Highly variable cancer subpopulations that exhibit enhanced transcriptome variability and metastatic fitness

abstract: ...Individual cells within a tumour can exhibit distinct genetic and molecular features. The impact of such diversification on metastatic potential is unknown. Here we identify clonal human breast cancer subpopulations that display different levels of morphological and molecular diversity. Highly variable subpopulations are more proficient at metastatic colonization and chemotherapeutic survival. Through single-cell RNA-sequencing, inter-cell transcript expression variability is identified as a defining feature of the highly variable subpopulations that leads to protein-level variation. Furthermore, we identify high variability in the spliceosomal machinery gene set. Engineered variable expression of the spliceosomal gene SNRNP40 promotes metastasis, attributable to cells with low expression. Clinically, low SNRNP40 expression is associated with metastatic relapse. Our findings reveal transcriptomic variability generation as a mechanism by which cancer subpopulations can diversify gene expression states, which may allow for enhanced fitness under changing environmental pressures encountered during cancer progression.

... subpopulations are more proficient at metastatic colonization and chemotherapeutic survival. Through single-cell RNA-sequencing, inter-cell transcript expression variability is identified as a defining feature of the highly variable subpopulations that leads to protein-level variation. Furthermore, we identify high variability in the spliceosomal machinery gene set. Engineered variable expression of the spliceosomal gene SNRNP40 promotes metastasis, attributable to cells with low expression. Clinically, low SNRNP40 expression is associated with metastatic relapse. Our findings reveal transcriptomic variability generation as a mechanism by which cancer subpopulations can diversify gene expression states, which may allow for enhanced fitness under changing environmental pressures encountered during cancer progression. Phenotypic and genetic intra-tumor heterogeneity have an important role in cancer progression and therapeutic resistance. Here, the authors show that phenotypically variable tumor

... subpopulations. Indeed, engineered variation of the SNRNP40 spliceosomal gene's expression among cells within a breast cancer population promoted their metastatic fitness. Further analysis revealed cell populations with low SNRNP40 expression exhibit enhanced metastatic capacity, displayed gene expression changes consistent with that seen in highly variable subpopulations, and contained increased unspliced pre-mRNAs. Clinically, low SNRNP40 expression was found to be associated with metastatic outcomes

... our findings, intron retention has been previously observed to be the most significant splicing alteration in breast cancer patient samples 27 . These findings reveal enhanced splicing variability as one feature of highly variable subpopulations. Variability in SNRNP40 expression enhances metastasis Finally, we sought to determine whether enforced modulation of a highly variable spliceosomal gene could recapitulate the metastatic capacity seen with HV subpopulations. While highly variable subpopulations displayed variability in many spliceosomal genes, focused study on a single spliceosomal gene could serve as a model by which variation of other spliceosomal genes may contribute to expression variation. However, focus on a single gene would be expected to recapitulate only a fraction of the effects seen in highly variable subpopulations. We focused on SNRNP40, a component of the U5 small nuclear RNP complex, because this gene exhibited high transcript variability in HV subpopulations ( Supplementary Fig. 8a ), was among the top three most variable spliceosomal gene transcripts ( Supplementary Table 2 ), has been described to directly interact with numerous highly variable spliceosomal genes ( Fig. 7a , Supplementary Table 2 ), and its protein expression could be readily quantified by immunofluorescence-based imaging ( Supplementary Fig. 8b ). Indeed, HV subpopulations displayed increased SNRNP40 protein-level variability ( Fig. 7b,c ). To determine whether population-level variation in SNRNP40 observed with HV cells was sufficient to enforce metastatic fitness, LV subpopulations were generated to express varying levels of SNRNP40 ( Supplementary Fig. 9a ). These populations were pooled to generate a mixed population with increased cell-to-cell SNRNP40 expression variation without significantly altering mean SNRNP40 expression ( Fig. 7d ; mean: Control=9.0, hiCV=8.9, P =0.19 by two-sided t -test; CV: Control=0.068, hiCV=0.104, P =7e-14 by Levene's test). Functional testing of this

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Gene: SNRNP40 - small nuclear ribonucleoprotein 40kDa (U5) - (NCBI)

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