Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor initiating cells

Artibani, Mara; Masuda, Kenta; Hu, Zhiyuan; Rauher, Pascal C.; Mallett, Garry; Wietek, Nina; Morotti, Matteo; Chong, Kay Y.; KaramiNejadRanjbar, Mohammad; Zois, Christos E.; Dhar, Sunanda; El-Sahhar, Salma; Campo, Leticia; Blagden, Sarah P.; Damato, Stephen; Pathiraja, Pubudu; Nicum, Shibani; Gleeson, Fergus; Laios, A; Alsaadi, Abdulkhaliq; González, Laura Santana; Motohara, Takeshi; Albukhari, Ashwag; Lü, Zhen; Bast, Robert C.; Harris, Adrian L.; Ejsing, Christer S.; Klemm, Robin W.; Yau, Christopher; Sauka‐Spengler, Tatjana; Ahmed, Ashfaq

doi:10.1172/jci.insight.147929

Cited by 14 publications

(11 citation statements)

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“…Effective ovarian cancer therapy requires the eradication of CSCs [1,20], which are thought to drive tumor initiation, metastasis, and therapy resistance [1,21,26]. Our previous study revealed that the cell surface proteins CD44v6 and EpCAM play crucial roles in regulating ovarian cancer stemness, promoting metastasis, and enhancing chemotherapy resistance [20,23,24,27].…”

Section: Discussionmentioning

confidence: 99%

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Surgical efficacy and quality of wide resection of the pelvic peritoneum in patients with epithelial ovarian cancer

Nishimura¹,

Motohara

Morinaga³

et al. 2022

Preprint

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Purpose The aim of study was to evaluate the impact of adding an extensive pelvic peritoneal stripping procedure, termed “wide resection of the pelvic peritoneum,” (WRPP) to standard surgery for epithelial ovarian cancer on survival effectiveness and to investigate the role of ovarian cancer stem cells (CSCs) in the pelvic peritoneum. Methods A total of 166 patients with ovarian cancer undergoing surgical treatment at Kumamoto University Hospital between 2002 and 2018 were retrospectively analyzed. Eligible patients were divided into three groups based on the surgical approach: standard surgery (SS) group (n = 36), WRPP group (standard surgery plus WRPP, n = 100), and rectosigmoidectomy (RS) group (standard surgery plus RS, n = 30). Survival outcomes were compared between the three groups. CD44 variant 6 (CD44v6) and EpCAM expression, as markers of ovarian CSCs, in peritoneal disseminated tumors were evaluated using immunofluorescence staining. Results With respect to patients with stage III–IV ovarian cancer, there were significant differences in overall and progression-free survival between the WRPP and SS groups, as revealed by univariate (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.17–0.69; P = 0.003 and HR, 0.54; 95% CI, 0.31–0.95; P = 0.032, respectively) and multivariate Cox proportional hazards model (HR, 0.35; 95% CI, 0.17–0.70; P = 0.003 and HR, 0.54; 95% CI, 0.31–0.95; P = 0.032, respectively). Further, no significant differences were observed in survival outcomes between the RS group and the SS or WRPP group. Regarding the safety of WRPP, no significant differences in major intraoperative and postoperative complications were found between the three groups. Immunofluorescence analysis revealed a high percentage of CD44v6/EpCAM double-positive ovarian cancer cells in peritoneal disseminated tumors. Conclusion The present study demonstrates that WRPP significantly contributes to improved survival in patients with stage III–IV advanced ovarian cancer. WRPP could result in eradicating ovarian CSCs and disrupting the CSC niche microenvironment in the pelvic peritoneum.

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Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence indicates that the bulk of cancer cells are generated by rare populations of selfrenewing, multipotent tumor-initiating cells, conceptually termed "cancer stem cells" (CSCs) [20,21]. CSCs are inherently responsible for metastasis and therapy resistance [1,22,23].…”

Section: Introductionmentioning

confidence: 99%

Surgical efficacy and quality of wide resection of the pelvic peritoneum in patients with epithelial ovarian cancer

Nishimura¹,

Motohara

Morinaga³

et al. 2022

Preprint

Self Cite

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“…Moreover, a transcriptomic study of single cell-derived spheroids from ovarian cancer ascites has shown that although 2D monolayers support proliferation and tumour growth cascades, 3D spheroids additionally capture aspects of cholesterol and lipid metabolism, which are features of metastatic disease 9 . These pathways are implicated in the lipid signature we observed in ovarian cancer MRD 4 ; thus, in this context, 3D models are essential for drug discovery.…”

