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Tumour mtDNA mutations drive aerobic glycolysis to enhance checkpoint blockade (part 2)

ABSTRACT: Mitochondrial DNA (mtDNA) encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutations in the cancer genome, with truncating mutations in complex I genes being over-represented1 . While mtDNA mutations have been associated with both improved and worsened prognoses in several cancer lineages1–3, whether these mutations are drivers, or exert any functional effect on tumour biology remains controversial. Here we discover that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment of mouse and human cancer in a mutation load-dependent fashion, encouraging an anti-tumour immune response. This subsequently sensitises both mouse and human cancers with high mtDNA mutant heteroplasmy to immune checkpoint blockade. Strikingly, patient lesions bearing >50% mtDNA mutation load demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Melanocyte

DISEASE(S): Melanoma

SUBMITTER: Sergio Lilla

LAB HEAD: Sara Rossana Zanivan

PROVIDER: PXD044987 | Pride | 2023-11-08

REPOSITORIES: Pride

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			Action	DRS
	20230607_SEL_LU_SA_MAM_R27_150523_TMT16_group1_001.raw	Raw
	20230607_SEL_LU_SA_MAM_R27_150523_TMT16_group1_002.raw	Raw
	20230607_SEL_LU_SA_MAM_R27_150523_TMT16_group1_003.raw	Raw
	20230607_SEL_LU_SA_MAM_R27_150523_TMT16_group1_004.raw	Raw
	20230607_SEL_LU_SA_MAM_R27_150523_TMT16_group1_005.raw	Raw

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Tumour mtDNA mutations drive aerobic glycolysis to enhance checkpoint blockade (part 2)

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