Supplementary Figures S1-S7 from Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma

Gopal, Raj K.; Vantaku, Venkata R.; Panda, Apekshya; Reimer, Bryn; Rath, Sneha; To, Tsz-Leung; Fisch, Adam S.; Cetinbas, Murat; Livneh, Maia; Calcaterra, Michael J.; Gigliotti, Benjamin J.; Pierce, Kerry A.; Clish, Clary B.; Dias-Santagata, Dora; Sadow, Peter M.; Wirth, Lori J.; Daniels, Gilbert H.; Sadreyev, Ruslan I.; Calvo, Sarah E.; Parangi, Sareh; Mootha, Vamsi K.

doi:10.1158/2159-8290.23726537.v1

cd-22-0976_supplementary_figures_s1-s7_suppsf1.pdf (2.32 MB)

Supplementary Figures S1-S7 from Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma

journal contribution

posted on 2023-07-21, 14:20 authored by Raj K. Gopal, Venkata R. Vantaku, Apekshya Panda, Bryn Reimer, Sneha Rath, Tsz-Leung To, Adam S. Fisch, Murat Cetinbas, Maia Livneh, Michael J. Calcaterra, Benjamin J. Gigliotti, Kerry A. Pierce, Clary B. Clish, Dora Dias-Santagata, Peter M. Sadow, Lori J. Wirth, Gilbert H. Daniels, Ruslan I. Sadreyev, Sarah E. Calvo, Sareh Parangi, Vamsi K. Mootha

Supplementary Figure 1: Mitochondrial and nuclear DNA alterations in an HCC cohort. Related to Figure 1. Supplementary Figure 2: Transcriptomic landscape of HCC. Related to Figure 2. Supplementary Figure 3: Metabolic signatures of HCC. Related to Figure 3. Supplementary Figure 4: Authentic models of HCC. Related to Figure 4. Supplementary Figure 5: CRISPR screen identifies vulnerability to GPX4 loss in HCC. Related to Figure 5. Supplementary Figure 6: NCI-HCC xenografts are sensitive to ferroptosis. Related to Figure 6. Supplementary Figure 7: Differential effects of OXPHOS inhibition on ferroptosis. Related to Figure 7.

History

ARTICLE ABSTRACT

Oncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA sequencing and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging to be increased in HCC. A CRISPR–Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against lipid peroxides and ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity. HCC harbors abundant mitochondria, mitochondrial DNA mutations, and chromosomal losses. Using a CRISPR–Cas9 screen inspired by transcriptomic and metabolomic profiling, we identify molecular effectors essential for cell fitness. We uncover lipid peroxide stress as a vulnerability coupled to mitochondrial complex I loss in HCC.