Section: Introductionmentioning

confidence: 92%

“…In a previous work we described how MRD cells show distinctive features such as the upregulation of cancer stem cell markers and genes involved in lipid metabolism, and a more pronounced mesenchymal profile 4 . We also developed an MRD 2D in vitro model where treatmentnaïve cancer cells were exposed to carboplatin concentrations to achieve >90% cell killing; the surviving cells recapitulated some of the features of MRD (such as upregulation of lipid metabolism), but lacked the complexity of multicellularity and three dimensionality.…”

Section: D Microtumours As a Superior Model Of Ovarian Cancer Mrdmentioning

confidence: 99%

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A 3D microtumour system that faithfully represents ovarian cancer minimal residual disease

Yang

Artibani

Jin

et al. 2023

Preprint

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Background: Bulk cancer and minimal residual disease (MRD) are characterised by different molecular drivers and therefore necessitate different therapeutic strategies. However, there are currently no 3D models that can faithfully recapitulate MRD ex vivo for therapy development. Methods: A microfluidic technique was implemented to construct 3D microtumours, in which tumour cells, either by themselves or with fibroblasts, were encapsulated in viscous hydrogels. The 3D microtumours were analysed for their response to first-line chemotherapeutics and characterised through RNA-Seq, by comparing them to both 2D cultures and clinical samples. Results: Our microfluidic platform guarantees the fabrication of 3D microtumours of tailorable size and cell content, which recreate key features of tumours such as hypoxia, characteristic organization of the cytoskeleton and a dose-response to chemotherapeutics close to the physiological range. The 3D microtumours were also used to examine non-genetic heterogeneity in ovarian cancer and could fully reflect the recently described 'Oxford Classic' five molecular signatures. The gene expression profile of 3D microtumours following chemotherapy treatment closely resembled that of MRD in ovarian cancer patients, showing the upregulation of genes involved in fatty acid metabolism. We demonstrate that these 3D microtumours are ideal for drug development by showing how they support the identification of a promising inhibitor of fatty acid oxidation, perhexiline, which specifically targets chemotherapy-resistant MRD ovarian cancer cells and not bulk cancer cells. Conclusion: We have obtained the first 3D model of ovarian cancer MRD by using microtumours generated through microfluidics. This system is ideal for high-throughput drug screening and, given its versatility, it can be readily extended to additional types of cancer, as well as accommodate multiple cell types to generate complex tumour microenvironments.

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Neoadjuvant Chemotherapy Induces Genomic and Transcriptomic Changes in Ovarian Cancer

et al. 2022

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The growing use of neoadjuvant chemotherapy to treat advanced stage high-grade serous ovarian cancer (HGSOC) creates an opportunity to better understand chemotherapy-induced mutational and gene expression changes. Here we performed a cohort study including 34 patients with advanced stage IIIC or IV HGSOC to assess changes in the tumor genome and transcriptome in women receiving neoadjuvant chemotherapy. RNA sequencing and panel DNA sequencing of 596 cancer-related genes was performed on paired formalin-fixed paraffin-embedded specimens collected before and after chemotherapy, and differentially expressed genes (DEG) and copy-number variations (CNV) in pre- and post-chemotherapy samples were identified. Following tissue and sequencing quality control, the final patient cohort consisted of 32 paired DNA and 20 paired RNA samples. Genomic analysis of paired samples did not reveal any recurrent chemotherapy-induced mutations. Gene expression analyses found that most DEGs were upregulated by chemotherapy, primarily in the chemotherapy-resistant specimens. AP-1 transcription factor family genes (FOS, FOSB, FRA-1) were particularly upregulated in chemotherapy-resistant samples. CNV analysis identified recurrent 11q23.1 amplification, which encompasses SIK2. In vitro, combined treatment with AP-1 or SIK2 inhibitors with carboplatin or paclitaxel demonstrated synergistic effects. These data suggest that AP-1 activity and SIK2 copy-number amplification are induced by chemotherapy and may represent mechanisms by which chemotherapy resistance evolves in HGSOC. AP-1 and SIK2 are druggable targets with available small molecule inhibitors and represent potential targets to circumvent chemotherapy resistance. Significance: Genomic and transcriptomic analyses identify increased AP-1 activity and SIK2 copy-number amplifications in resistant ovarian cancer following neoadjuvant chemotherapy, uncovering synergistic effects of AP-1 and SIK2 inhibitors with chemotherapy.

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Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor initiating cells

Cited by 14 publications

References 50 publications

Surgical efficacy and quality of wide resection of the pelvic peritoneum in patients with epithelial ovarian cancer

Surgical efficacy and quality of wide resection of the pelvic peritoneum in patients with epithelial ovarian cancer

A 3D microtumour system that faithfully represents ovarian cancer minimal residual disease

Neoadjuvant Chemotherapy Induces Genomic and Transcriptomic Changes in Ovarian Cancer

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