- Understanding The Effect Of Mitochondrial Complex I Deficiency In Cancer Cells And Their Microenvironment
- Umesh Ganesh, Nikkitha <1993>
Subject
- MED/03 Genetica medica
Description
- Targeting metabolism has become a valid anticancer strategy to pursue. Among others, respiratory complex-I (CI) has been identified as a valid target. In this context, a genetic ablation of mitochondrial CI enzyme in colorectals (HCT) and osteosarcomas (143B) was associated with the lack of HIF-1α stabilization and subsequent inability to adapt to hypoxic environment, suggesting this may contribute to the anti-tumorigenic effect of CI deficiency. However, most recent data imply that, despite the lack of HIF-1α, the progression of CI-deficient tumors seems to be supported by components of tumor-microenvironment (TME), in particular tumor associated macrophages (TAMs). Thus, the aim of this thesis was (i) to prove that the lack of HIF-1α stabilization and subsequent inability to adapt to hypoxic environment is a generalized phenomenon in murine, human cancers and in an orthotopic system and may contribute to the anti-tumorigenic effect of CI deficiency (ii) to prove that the CI-deficient tumors activate macrophages to progress despite HIF-1α destabilization (iii) to identify common targetable factors responsible for macrophage recruitment among the CI deficient 143B and HCT models. By introducing a non-degradable form of HIF-1α (HIF-TM) in CI deficient models, we demonstrated that HIF-TM rescued their tumorigenic potential, mature vasculature and vessel size. Moreover, in 143B CI deficient model (143B-/-), lack of HIF-1 activity correlated with macrophage migration inhibitory factor (MIF) downregulation and macrophage abundance. This indicated that the disruption of HIF-1-MIF axis leading to vasculature remodeling and TAM recruitment is one of the adaptive mechanisms activated by the 143B-/- tumors. However, this mechanism may not be generalized to the epithelial HCT model. Large-scale omics approach on CI deficient and CI competent 143B and HCT xenografts derived supernatants identified nine common metabolites secreted specifically from both the CI deficient models, allowing to hypothesize a potential cytokine-like function of these metabolites in attracting TAMs.
Date
- 2021-03-17
Type
- Doctoral Thesis
- PeerReviewed
Format
- application/pdf
Identifier
urn:nbn:it:unibo-27497
Umesh Ganesh, Nikkitha (2021) Understanding The Effect Of Mitochondrial Complex I Deficiency In Cancer Cells And Their Microenvironment, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze mediche generali e scienze dei servizi