Cancer Cell nucleus


 According to mainstream oncology thinking,  cancer is purported to be a genetic disease (1) Since the genome is localized in the nucleus it is only natural to assume that we would cure a cancer cell by replacing its nucleus with a healthy nucleus.
Has anyone put this hypothesis to the test ?
The answer is yes, see blog.

The reasons why the malignant cell is not cured by a nuclear replacement are various and complex. Metabolism of the cytoplasm seems to play a huge role in that. This is why cancer is now also considered a metabolic disease and not a mere genetic disease.

There are also changes in the mitochondria of cancer cells, that will continue to drive the cells towards growth and division even after you replaced the nucleus.

Additionally some of the key changes during tumorigenesis are conveyed by epigenetic proteins that can reside in the cytoplasm and just occasionally translocate into the nucleus. Those proteins (e.g. HDACs) are often overexpressed in cancer and will still affect the cells after the replacement of the cell’s nucleus.

The thing to understand here is that the nucleus and the genome are not the only things involved in the development of cancer. A recent study has shown that you can induce a very aggressive glioblastoma phenotype by inducing just 4 transcription factors that will alter the whole expression profile of the cell without causing a single mutation.

Cell. Author manuscript; available in PMC 2015 Apr 24.
Published in final edited form as:
PMCID: PMC4004670
PMID: 24726434

Reconstructing and reprogramming the tumor propagating potential of glioblastoma stem-like cells

Associated Data

Supplementary Materials


In mammalian development, stem and progenitor cells differentiate hierarchically to give rise to germ layers, lineages and specialized cell types. These cell fate decisions are dictated and sustained by master regulator transcription factors (TFs), chromatin regulators and associated cellular networks. It is now well established that developmental decisions can be overridden by artificial induction of combinations of ‘core’ TFs that yield induced pluripotent stem (iPS) cells or direct lineage conversion (Hanna et al., 2010; Morris and Daley, 2013; Orkin and Hochedlinger, 2011; Takahashi and Yamanaka, 2006; Vierbuchen and Wernig, 2011). These TFs bind and activate cis-regulatory elements that modulate transcription, and thereby direct cell type-specific gene expression programs (Lee and Young, 2013).

Increasing evidence suggests that certain malignant tumors also depend on a cellular hierarchy, with privileged sub-populations driving tumor propagation and growth. Moreover, many TFs that direct developmental decisions can also function as oncogenes by promoting the re-acquisition of developmental programs required for tumorigenesis (Suva et al., 2013). For example, the pluripotency and neurodevelopmental factor Sox2 is an essential driver of stem-like populations in multiple malignancies. Studies of leukemia pioneered the concept that triggering cellular differentiation can abolish certain malignant programs and override genetic alterations (Ito et al., 2008; Wang and Dick, 2005). Similarly, iPS reprogramming experiments have shown that artificially changing cancer cell identity profoundly alters their properties (Stricker et al., 2013). These findings suggest that epigenetic circuits superimposed upon genetic mutations determine key features of cancer cells.

The extent to which unidirectional differentiation hierarchies underlie tumor heterogeneity remains controversial (Visvader and Lindeman, 2012). For example, recent studies indicate that stem-like cells in breast cancer and melanoma exist in dynamic equilibrium with phenotypically distinct populations incapable of tumor propagation (Chaffer et al., 2013; Roesch et al., 2010). Alternatively, there is evidence supporting more classical hierarchies in other cancers, particularly in leukemias (Wang and Dick, 2005). In GBM models, reversibility seems to depend on the differentiation stimulus and time of exposure. Short-term exposure of GBM stem-like cells to BMP4 is sufficient to abolish their tumor-propagating potential, consistent with unidirectional differentiation (Piccirillo et al., 2006). Serum-triggered differentiation appears to proceed more gradually; short-term exposure can be reversed (Lee et al., 2006; Natsume et al., 2013), while longer-term exposure fully abolishes tumor-propagating potential (Janiszewska et al., 2012; Lee et al., 2006; Wakimoto et al., 2009). A better understanding of the molecular underpinnings that distinguish stem-like cancer cells and control plasticity within tumors is a critical goal with broad implications for diagnosis and therapy.

GBM is the most common malignant brain tumor in adults and remains incurable despite aggressive treatment (Jansen et al., 2010). Genome sequencing and transcriptional profiling studies have highlighted a large number of genetic events and identified multiple biologically relevant GBM subtypes, representing a major challenge for targeted therapy (Sturm et al., 2012; Verhaak et al., 2010). There is strong evidence that differentiation status significantly impacts GBM cell properties, with stem-like cells likely driving tumor propagation and therapeutic resistance (Bao et al., 2006; Chen et al., 2012). Although putative stem-like populations in GBM can be enriched using cell surface markers such as CD133 (Singh et al., 2004), SSEA-1 (Son et al., 2009), CD44 (Anido et al., 2010), and integrin alpha 6 (Lathia et al., 2010), the consistency of the various markers and the extent to which genetic heterogeneity contributes to observed phenotypic differences remains controversial. A TF code for GBM stem-like cells, analogous to those identified in iPS reprogramming and direct lineage conversion experiments, could thus provide critical insights into the epigenetic circuitry underlying GBM pathogenesis.

Here we combine functional genomics and cellular reprogramming to reconstruct the transcriptional circuitry that governs the developmental hierarchy in human GBM. By comparing the epigenetic landscapes of stem-like GBM cells against their differentiated counterparts, we identify four core TFs – POU3F2 (BRN2), SOX2, SALL2 and OLIG2 – whose induction is sufficient to reprogram differentiated GBM into stem-like cells capable of in vivo tumor propagation. We use this TF code to identify candidate tumor propagating cells in primary GBM tumors. Genome-wide binding maps and transcriptional profiles identify key regulatory targets of the core TFs, including the RCOR2/LSD1 histone demethylase complex. RCOR2 can substitute for OLIG2 in the reprogramming cocktail and, moreover, stem-like GBM cells are highly sensitive to LSD1 suppression, thus validating the regulatory model. Our findings demonstrate a cellular hierarchy in GBM, provide detailed insight into its transcriptional and epigenetic basis, and propose therapeutic strategies for eliminating stem-like tumor propagating cells in human GBM.

Reconstructing and reprogramming the tumor propagating potential of glioblastoma stem-like cells

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