tumor initiation
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More options are needed for the effective treatment of melanoma. In a previous study, we discovered the small molecule drug YK-4-279 almost completely inhibited tumor progression in the BrafCA;Tyr-CreERT2;Ptenflox/flox transgenic mouse model. YK-4-279 had no effect on tumor initiation but blocked progression of invasive melanoma. Our current study was designed as a treatment model, where YK-4-279 was administered during pigmented lesion formation. The study design included the use of three groups: (1) a control group that received only DMSO without a drug (MOCK), (2) mice following our prior studies with YK-4-279 administered at the time of tumor induction (YK-4-279), and (3) mice treated during tumor initiation (YK-4-279 delay). While the MOCK mice had progression of tumors, both YK-4-279 and YK-4-279 delay groups had a significant block or delay of progression. The majority of mice in the YK-4-279 groups had a block of progression, while the YK-4-279 delay group had either a partial block (60% in male mice or 29% in females) or a delay in disease progression in females (28 days in controls to 50 days in YK-4-279 delay group). Here, we demonstrate that YK-4-279 has a significant impact on blocking or delaying tumor progression in a pre-clinical treatment model of melanoma.

Glioblastoma (GBM) is the most aggressive brain tumor in adults and is characterized by an immunosuppressive microenvironment. Different factors shaping this tumor microenvironment (TME) regulate tumor initiation, progression, and treatment response. Genetic alterations and metabolism pathways are two main elements that influence tumor immune cells and TME. In this manuscript, we review how both factors can contribute to an immunosuppressive state and overview the strategies being tested.

Epstein-Barr Virus (EBV) is associated with several malignant diseases, including Burkitt’s lymphoma, nasopharyngeal carcinoma (NPC), certain types oflymphomas,and a portion of gastric cancers. Virus-encoded oncoprotein LMP1 induces the epithelial-to-mesenchymal transition (EMT), leading to cancer stem cell formation. In the current study, we investigated how LMP1 contributes to cancer stem cell development in NPC. We found that LMP1 plays an essential role in acquiring CSC characteristics, including tumor initiation, metastasis, and therapeutic resistance by activating the PI3K/mTOR/Akt signaling pathway. We dissected the functions of distinct signaling (mTORC1 and mTORC2) in the acquisition of different CSC characteristics. Side population (SP) formation, which represents the chemotherapy resistance feature of CSC, requires mTORC1 signaling. Tumor initiation capability is mainly attributed to mTORC2, which confers on NPC the capabilities of proliferation and survival by activating mTORC2 downstream genes c-Myc. Both mTORC1 and mTORC2 enhance cell migration and invasion of NPC cells, suggesting that mTORC1/2 co-regulate metastasis of NPC. The revelation of the roles of the mTOR signaling pathways in distinct tumorigenic features provides a guideline for designing efficient therapies by choosing specific mTOR inhibitors targeting mTORC1, mTORC2, or both to achieve durable remission of NPC in patients.

Abstract Background Cancer stem cells (CSC) have been implicated in tumor progression. In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, thus contributing to the high death-to-incidence ratio of this disease. However, the molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been elucidated only to a limited extent. In this context, the functional contribution of the L1 cell adhesion molecule (L1CAM) to OC stemness remains elusive. Methods The expression of L1CAM was investigated in patient-derived OCSC. The genetic manipulation of L1CAM in OC cells provided gain and loss-of-function models that were then employed in cell biological assays as well as in vivo tumorigenesis experiments to assess the role of L1CAM in OC cell stemness and in OCSC-driven tumor initiation. We applied antibody-mediated neutralization to investigate L1CAM druggability. Biochemical approaches were then combined with functional in vitro assays to study the molecular mechanisms underlying the functional role of L1CAM in OCSC. Results We report that L1CAM is upregulated in patient-derived OCSC. Functional studies showed that L1CAM promotes several stemness-related properties in OC cells, including sphere formation, tumor initiation and chemoresistance. These activities were repressed by an L1CAM-neutralizing antibody, pointing to L1CAM as a druggable target. Mechanistically, L1CAM interacted with and activated fibroblast growth factor receptor-1 (FGFR1), which in turn induced the SRC-mediated activation of STAT3. The inhibition of STAT3 prevented L1CAM-dependent OC stemness and tumor initiation. Conclusions Our study implicate L1CAM in the tumorigenic function of OCSC and point to the L1CAM/FGFR1/SRC/STAT3 signaling pathway as a novel driver of OC stemness. We also provide evidence that targeting this pathway can contribute to OC eradication.

