Effect of miR-206 Derived from Bone Marrow Mesenchymal Stem Cells (BMSCs) on CD8 Expression in Gastric Cancer

The BMSCs are one of the components of tumor micro-environment and participate in tumor evolution. Our study aimed to discuss the effect of exosome derived from BMSC on gastric cancer cells. Tumor and para-tumor tissues were isolated to measure miR-206 level by RT-PCR. Gastric cancer cell behaviors were analyzed using MTT assay and scratch test. Gastric cancer model was established and treated TIGIT inhibitor to assess its role in the tumor growth in vivo. The miR-206 in exosome from BMSCs in cancer tissue was detected. CD8 expression excreted by DC could be induced after miR-206 treatment possibly through regulating the signaling pathway of TIGIT/PVR. Inhibition of TIGIT decreased tumor growth, development and reversed tumor phenotype. In conclusion, miR-206 derived from BMSCs induces CD8 expression in gastric cancer through regulating the signaling pathway of TIGIT/PVR, indicating that it might be a novel target for the treatment of gastric cancer.

Transgenerational transcriptional heterogeneity from cytoplasmic chromatin

Transcriptional heterogeneity from plasticity of the epigenetic state of chromatin is thought to contribute to tumor evolution, metastasis, and drug resistance. However, the mechanisms leading to nongenetic cell-to-cell variation in gene expression remain poorly understood. Here we demonstrate that heritable transcriptional changes can result from the formation of micronuclei, aberrations of the nucleus that are common in cancer. Micronuclei have fragile nuclear envelopes (NE) that are prone to spontaneous rupture, which exposes chromosomes to the cytoplasm and disrupts many nuclear activities. Using a combination of long-term live-cell imaging and same-cell, single-cell RNA sequencing (Look-Seq2), we identified significant reduction of gene expression in micronuclei, both before and after NE rupture. Furthermore, chromosomes in micronuclei fail to normally recover histone 3 lysine 27 acetylation, a critical step for the reestablishment of normal transcription after mitosis. These transcription and chromatin defects can persist into the next generation in a subset of cells, even after these chromosomes are incorporated into normal daughter nuclei. Moreover, persistent transcriptional repression is strongly associated with, and may be explained by, surprisingly long-lived DNA damage to these reincorporated chromosomes. Therefore, heritable alterations in transcription can originate from aberrations of nuclear architecture.

Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma

Glioblastoma is the most aggressive brain tumor with a median survival ranging from 6.2 to 16.7 months. The complex interactions between the tumor and the cells of tumor microenvironment leads to tumor evolution which ultimately results in treatment failure. Immunotherapy has shown great potential in the treatment of solid tumors but has been less effective in treating glioblastoma. Failure of immunotherapy in glioblastoma has been attributed to low T-cell infiltration in glioblastoma and dysfunction of the T-cells that are present in the glioblastoma microenvironment. Recent advances in single-cell sequencing have increased our understanding of the transcriptional changes in the tumor microenvironment pre and post-treatment. Another treatment modality targeting the tumor microenvironment that has failed in glioblastoma has been anti-angiogenic therapy such as the VEGF neutralizing antibody bevacizumab, which did not improve survival in randomized clinical trials. Interestingly, the immunosuppressed microenvironment and abnormal vasculature of glioblastoma interact in ways that suggest the potential for synergy between these two therapeutic modalities that have failed individually. Abnormal tumor vasculature has been associated with immune evasion and the creation of an immunosuppressive microenvironment, suggesting that inhibiting pro-angiogenic factors like VEGF can increase infiltration of effector immune cells into the tumor microenvironment. Remodeling of the tumor vasculature by inhibiting VEGFR2 has also been shown to improve the efficacy of PDL1 cancer immunotherapy in mouse models of different cancers. In this review, we discuss the recent developments in our understanding of the glioblastoma tumor microenvironment specially the tumor vasculature and its interactions with the immune cells, and opportunities to target these interactions therapeutically. Combining anti-angiogenic and immunotherapy in glioblastoma has the potential to unlock these therapeutic modalities and impact the survival of patients with this devastating cancer.

Pervasive conditional selection of driver mutations and modular epistasis networks in cancer

Cancer driver mutations often display mutual exclusion or co-occurrence, underscoring the key role of epistasis in carcinogenesis. However, estimating the magnitude of epistatic interactions and their quantitative effect on tumor evolution remains a challenge. We developed a method to quantify COnditional SELection on the Excess of Nonsynonymous Substitutions (Coselens) in cancer genes. Coselens infers the number of drivers per gene in different partitions of a cancer genomics dataset using covariance-based mutation models and determines whether coding mutations in a gene affect selection for drivers in any other gene. Using Coselens, we identified 296 conditionally selected gene pairs across 16 cancer types in the TCGA dataset. Conditional selection accounts for 25-50% of driver substitutions in tumors with >2 drivers. Conditionally co-selected genes form modular networks, whose structures challenge the traditional interpretation of within-pathway mutual exclusivity and across-pathway synergy, suggesting a more complex scenario, where gene-specific across-pathway interactions shape differentiated cancer subtypes.

