Differentiation therapy and the mechanisms that terminate cancer cell proliferation without harming normal cells

Abstract

Chemotherapeutic drugs have a common intent to activate apoptosis in tumor cells. However, master regulators of apoptosis (e.g., p53, p16/CDKN2A) are frequently genetically inactivated in cancers, resulting in multidrug resistance. An alternative, p53-independent method for terminating malignant proliferation is to engage terminal-differentiation. Normally, the exponential proliferation of lineage-committed progenitors, coordinated by the master transcription factor (TF) MYC, is self-limited by forward-differentiation to terminal lineage-fates. In cancers, however, this exponential proliferation is disengaged from terminal-differentiation. The mechanisms underlying this decoupling are mostly unknown. We performed a systematic review of published literature (January 2007–June 2018) to identify gene pathways linked to differentiation-failure in three treatment-recalcitrant cancers: hepatocellular carcinoma (HCC), ovarian cancer (OVC), and pancreatic ductal adenocarcinoma (PDAC). We analyzed key gene alterations in various apoptosis, proliferation and differentiation pathways to determine whether it is possible to predict treatment outcomes and suggest novel therapies. Poorly differentiated tumors were linked to poorer survival across histologies. Our analyses suggested loss-of-function events to master TF drivers of lineage-fates and their cofactors as being linked to differentiation-failure: genomic data in TCGA and ICGC databases demonstrated frequent haploinsufficiency of lineage master TFs (e.g., GATA4/6) in poorly differentiated tumors; the coactivators that these TFs use to activate genes (e.g. ARID1A, PBRM1) were also frequently inactivated by genetic mutation and/or deletion. By contrast, corepressor components (e.g., DNMT1, EED, UHRF1, and BAZ1A/B), that oppose coactivators to repress or turn off genes, were frequently amplified instead, and the level of amplification was highest in poorly differentiated lesions. This selection by neoplastic evolution towards unbalanced activity of transcriptional corepressors suggests these enzymes as candidate targets for inhibition aiming to re-engage forward-differentiation. This notion is supported by both pre-clinical and clinical trial literature.

Elevated PDK1 Expression Drives PI3K/AKT/MTOR Signaling Promotes Radiation-Resistant and Dedifferentiated Phenotype of Hepatocellular Carcinoma

“…Our data indicating that the aberrant expression of PDK1 characterizes poorly differentiated aggressive HCC cells is of translational relevance, considering that PDK1 facilitates the phosphorylation of its protein substrates, and phosphorylation has been shown to modulate the maintenance or repression of pluripotency, which is the ability of individual cells to differentiate into any somatic cell lineage [26,27]. Understanding that malignant cells differ from normal cells based, among other traits, on their propensity to proliferate without terminal differentiation; we posit that the observed aberration in PDK1 expression and/or activity permits and facilitates the occurrence of perpetual/unlimited proliferation of HCC lineage-committed progenitors while deterring terminal differentiation of the cancerous cells [28]. In fact, differentiation-failure and the degree of such differentiation-failure, as reflected by the undifferentiated or poorly differentiated cell status, distinguish benign from malignant tumors and dictate the degree of malignant transformations [28].…”

“…Understanding that malignant cells differ from normal cells based, among other traits, on their propensity to proliferate without terminal differentiation; we posit that the observed aberration in PDK1 expression and/or activity permits and facilitates the occurrence of perpetual/unlimited proliferation of HCC lineage-committed progenitors while deterring terminal differentiation of the cancerous cells [28]. In fact, differentiation-failure and the degree of such differentiation-failure, as reflected by the undifferentiated or poorly differentiated cell status, distinguish benign from malignant tumors and dictate the degree of malignant transformations [28]. Our findings thus indicate the complicity of PDK1 in differentiation-failure oncogenic transformation, and the therapy-resistant phenotype of HCC cells, especially as cellular differentiation depends on the activity of master pluripotency transcription factors (TFs) such as MYC, OCT4, or SOX2 and cofactors like PDK1 invariably serving as important transcriptional coactivator or corepressor that use adenosine triphosphate (ATP) for chromatin remodeling, which 'switches on' or 'switches off' substrates/target genes, enhancing the proliferative index and consequently eliciting treatment failure and poor prognosis [27,28].…”

Hypersilencing of SRRM4 suppresses basal microexon inclusion and promotes tumor growth across cancers

“…This antiproliferative activity is also linked to the induction of neuronal differentiation-related genes and splicing patterns, in accordance with the known function of SRRM4 in promoting neuronal differentiation. Proliferation and differentiation are widely considered to be distinct and antagonistic cell states, where terminal differentiation is normally accompanied by exit from the cell cycle and loss of proliferative capacity, and conversely cancer cells evade pro-differentiation programs to promote their proliferation and self-renewing abilities 27,[33][34][35] . We therefore surmise that silencing of SRRM4 provides a selective advantage to cancer cells by shifting the cell state away from differentiation and towards proliferation.…”

<p>Is there a CDKN2A-centric network in pancreatic ductal adenocarcinoma?</p>

“…141,142 TP53 and CDKN2A are often biallelically inactivated in human malignancies, which has a significant impact on treatment. 143,144 MYC induces the inactivation or loss of TP53 by activating the tumor suppressor p19ARF, at this time p19ARF and MYC have a significant carcinogenic synergy. 145 Disruption of the TP53 pathway in PDAC may lose the intrinsic proliferation pathway triggered by MYC activation through mechanisms other than apoptosis inhibition and promote tumorigenesis.…”