Multi-modal transcriptomic analysis unravels enrichment of hybrid epithelial/mesenchymal state and enhanced phenotypic heterogeneity in basal breast cancer.

Autor:	Sahoo S; Department of Bioengineering, Indian Institute of Science, Bangalore, 560012, India., Ramu S; Department of Bioengineering, Indian Institute of Science, Bangalore, 560012, India., Nair MG; Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, 560012, India., Pillai M; Department of Bioengineering, Indian Institute of Science, Bangalore, 560012, India.; Current affiliation: Feinberg School of Medicine, Northwestern University, Chicago, 60611, USA., San Juan BP; Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia., Milioli HZ; Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia., Mandal S; Department of Bioengineering, Indian Institute of Science, Bangalore, 560012, India., Naidu CM; Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, 560012, India., Mavatkar AD; Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, 560012, India., Subramaniam H; Department of Bioengineering, Indian Institute of Science, Bangalore, 560012, India., Neogi AG; Department of Bioengineering, Indian Institute of Science, Bangalore, 560012, India., Chaffer CL; Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.; University of New South Wales, UNSW Medicine, UNSW Sydney, NSW, 2052, Australia., Prabhu JS; Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, 560012, India., Somarelli JA; Department of Medicine, Duke University, Durham, NC 27708, USA., Jolly MK; Department of Bioengineering, Indian Institute of Science, Bangalore, 560012, India.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 02. Date of Electronic Publication: 2023 Oct 02.
DOI:	10.1101/2023.09.30.558960
Abstrakt:	Intra-tumoral phenotypic heterogeneity promotes tumor relapse and therapeutic resistance and remains an unsolved clinical challenge. It manifests along multiple phenotypic axes and decoding the interconnections among these different axes is crucial to understand its molecular origins and to develop novel therapeutic strategies to control it. Here, we use multi-modal transcriptomic data analysis - bulk, single-cell and spatial transcriptomics - from breast cancer cell lines and primary tumor samples, to identify associations between epithelial-mesenchymal transition (EMT) and luminal-basal plasticity - two key processes that enable heterogeneity. We show that luminal breast cancer strongly associates with an epithelial cell state, but basal breast cancer is associated with hybrid epithelial/mesenchymal phenotype(s) and higher phenotypic heterogeneity. These patterns were inherent in methylation profiles, suggesting an epigenetic crosstalk between EMT and lineage plasticity in breast cancer. Mathematical modelling of core underlying gene regulatory networks representative of the crosstalk between the luminal-basal and epithelial-mesenchymal axes recapitulate and thus elucidate mechanistic underpinnings of the observed associations from transcriptomic data. Our systems-based approach integrating multi-modal data analysis with mechanism-based modeling offers a predictive framework to characterize intra-tumor heterogeneity and to identify possible interventions to restrict it. Competing Interests: Conflict of Interest The authors declare no conflicts of interest.
Databáze:	MEDLINE
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