrid modeling; Metabolic reprogramming.

Graphical abstract

Fig. 1

General architecture of the hybrid modeling framework.

Fig. 2

CellDesigner visualization of the (A) original CAF-map from ACSN and (B) CAF-map V2 with associated zoom-ins on glucose-related pathways. The CAF-map V2 depicts a standard-compliant formal representation and layout revision with a clear signal flow. Components are precisely attributed to biologically relevant compartments. Glucose pathways are compartmentalized and are no longer represented only as phenotypes but properly detailed. Up-to-date mechanistic information was further added.

Fig. 3

Visualization of major active metabolic pathways for maximal cellular ATP production in (A) control and (B) breast CAF-specific conditions according to Flux Balance Analysis.