MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression

Chen, Jiayu; Zheng, Qizhi; Hicks, Jessica L.; Trabzonlu, Levent; Ozbek, Büşra; Jones, Tracy; Vaghasia, Ajay; Larman, Tatianna; Wang, Rulin; Markowski, Mark C.; Denmeade, S.; Pienta, Ken J.; Hruban, Ralph H.; Antonaraskis, Emmanuel S; Gupta, Anuj; Dang, Chi V.; Yegnasubramanian, Srinivasan; Marzo, Angelo M. De

doi:10.1101/2023.02.20.529259

Cited by 3 publications

(2 citation statements)

References 104 publications

(198 reference statements)

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“…Genes positively correlated with MYC transgene expression in luminal cells were associated with several biological pathways linked to MYC activation (Figure 3F), including cell cycle progression, ribosome biogenesis, RNA processing, protein degradation, and mitochondrial function 54,[61][62][63] .…”

Section: Myc Activity Reprograms Neighboring Benign Epithelial Cells ...mentioning

confidence: 99%

Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer

Graham,

Wang,

Chikarmane

et al. 2023

Preprint

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The tissue microenvironment in prostate cancer is profoundly altered. While such alterations have been implicated in driving prostate cancer initiation and progression to aggressive disease, how prostate cancer cells and their precursors mediate those changes is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we performed extensive single-cell RNA-sequencing (scRNA-seq) and rigorous molecular pathology of the comparative biology between human prostate cancer and key time points in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues, with validation in a large external data set, revealed that cancer cell-intrinsic activation of MYC signaling was the top up-regulated pathway in human cancers, representing a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Likewise, numerous non-malignant cell states in the tumor microenvironment (TME), including non-cancerous epithelial, immune, and fibroblast cell compartments, were conserved across individuals, raising the possibility that these cell types may be a sequelae of the convergent MYC activation in the cancer cells. To test this hypothesis, we employed a GEMM of prostate epithelial cell-specific MYC activation in two mouse strains. Cell communication network and pathway analyses suggested that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogrammed the TME during carcinogenesis, leading to the emergence of cascading cell state alterations in neighboring epithelial, immune, and fibroblast cell types that paralleled key findings in human prostate cancer. Importantly, among these changes, the progression from a precursor-enriched to invasive-cancer-enriched state was accompanied by a cell-intrinsic switch from pro-immunogenic to immunosuppressive transcriptional programs with coinciding enrichment of immunosuppressive myeloid and Treg cells in the immune microenvironment. These findings implicate activation of MYC signaling in reshaping convergent aspects of the TME of prostate cancer as a common denominator across the otherwise well-documented molecular heterogeneity of human prostate cancer.

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Section: Myc Activity Reprograms Neighboring Benign Epithelial Cells ...mentioning

confidence: 99%

Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer

Graham,

Wang,

Chikarmane

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…These observations highlight the intimate interplay between cancer metabolism and lineage plasticity. Specifically, SCN-associated oncogenes such as MYC [23][24][25][26][27] , AKT 28,29 , TP53 30,31 , and RB1 [32][33][34] , regulate metabolic pathways individually, but their collective impact on metabolic reprogramming and lineage determination during SCNC remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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

Varuzhanyan,

Chen,

Freeland

et al. 2024

Preprint

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Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers comprised of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how PGC-1a, a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), influences SCN cancer (SCNC) progression. Comprehensive bioinformatics analyses across thousands of patient tumors and human cancer cell lines, and in multiple clinical SCNC datasets, revealed increased PGC-1a expression in multiple SCNC types. PGC-1a correlated tightly with increased ASCL1 expression through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1a expression and OXPHOS activity. PGC-1a inhibition blunted OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. PGC-1a overexpression enhanced OXPHOS, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These observations reveal the metabolic heterogeneity among SCNC subtypes and identify PGC-1a-induced OXPHOS as a regulator of SCNC lineage plasticity.

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The role of mitochondria in tumor metastasis and advances in mitochondria-targeted cancer therapy

Chen,

Xue,

Zhang

et al. 2024

Cancer Metastasis Rev

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Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies.

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MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression

Cited by 3 publications

References 104 publications

Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer

Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer

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

The role of mitochondria in tumor metastasis and advances in mitochondria-targeted cancer therapy

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