Tumor Microenvironment-induced FOXM1 Regulates Ovarian Cancer Stemness

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2024 May 28

PMID 38806454

Authors

Chiara Battistini

Hilary A Kenny

Melissa Zambuto

Valentina Nieddu

Valentina Melocchi

Alessandra Decio

Pietro Lo Riso

Carlo Emanuele Villa

Alessia Gatto

Mariacristina Ghioni

Francesca M Porta

Giuseppe Testa

Raffaella Giavazzi

Nicoletta Colombo

Fabrizio Bianchi

Ernst Lengyel

Ugo Cavallaro

Affiliations

Soon will be listed here.

Abstract

In ovarian tumors, the omental microenvironment profoundly influences the behavior of cancer cells and sustains the acquisition of stem-like traits, with major impacts on tumor aggressiveness and relapse. Here, we leverage a patient-derived platform of organotypic cultures to study the crosstalk between the tumor microenvironment and ovarian cancer stem cells. We discovered that the pro-tumorigenic transcription factor FOXM1 is specifically induced by the microenvironment in ovarian cancer stem cells, through activation of FAK/YAP signaling. The microenvironment-induced FOXM1 sustains stemness, and its inactivation reduces cancer stem cells survival in the omental niche and enhances their response to the PARP inhibitor Olaparib. By unveiling the novel role of FOXM1 in ovarian cancer stemness, our findings highlight patient-derived organotypic co-cultures as a powerful tool to capture clinically relevant mechanisms of the microenvironment/cancer stem cells crosstalk, contributing to the identification of tumor vulnerabilities.

References

Kenny H, Kaur S, Coussens L, Lengyel E . The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin. J Clin Invest. 2008; 118(4):1367-79. PMC: 2267016. DOI: 10.1172/JCI33775. View

Lupia M, Angiolini F, Bertalot G, Freddi S, Sachsenmeier K, Chisci E . CD73 Regulates Stemness and Epithelial-Mesenchymal Transition in Ovarian Cancer-Initiating Cells. Stem Cell Reports. 2018; 10(4):1412-1425. PMC: 5998305. DOI: 10.1016/j.stemcr.2018.02.009. View

Kenny H, Krausz T, Yamada S, Lengyel E . Use of a novel 3D culture model to elucidate the role of mesothelial cells, fibroblasts and extra-cellular matrices on adhesion and invasion of ovarian cancer cells to the omentum. Int J Cancer. 2007; 121(7):1463-72. DOI: 10.1002/ijc.22874. View

Fan Q, Cai Q, Xu Y . FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer. Oncotarget. 2015; 6(29):27688-99. PMC: 4695018. DOI: 10.18632/oncotarget.4280. View

. Integrated genomic analyses of ovarian carcinoma. Nature. 2011; 474(7353):609-15. PMC: 3163504. DOI: 10.1038/nature10166. View

Raychaudhuri P, Park H . FoxM1: a master regulator of tumor metastasis. Cancer Res. 2011; 71(13):4329-33. PMC: 3129416. DOI: 10.1158/0008-5472.CAN-11-0640. View

Ning Y, Li Q, Ren K, Quan M, Cao J . 7-difluoromethoxyl-5,4'-di-n-octyl genistein inhibits ovarian cancer stem cell characteristics through the downregulation of FOXM1. Oncol Lett. 2014; 8(1):295-300. PMC: 4063643. DOI: 10.3892/ol.2014.2080. View

Domcke S, Sinha R, Levine D, Sander C, Schultz N . Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun. 2013; 4:2126. PMC: 3715866. DOI: 10.1038/ncomms3126. View

Ritch S, Telleria C . The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination. Front Endocrinol (Lausanne). 2022; 13:886533. PMC: 9096207. DOI: 10.3389/fendo.2022.886533. View

10.

Wu S, Huang S, Lin Q, Tang Y, Huang L, Xu Y . FDI-6 and olaparib synergistically inhibit the growth of pancreatic cancer by repressing BUB1, BRCA1 and CDC25A signaling pathways. Pharmacol Res. 2021; 175:106040. DOI: 10.1016/j.phrs.2021.106040. View

11.

Marchetti C, De Felice F, Romito A, Iacobelli V, Sassu C, Corrado G . Chemotherapy resistance in epithelial ovarian cancer: Mechanisms and emerging treatments. Semin Cancer Biol. 2021; 77:144-166. DOI: 10.1016/j.semcancer.2021.08.011. View

12.

Kenny H, Lal-Nag M, Shen M, Kara B, Nahotko D, Wroblewski K . Quantitative High-Throughput Screening Using an Organotypic Model Identifies Compounds that Inhibit Ovarian Cancer Metastasis. Mol Cancer Ther. 2019; 19(1):52-62. PMC: 6946883. DOI: 10.1158/1535-7163.MCT-19-0052. View

13.

Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6):394-424. DOI: 10.3322/caac.21492. View

14.

Gonzalez-Martin A, Pothuri B, Vergote I, Christensen R, Graybill W, Mirza M . Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2019; 381(25):2391-2402. DOI: 10.1056/NEJMoa1910962. View

15.

Hu Y, Smyth G . ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009; 347(1-2):70-8. DOI: 10.1016/j.jim.2009.06.008. View

16.

Cooper J, Giancotti F . Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance. Cancer Cell. 2019; 35(3):347-367. PMC: 6684107. DOI: 10.1016/j.ccell.2019.01.007. View

17.

Nwani N, Sima L, Nieves-Neira W, Matei D . Targeting the Microenvironment in High Grade Serous Ovarian Cancer. Cancers (Basel). 2018; 10(8). PMC: 6115937. DOI: 10.3390/cancers10080266. View

18.

Kenny H, Chiang C, White E, Schryver E, Habis M, Romero I . Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion. J Clin Invest. 2014; 124(10):4614-28. PMC: 4191043. DOI: 10.1172/JCI74778. View

19.

Huang Y, McCarthy D, Stegle O . Vireo: Bayesian demultiplexing of pooled single-cell RNA-seq data without genotype reference. Genome Biol. 2019; 20(1):273. PMC: 6909514. DOI: 10.1186/s13059-019-1865-2. View

20.

Rausch V, Hansen C . The Hippo Pathway, YAP/TAZ, and the Plasma Membrane. Trends Cell Biol. 2019; 30(1):32-48. DOI: 10.1016/j.tcb.2019.10.005. View