Time-resolved, integrated analysis of clonal genome evolution in parthenogenetic animals and in cancer

Clonal genome evolution is a key aspect for parthenogenetic species and cancer. While many studies describe precise landscapes of clonal evolution in cancer, few studies determine the underlying evolutionary parameters from molecular data, and fewer integrate theory with data. We derived theoretical results linking mutation rate, time, expansion dynamics, transition to recurrence, and survival. With this, we inferred time-resolved estimates of evolutionary parameters from mutation accumulation, mutational signatures and selection. Using this framework we traced the speciation of the rapidly emerging and invasive marbled crayfish to a time window between 1947 and 1996, which is consistent with biological records. In glioblastoma samples, we determined tumor expansion patterns, and tumor cell survival ratio at resection. Interestingly, our results suggest that the expansion pattern in the primary tumor is predictive of the progress and time to recurrence. In addition, tumor cell survival was always higher after resection and was associated with the expansion pattern and time to recurrence. We further observed selection events in a subset of tumors, with longer and purifying-only selection phases in recurrent tumors. In conclusion, our framework allowed a time-resolved, integrated analysis of key parameters in clonally evolving genomes, and provided novel insights into the evolutionary age of marbled crayfish and the progression of glioblastoma.

The Multiple Faces of MNT and Its Role as a MYC Modulator

MNT is a crucial modulator of MYC, controls several cellular functions, and is activated in most human cancers. It is the largest, most divergent, and most ubiquitously expressed protein of the MXD family. MNT was first described as a MYC antagonist and tumor suppressor. Indeed, 10% of human tumors present deletions of one MNT allele. However, some reports show that MNT functions in cooperation with MYC by maintaining cell proliferation, promoting tumor cell survival, and supporting MYC-driven tumorigenesis in cellular and animal models. Although MAX was originally considered MNT’s obligate partner, our recent findings demonstrate that MNT also works independently. MNT forms homodimers and interacts with proteins both outside and inside of the proximal MYC network. These complexes are involved in a wide array of cellular processes, from transcriptional repression via SIN3 to the modulation of metabolism through MLX as well as immunity and apoptosis via REL. In this review, we discuss the present knowledge of MNT with a special focus on its interactome, which sheds light on the complex and essential role of MNT in cell biology.

The Nucleus/Mitochondria-Shuttling LncRNAs Function as New Epigenetic Regulators of Mitophagy in Cancer

Mitophagy is a specialized autophagic pathway responsible for the selective removal of damaged or dysfunctional mitochondria by targeting them to the autophagosome in order to maintain mitochondria quality. The role of mitophagy in tumorigenesis has been conflicting, with the process both supporting tumor cell survival and promoting cell death. Cancer cells may utilize the mitophagy pathway to augment their metabolic requirements and resistance to cell death, thereby leading to increased cell proliferation and invasiveness. This review highlights major regulatory pathways of mitophagy involved in cancer. In particular, we summarize recent progress regarding how nuclear-encoded long non-coding RNAs (lncRNAs) function as novel epigenetic players in the mitochondria of cancer cells, affecting the malignant behavior of tumors by regulating mitophagy. Finally, we discuss the potential application of regulating mitophagy as a new target for cancer therapy.

Targeting tumor-macrophage interaction via the Notch2-Jag1 axis reverses tumor resistance to paclitaxel

Taxanes are widely used in chemotherapy, but intrinsic and acquired resistance limit the clinical outcomes. Studies showed tumor interaction with suppressive macrophages plays a key role in taxane resistance, yet therapeutic strategies that deplete or repolarize macrophages are challenging. Here we uncovered a novel tumor-macrophage interaction via Notch2-Jag1 justacrine signaling that can be targeted to sensitize paclitaxel response without affecting the broad macrophage functions. Using translatome profiling, we identified Notch2 upregulation during taxol-induced prolonged mitosis. Notch2 was subsequently activated in the post-mitotic G1 phase by Jag1 expressed on neighboring macrophages, which promoted tumor cell survival by upregulating p38 and anti-apoptotic proteins. Notch2 also upregulated cytokines that further recruited Jag1-expressing macrophages. By targeting this Notch2-Jag1 interaction with a pan-Notch inhibitor, RO4929097, taxol resistance was significantly attenuated in multiple mouse tumor models. Our results point to combining Notch inhibitor with taxane as an effective strategy to selectively disrupt tumor-macrophage interaction underlying chemoresistance.

Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response

Caveolae-associated protein 3 (cavin3) is inactivated in most cancers. We characterized how cavin3 affects the cellular proteome using genome-edited cells together with label-free quantitative proteomics. These studies revealed a prominent role for cavin3 in DNA repair, with BRCA1 and BRCA1 A-complex components being downregulated on cavin3 deletion. Cellular and cell-free expression assays revealed a direct interaction between BRCA1 and cavin3 that occurs when cavin3 is released from caveolae that are disassembled in response to UV and mechanical stress. Overexpression and RNAi-depletion revealed that cavin3 sensitized various cancer cells to UV-induced apoptosis. Supporting a role in DNA repair, cavin3-deficient cells were sensitive to PARP inhibition, where concomitant depletion of 53BP1 restored BRCA1-dependent sensitivity to PARP inhibition. We conclude that cavin3 functions together with BRCA1 in multiple cancer-related pathways. The loss of cavin3 function may provide tumor cell survival by attenuating apoptotic sensitivity and hindering DNA repair under chronic stress conditions.