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Stable differences in intrinsic mitochondrial membrane potential of tumor cell subpopulations reflect phenotypic heterogeneity.

ABSTRACT: Heterogeneity among cells that constitute a solid tumor is important in determining disease progression. Our previous work established that, within a population of metastatic colonic tumor cells, there are minor subpopulations of cells with stable differences in their intrinsic mitochondrial membrane potential (??m), and that these differences in ??m are linked to tumorigenic phenotype. Here we expanded this work to investigate primary mammary, as well as colonic, tumor cell lines. We show that within a primary mammary tumor cell population, and in both primary and metastatic colonic tumor cell populations, there are subpopulations of cells with significant stable variations in intrinsic ??m. In each of these 3 tumor cell populations, cells with relatively higher intrinsic ??m exhibit phenotypic properties consistent with promotion of tumor cell survival and expansion. However, additional properties associated with invasive potential appear in cells with higher intrinsic ??m only from the metastatic colonic tumor cell line. Thus, it is likely that differences in the intrinsic ??m among cells that constitute primary mammary tumor populations, as well as primary and metastatic colonic tumor populations, are markers of an acquired tumor phenotype which, within the context of the tumor, influence the probability that particular cells will contribute to disease progression.

SUBMITTER: Houston MA

PROVIDER: S-EPMC3132547 | biostudies-other | 2011

REPOSITORIES: biostudies-other

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Stable differences in intrinsic mitochondrial membrane potential of tumor cell subpopulations reflect phenotypic heterogeneity.

Houston Michele A MA Augenlicht Leonard H LH Heerdt Barbara G BG

International journal of cell biology 20110702

Heterogeneity among cells that constitute a solid tumor is important in determining disease progression. Our previous work established that, within a population of metastatic colonic tumor cells, there are minor subpopulations of cells with stable differences in their intrinsic mitochondrial membrane potential (ΔΨm), and that these differences in ΔΨm are linked to tumorigenic phenotype. Here we expanded this work to investigate primary mammary, as well as colonic, tumor cell lines. We show that ...[more]

PMID: 21760799

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Project description:We have established previously that minor subpopulations of cells with stable differences in their intrinsic mitochondrial membrane potential (??m) exist within populations of mammary and colonic carcinoma cells and that these differences in ??m are linked to tumorigenic phenotypes consistent with increased probability of participating in tumor progression. However, the mechanism(s) involved in generating and maintaining stable differences in intrinsic ??m and how they are linked to phenotype are unclear. Because the mucin 1 (MUC1) oncoprotein is over-expressed in many cancers, with the cytoplasmic C-terminal fragment (MUC1 C-ter) and its integration into the outer mitochondrial membrane linked to tumorigenic phenotypes similar to those of cells with elevated intrinsic ??m, we investigated whether endogenous differences in MUC1 levels were linked to stable differences in intrinsic ??m and/or to the tumor phenotypes associated with the intrinsic ??m. We report that levels of MUC1 are significantly higher in subpopulations of cells with elevated intrinsic ??m derived from both mammary and colonic carcinoma cell lines. However, using siRNA we found that down-regulation of MUC1 failed to significantly affect either the intrinsic ??m or the tumor phenotypes associated with increased intrinsic ??m. Moreover, whereas pharmacologically mediated disruption of the ??m was accompanied by attenuation of tumor phenotype, it had no impact on MUC1 levels. Therefore, while MUC1 over-expression is associated with subpopulations of cells with elevated intrinsic ??m, it is not directly linked to the generation or maintenance of stable alterations in intrinsic ??m, or to intrinsic ??m associated tumor phenotypes. Since the ??m is the focus of chemotherapeutic strategies, these data have important clinical implications in regard to effectively targeting those cells within a tumor cell population that exhibit stable elevations in intrinsic ??m and are most likely to contribute to tumor progression.

Project description:The classification of immune subtypes was based on immune signatures highlighting the tumor immuno-microenvironment. It was found that immune subtypes associated with mutation and expression patterns in the tumor. How the intrinsic genetic and transcriptomic alterations contribute to the immune subtypes and how to select drug combinations from both targeted drugs and immune therapeutic drugs according to different immune subtypes are still not clear. Through statistical analysis of genetic alterations and transcriptional profiles of breast invasive carcinoma (BRCA) samples, we found significant differences in the number of somatic missense mutations and frameshift deletions among the different immune subtypes. The high mutation load for somatic missense mutations and frameshift deletions may be explained by the high frequency of mutations and high expression of DNA double-strand break repair pathway genes. Extensive analysis of signaling pathways in both the genetic and transcriptomic levels reveals significantly altered pathways such as tumor protein Tumor Protein P53 (TP53) and receptor tyrosine kinase (RTK)/RAS signaling pathways among different subtypes. Drug targets in the signaling pathways such as mitogen-activated protein kinase kinase kinase 1 (MAP3K1) and Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) show genetic alteration in specific subtypes, which may be potential targets for patients of a specific subtype. More drug targets which show transcriptional difference among immune subtypes were discovered, such as cyclin-dependent kinase (CDK)4, CDK6, Erb-B2 receptor tyrosine kinase 2 (ERBB2), etc. Moreover, differences in functional activity between tumor growth and immune-related pathways also elucidate the extrinsic factors of differences in prognosis and suggest potential drug combinations for different immune subtypes. These results help to explain how intrinsic alterations are associated with the immune subtypes and provide clues for possible combination therapy for different immune subtypes.

Project description:For women with access to healthcare and early detection, breast cancer deaths are caused primarily by metastasis rather than growth of the primary tumor. Metastasis has been difficult to study because it happens deep in the body, occurs over years, and involves a small fraction of cells from the primary tumor. Furthermore, within-tumor heterogeneity relevant to metastasis can also lead to therapy failures and is obscured by studies of bulk tissue. Here we exploit heterogeneity to identify molecular mechanisms of metastasis. We use "organoids", groups of hundreds of tumor cells taken from a patient and grown in the lab, to probe tumor heterogeneity, with potentially thousands of organoids generated from a single tumor. We show that organoids have the character of biological replicates: within-tumor and between-tumor variation are of similar magnitude. We develop new methods based on population genetics and variance components models to build between-tumor and within-tumor statistical tests, using organoids analogously to large sibships and vastly amplifying the test power. We show great efficiency for tests based on the organoids with the most extreme phenotypes and potential cost savings from pooled tests of the extreme tails, with organoids generated from hundreds of tumors having power predicted to be similar to bulk tests of hundreds of thousands of tumors. We apply these methods to an association test for molecular correlates of invasion, using a novel quantitative invasion phenotype calculated as the spectral power of the organoid boundary. These new approaches combine to show a strong association between invasion and protein expression of Keratin 14, a known biomarker for poor prognosis, with p = 2 × 10-45 for within-tumor tests of individual organoids and p < 10-6 for pooled tests of extreme tails. Future studies using these methods could lead to discoveries of new classes of cancer targets and development of corresponding therapeutics. All data and methods are available under an open source license at https://github.com/baderzone/invasion_2019.

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Stable differences in intrinsic mitochondrial membrane potential of tumor cell subpopulations reflect phenotypic heterogeneity.

Publications

Stable differences in intrinsic mitochondrial membrane potential of tumor cell subpopulations reflect phenotypic heterogeneity.

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