ABSTRACTA small population of self-renewing stem cells initiate tumors and maintain therapeutic resistance in glioblastoma. Given the limited treatment options and dismal prognosis for this disease there is urgent need to identify drivers of stem cells that could be druggable targets. Previous work showed that the endosomal pH regulator NHE9 is upregulated in glioblastoma and correlates with worse survival prognosis. Here, we probed for aberrant signaling pathways in patient-derived glioblastoma cells and found that NHE9 increases cell surface expression and phosphorylation of multiple receptor tyrosine kinases by promoting their escape from lysosomal degradation. Downstream of NHE9-mediated receptor activation, oncogenic signaling pathways converged on the JAK2-STAT3 transduction axis to induce pluripotency genes Oct4 and Nanog and suppress markers of glial differentiation. We used both genetic and chemical approaches to query the role of endosomal pH in glioblastoma phenotypes. Loss-of-function mutations in NHE9 that failed to alkalinize endosomal lumen did not increase self-renewal capacity of gliomaspheres in vitro. However, monensin, a chemical mimetic of Na+/H+ exchanger activity, and the H+ pump inhibitor bafilomycin bypassed NHE9 to directly alkalinize the endosomal lumen resulting in stabilization of receptor tyrosine kinases and induction of Oct4 and Nanog. Using orthotopic models of primary glioblastoma cells we found that NHE9 increased tumor initiation in vivo. We propose that NHE9 initiates inside-out signaling from the endosomal lumen, distinct from the established effects of cytoplasmic and extracellular pH on tumorigenesis. Endosomal pH may be an attractive therapeutic target that diminishes stemness in glioblastoma, agnostic of specific receptor subtype.SignificanceA well-known hallmark of cancer is excessive acidification of tumor microenvironment, caused by upregulation of Na+/H+ exchanger activity on the cancer cell membrane. However, the role of organellar pH in tumor biology has not been established. This study identifies a mechanistic link between upregulation of the endosomal Na+/H+ exchanger NHE9 and stemness properties in glioblastoma, the most malignant and common brain tumor in adults. By increasing pH of the recycling endosome, NHE9 exerts a broad effect on post-translational stability and activation of multiple receptor tyrosine kinases, leading to increased stem cell-like properties of self-renewal and tumor initiation in glioblastoma models. Our findings suggest that targeting NHE9 or endosomal pH could be an effective strategy for receptor agnostic glioblastoma treatment.

Genes encoding subunits of SWItch/Sucrose Non-Fermenting (SWI/SNF) chromatin remodeling complexes are collectively mutated in 20% of all human cancers, among which the AT-rich interacting domain−containing protein 1A (ARID1A, also known as BAF250a, B120, C1orf4, Osa1) that encodes protein ARID1A is the most frequently mutated, and mutations in ARID1A have been found in various types of cancer. ARID1A is thought to play a significant role both in tumor initiation and in tumor suppression, which is highly dependent upon context. Recent molecular mechanistic research has revealed that ARID1A participates in tumor progression through its effects on control of cell cycle, modulation of cellular functions such as EMT, and regulation of various signaling pathways. In this review, we synthesize a mechanistic understanding of the role of ARID1A in human tumor initiation as well as in tumor suppression and further discuss the implications of these new discoveries for potential cancer intervention. We also highlight the mechanisms by which mutations affecting the subunits in SWI/SNF complexes promote cancer.