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Effects of mitochondrial stress on intestinal tumor development depends on Apc status

ABSTRACT: Mitochondrial stress triggers both metabolic and transcriptomic reprogramming but its effects on tumor development remains unclear. It is also unknown whether the genetic status has any influence on the capacity of mitochondrial stress to control tumor development. To explore these issues, we generated a mouse model lacking the lipid transfer protein Stard7 in intestinal epithelial cells (IECs) and assessed tumor development in both Wnt-dependent tumor initiation and in inflammation-driven tumor development. The loss of Stard7 in both models of intestinal tumors impaired mitochondrial Complex I activity, led to a severe metabolic and lipidomic reprogramming and potentiated mTORC1 activation. As a result, levels of enzymes involved in serine biosynthesis were enhanced in Stard7-deficient IECs showing or not constitutive Wnt signaling. Strikingly, despite similar molecular signatures upon Stard7 deficiency in intestinal crypts showing or not constitutive Wnt signaling, Stard7 contributed to tumor development in AOM/DSS-treated mice but inhibits Wnt-driven cancer initiation in the intestine. Apc+/min mice lacking Stard7 in IECs developed more tumors in the distal colon as well as a specific microbiota signature. Collectively, our results suggest that the Apc genetic status critically controls the effects of mitochondrial stress on intestinal tumor development.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Colon

DISEASE(S): Colon Cancer

SUBMITTER: Alex von Kriegsheim

LAB HEAD: Chariot Alain

PROVIDER: PXD046922 | Pride | 2026-02-19

REPOSITORIES: Pride

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Project description:Expression profiling is a well established tool for the genome-wide analysis of the transcriptional activity of human neoplasia. However, the high sensitivity of this approach combined with the well-known cellular and molecular heterogeneity of cancer often result in extremely complex and extended expression signatures of difficult functional interpretation. The majority of sporadic colorectal cancer cases are triggered by mutations in the APC tumor suppressor gene leading to constitutive activation of the Wnt/b-catenin signaling pathway and adenoma formation. Notwithstanding this common genetic basis, colorectal cancers are very heterogeneous in their degree of differentiation, growth rate and malignant potential. Here, we applied cross-species comparison of expression profiles of intestinal polyps derived from hereditary colorectal cancer patients carrying APC germline mutations, and from a mouse model carrying a targeted inactivating mutation in the mouse homologue Apc. This comparative approach resulted in the establishment of a conserved signature encompassing 166 genes differentially expressed between adenomas and normal intestinal mucosa in both species. Functional analysis of the conserved genes revealed a general increase in cell proliferation and the activation of the Wnt/b-catenin signal transduction pathway, as expected from the selection of APC/Apc-mutant intestinal adenomas. Moreover, the conserved signature is able to resolve expression profiles from hereditary polyposis patients carrying APC germline mutations from those with bi-allelic incativation of the MYH gene. Keywords: normal versus tumor comparison; compare expression profiles from microdissected samples with distinct germline mutations (FAP vs. MAP). Here, we report the expression profiles from normal and intestinal adenomatous tissue from FAP (familial adenomatous polyposis) and MAP (MUTY-associated polyposis) patients with established APC and MUTY germline mutations. Total RNA samples were obtianed by laser capture microdissection.

			Action	DRS
	20220817-APCmiceStemC.zip	Other
	APCminmiceKO_1531.raw	Raw
	APCminmiceKO_1539.raw	Raw
	APCminmiceKO_1542.raw	Raw
	APCminmiceKO_1544.raw	Raw

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Effects of mitochondrial stress on intestinal tumor development depends on Apc status

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