Mutations in mitochondrial DNA (mtDNA) in cancer cells confer resistance to apoptosis and promote metastasis
by Izzy Gomes
1. Experimental Results:
1.1. Sequencing: Whole genome sequence of mtDNA in breast cancer cell lines revealed multiple mutations
1.2. Mitochondrial Membrane Potential and ROS Levels: Analysis showed increased membrane potential but no significant change in ROS levels
1.3. Metastasis Studies: Tail-vein injection in mice demonstrated increased lung metastasis in mutant cybrids
2. Additional Findings:
2.1. Mitochondrial Dysfunction: Mitochondrial dysfunction in cancer cells is linked to altered metabolism and resistance to cell death
2.2. Cancer Metabolism: Cancer cells often exhibit the Warburg effect, preferring glycolysis over oxidative phosphorylation even in the presence of oxygen
2.3. Therapeutic Implications: Targeting mitochondral pathways could provide new strategies for cancer treatment
3. Collagen in Cancer Progression (Chapter 20):
3.1. Extracellular Matric (ECM) (Chapter 20): Collagens are major components of the ECM, providing structural support and influencing cell behavior
3.2. Tumor Microenvironment: Collagens contribute to the stiffness of the tumor microenvironment promoting cancer cell invasion and metastassis
3.3. Collagen Types: Various types of collagens (e.g.. collagen I, III, IV) are involved in cancer progression (Chapter 20)
3.4. Collagen Receptors: Cancer cells interact with collagens through receptors like integrins, which influence cell migration, proliferation, and survival (Chapter 20)
3.5. Desmoplasia: Increased collagen deposition (desmoplasia) is associated with tumor progression and poor prognosis
3.6. Protein Sorting (Chapter 15):
3.6.1. Golgi Apparatus: The Golgi apparatus plays a key role in protein sorting, glycosylation, and secretion, which are essential for collagen modification and ECM remodeling (Chapter 15)
3.6.2. Exosomes: Exosome-mediated protein sorting and secretion contribute to the transfer of collagen-modifying enzymes and other proteins that remodel the ECM and promote metastasis
4. Cell Junctions and Cadherins (Chapter 20):
4.1. Adherens Junctions (Chapter 20): Cadherins are key components of adherens junctions, which mediate cell-cell adhesion and maintain tissue architecture
4.2. E-cadherin: Loss of E-cadherin is associated with epitherlial-to-messenchymal transition (EMT), leading to increased cancer cell motility and invasion
4.3. N-cadherin (Chapter 20): Upregulation of N-cadherin promotes metastasis by enhancing cell migration and invasion
4.4. Cadherin Switch: The switch from E-cadherin to N-cadherin (cadherin switch) is a hallmark of EMT and is linked to poor prognosis
4.5. Signaling Pathways (Chapter 16): Cadhering interact with signaling pathways such as PI3K/Akt and Rho GTPases influencing cell survival, migration, and invasion
5. Signal Molecules in Cancer Metastasis (Chapter 16):
5.1. Growth Factors and Cytokines: Signal molecules like epidermal growth factor (EGF), transforming growth factor-beta (TGF-β), and interleukins promote cancer cell proliferation, survival, and metastasis
5.2. Chemokines: Chemokines such as CSCL12 and its receptor CXCR4 guide cancer cell migration and invasion
5.3. Neurotransmitters and Neuropeptides: Molecules like norepinephrine, substance P, and neuropeptide Y influence cancer progression by modulating the tumor microenvironment and promoting angiogenesis
5.4. Metabolix Signaling: Metabolites like lactate and succinate act as signaling molecules, activating pathways that support cancer cell survival and metastasis.
6. Mitochondrial DNA mutations:
6.1. Breast Cancer Cell Lines: Mutations found in mtDNA of MCF7, MDA-MB-231, and MDA-MB-435 cell lines
6.2. Specific Mutations:
6.2.1. MDA-MB-435: Mutation in the tRNALeu(CUN) gene, known to be involved in mitochondrial diseases
6.2.2. Common mutations in the D-loop region (A263G and T16519C) across all three cell lines