Dataset Information

Chromosomal instability adaptation dependencies confer unique targetable vulnerabilities in therapy refractory lethal prostate cancer

ABSTRACT: Chromosomal instability (CIN), an ongoing rate of chromosome missegregation during mitosis, is a defining feature of cancer. However, high chromosomal aberrations are detrimental for cell fitness. Here we investigated mechanisms allowing lethal prostate cancer (PCa) to tolerate and survive increasing CIN. Transcriptomic and proteomic analysis of patient datasets and experimental models showed a concomitant increase of CIN and cell division fidelity kinases in lethal PCa. Functional studies identified MASTL as a key kinase to which therapy-resistant PCa cells become addicted to restrain lethal CIN and ensure survival. Combined analysis of transcription factors increased in high CIN PCa patient datasets with detailed promoter analysis identified that MASTL expression is regulated by the Androgen Receptor variant 7 (AR-V7) and E2F7. Finally, targeting MASTL addiction vulnerability in vivo using the small molecule inhibitor GKI-1, improves survival of pre-clinical models. These findings provide proof-of-concept for exploiting CIN levels as a therapeutic approach in cancer.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Prostate Cancer Cell Line

DISEASE(S): Prostate Adenocarcinoma

SUBMITTER: Zhuoning Li

LAB HEAD: Veronica Rodriguez-Bravo

PROVIDER: PXD028271 | Pride | 2023-01-14

REPOSITORIES: Pride

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			Action	DRS
	Phospho_Forward1_PairE.raw	Raw
	Phospho_Forward2_PairF.raw	Raw
	Phospho_Forward3_PairK.raw	Raw
	Phospho_Proteome_proteinGroups.xlsx	Xlsx
	Phospho_Reverse1_PairG.raw	Raw

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Project description:MASTL (Microtubule associated serine-threonine kinase-like) is a relatively recently identified mitotic accelerator. There are also indications of its role in cancer progression, especially in breast cancer, but the molecular mechanisms behind this and the cell cycle independent functions of MASTL are poorly understood. Regulation of cell adhesion and actin dynamics play a central role in governing cell contractility, migration and cell division in normal and cancer cells. Here, we identify MASTL as regulator of cell contractility and activator of the transcriptional co-activator MTRF-A. We show that depletion of MASTL increases cell contact with the extracellular matrix, reduces contractile actin stress fibers in normal and breast cancer cells. Importantly, depletion of MASTL also leads to strongly impairs motility of breast cancer cells. Our transcriptome and proteome profiling revealed that depletion of MASTL impairs transcription and expression of several MRTF-A target genes implicated in cellular movement and actomyosin contraction, including Rho Guanine nucleotide exchange factor 2 (GEF-H1, ARHGEF2) and tropomyosin 4.2 (TPM4). Mechanistically, we find that MASTL is necessary for serum-induced activation of SRF/MTRF-A transcription and that exogenous expression of GEF-H1 in MASTL depleted cells is sufficient to restore cell contractility. Taken together, our results suggest that MASTL is a previously undescribed key regulator of cell morphology and the actin cytoskeleton through transcriptional control of multiple adhesion and actin cytoskeleton regulating genes with key roles in contractility, cell adhesion and migration. MASTL (Microtubule associated serine-threonine kinase-like) is a relatively recently identified mitotic accelerator. There are also indications of its role in cancer progression, especially in breast cancer, but the molecular mechanisms behind this and the cell cycle independent functions of MASTL are poorly understood. Regulation of cell adhesion and actin dynamics play a central role in cell migration, morphology and cancer progression, but the role of MASTL in these processes has not been evaluated. Here, we show that depletion of MASTL increases cell contact with the extracellular matrix in breast cancer cells. Importantly, depletion of MASTL also leads to reduction of contractile actin stress fibers and decreased cell motility. Further, our transcriptome and proteome profiling revealed that mechanistically depletion of MASTL impairs transcription and expression of regulators of cellular movement and actomyosin contraction, including Rho Guanine nucleotide exchange factor 2 (GEF-H1, ARHGEF2) and tropomyosin 4.2 (TPM4). Further, we show that the transcriptional changes are caused by defectiveness of the serum response factor (SRF) signalling. Importantly, this study reveals advanced role for MASTL in interphase cells that activates a transcriptional program strongly impacting on the expression of regulators of cellular motility and actomyosin contraction.

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Chromosomal instability adaptation dependencies confer unique targetable vulnerabilities in therapy refractory lethal prostate cancer

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