PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity

Menée à l'aide notamment de lignées cellulaires de tumeurs neuroendocrines à petites cellules du poumon ou de la prostate, cette étude met en évidence un mécanisme par lequel le co-activateur transcriptionnel PGC-1 alpha favorise la progression de la tumeur vers un sous-type exprimant ASCL1 et présentant une forte activité mitochondriale

Résumé en anglais

Our study provides functional evidence that metabolic reprogramming can directly impact cancer phenotypes and establishes proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-induced mitochondrial metabolism as a driver of small cell neuroendocrine cancer (SCNC) progression and lineage determination. These mechanistic insights reveal common metabolic vulnerabilities across SCNCs originating from multiple tissues, opening additional avenues for pan-SCN cancer therapeutic strategies. Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.