Transition Therapy: Tackling the Ecology of Tumor Phenotypic Plasticity

Phenotypic switching in cancer cells has been found to be present across tumor types. Recent studies on Glioblastoma report a remarkably common architecture of four well-defined phenotypes coexisting within high levels of intra-tumor genetic heterogeneity. Similar dynamics have been shown to occur in breast cancer and melanoma and are likely to be found across cancer types. Given the adaptive potential of phenotypic switching (PHS) strategies, understanding how it drives tumor evolution and therapy resistance is a major priority. Here we present a mathematical framework uncovering the ecological dynamics behind PHS. The model is able to reproduce experimental results, and mathematical conditions for cancer progression reveal PHS-specific features of tumors with direct consequences on therapy resistance. In particular, our model reveals a threshold for the resistant-to-sensitive phenotype transition rate, below which any cytotoxic or switch-inhibition therapy is likely to fail. The model is able to capture therapeutic success thresholds for cancers where nonlinear growth dynamics or larger PHS architectures are in place, such as glioblastoma or melanoma. By doing so, the model presents a novel set of conditions for the success of combination therapies able to target replication and phenotypic transitions at once. Following our results, we discuss transition therapy as a novel scheme to target not only combined cytotoxicity but also the rates of phenotypic switching.

Conditional prediction of consecutive tumor evolution using cancer progression models: What genotype comes next?

Accurate prediction of tumor progression is key for adaptive therapy and precision medicine. Cancer progression models (CPMs) can be used to infer dependencies in mutation accumulation from cross-sectional data and provide predictions of tumor progression paths. However, their performance when predicting complete evolutionary trajectories is limited by violations of assumptions and the size of available data sets. Instead of predicting full tumor progression paths, here we focus on short-term predictions, more relevant for diagnostic and therapeutic purposes. We examine whether five distinct CPMs can be used to answer the question “Given that a genotype with n mutations has been observed, what genotype with n + 1 mutations is next in the path of tumor progression?” or, shortly, “What genotype comes next?”. Using simulated data we find that under specific combinations of genotype and fitness landscape characteristics CPMs can provide predictions of short-term evolution that closely match the true probabilities, and that some genotype characteristics can be much more relevant than global features. Application of these methods to 25 cancer data sets shows that their use is hampered by a lack of information needed to make principled decisions about method choice. Fruitful use of these methods for short-term predictions requires adapting method’s use to local genotype characteristics and obtaining reliable indicators of performance; it will also be necessary to clarify the interpretation of the method’s results when key assumptions do not hold.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 7: PD-L1 Expression in Liquid Biopsy

Liquid biopsy is an accessible, non-invasive diagnostic tool for advanced prostate cancer (PC) patients, potentially representing a real-time monitoring test for tumor evolution and response to treatment through the analysis of circulating tumor cells (CTCs) and exosomes. We performed a systematic literature review (PRISMA guidelines) to describe the current knowledge about PD-L1 expression in liquid biopsies of PC patients: 101/159 (64%) cases revealed a variable number of PD-L1+ CTCs. Outcome correlations should be investigated in larger series. Nuclear PD-L1 expression by CTCs was occasionally associated with worse prognosis. Treatment (abiraterone, enzalutamide, radiotherapy, checkpoint-inhibitors) influenced PD-L1+ CTC levels. Discordance in PD-L1 status was detected between primary vs. metastatic PC tissue biopsies and CTCs vs. corresponding tumor tissues. PD-L1 is also released by PC cells through soluble exosomes, which could inhibit the T cell function, causing immune evasion. PD-L1+ PC-CTC monitoring and genomic profiling may better characterize the ongoing aggressive PC forms compared to PD-L1 evaluation on primary tumor biopsies/prostatectomy specimens (sometimes sampled a long time before recurrence/progression). Myeloid-derived suppressor cells and dendritic cells (DCs), which may have immune-suppressive effects in tumor microenvironment, have been found in PC patients circulation, sometimes expressing PD-L1. Occasionally, their levels correlated to clinical outcome. Enzalutamide-progressing castration-resistant PC patients revealed increased PD-1+ T cells and circulating PD-L1/2+ DCs.

A Novel Oncogenic Function of PRC2 Heterogeneity in Medulloblastoma

Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Medulloblastomas, the most common childhood malignant brain tumor, are classified into four subtypes including SHH medulloblastomas, which are characterized by elevated SHH signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Medulloblastomas are highly associated with epigenetic abnormalities. We observed that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. Using mouse models, we showed that while a complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete EED deletion led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, we found that medulloblastomas with mosaic EED levels grew faster than did control wildtype tumors and expressed increased levels of oncogenes such as Igf2. Igf2 is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. We showed that IGF2 mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Using a human medulloblastoma cell line, we generated clones with different EED levels and confirmed that EEDlow cells could stimulate the growth of EEDhigh cells through derepressed IGF2 signals. Thus, PRC2 heterogeneity controls medulloblastoma growth through both intrinsic growth competence and non-cell autonomous mechanisms in distinct tumor subclones. We reveal a novel oncogenic function of PRC2 heterogeneity in tumor development.