bims-cadres 2022-11-20 papers

Issue of 2022–11–20
seven papers selected by
Rana Gbyli, Yale University

Cancer Discov. 2022 Nov 18. OF1

FOXA2 Promotes Prostate Cancer Lineage Plasticity through KIT.

FOXA2 drives the adeno-to-neuroendocrine lineage transition in prostate cancer through KIT activation.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-201

Mutat Res Rev Mutat Res. 2022 Nov 09. pii: S1383-5742(22)00035-7. [Epub ahead of print] 108445

Clonal evolution and expansion associated with therapy resistance and relapse of Colorectal Cancer.

S Anupriya, Averi Chakraborty, Srinivas Patnaik.

Colorectal cancer (CRC) arises by a continuous process of genetic diversification and clonal evolution. Multiple genes and pathways have a role in tumor initiation and progression. The gradual accumulation of genetic and epigenetic processes leads to the establishment of adenoma and cancer. The important 'driver' mutations in tumor suppressor genes (such as TP53, APC, and SMAD4) and oncogenes (such as KRAS, NRAS, MET, and PIK3CA) confer selective growth advantages and cause CRC advancement. Clonal evolution induced by therapeutic pressure, as well as intra-tumoral heterogeneity, has been a great challenge in the treatment of metastatic CRC. Tumors often develop resistance to treatments as a result of intra-tumor heterogeneity, clonal evolution, and selection. Hence, the development of a multidrug personalized approach should be prioritized to pave the way for therapeutics repurposing and combination therapy to arrest tumor progression. This review summarizes how selective drug pressure can impact tumor evolution, resulting in the formation of polyclonal resistance mechanisms, ultimately promoting cancer progression. Current strategies for targeting clonal evolution are described. By understanding sources and consequences of tumor heterogeneity, customized and effective treatment plans to combat drug resistance may be devised.

Keywords: Clonal evolution; Colorectal cancer (CRC); Metastasis; Subclonal mutations; Tumor heterogeneity

DOI: https://doi.org/10.1016/j.mrrev.2022.108445

Cancer Cell. 2022 Nov 09. pii: S1535-6108(22)00520-7. [Epub ahead of print]

Revealing de novo pyrimidine synthesis as a key vulnerability in brain tumors.

Tanya Schild, Kayvan R Keshari.

Brain tumors are notoriously difficult to treat. Three recent Cancer Cell articles aim to uncover novel druggable targets in IDH mutant gliomas, diffuse midline gliomas, and medulloblastomas, respectively, and show that these brain tumor types shift their metabolism to become reliant on de novo pyrimidine synthesis.

DOI: https://doi.org/10.1016/j.ccell.2022.10.023

Nat Commun. 2022 Nov 14. 13(1): 6907

Replication collisions induced by de-repressed S-phase transcription are connected with malignant transformation of adult stem cells.

Ting Zhang, Carsten Künne, Dong Ding, Stefan Günther, Xinyue Guo, Yonggang Zhou, Xuejun Yuan, Thomas Braun.

Transcription replication collisions (TRCs) constitute a major intrinsic source of genome instability but conclusive evidence for a causal role of TRCs in tumor initiation is missing. We discover that lack of the H4K20-dimethyltransferase KMT5B (also known as SUV4-20H1) in muscle stem cells de-represses S-phase transcription by increasing H4K20me1 levels, which induces TRCs and aberrant R-loops in oncogenic genes. The resulting replication stress and aberrant mitosis activate ATR-RPA32-P53 signaling, promoting cellular senescence, which turns into rapid rhabdomyosarcoma formation when p53 is absent. Inhibition of S-phase transcription ameliorates TRCs and formation of R-loops in Kmt5b-deficient MuSCs, validating the crucial role of H4K20me1-dependent, tightly controlled S-phase transcription for preventing collision errors. Low KMT5B expression is prevalent in human sarcomas and associated with tumor recurrence, suggesting a common function of KMT5B in sarcoma formation. The study uncovers decisive functions of KMT5B for maintaining genome stability by repressing S-phase transcription via control of H4K20me1 levels.

DOI: https://doi.org/10.1038/s41467-022-34577-y

Nat Commun. 2022 Nov 17. 13(1): 7040

Single cell characterization of myeloma and its precursor conditions reveals transcriptional signatures of early tumorigenesis.

Rebecca Boiarsky, Nicholas J Haradhvala, Jean-Baptiste Alberge, Romanos Sklavenitis-Pistofidis, Tarek H Mouhieddine, Oksana Zavidij, Ming-Chieh Shih, Danielle Firer, Mendy Miller, Habib El-Khoury, Shankara K Anand, François Aguet, David Sontag, Irene M Ghobrial, Gad Getz.

Multiple myeloma is a plasma cell malignancy almost always preceded by precursor conditions, but low tumor burden of these early stages has hindered the study of their molecular programs through bulk sequencing technologies. Here, we generate and analyze single cell RNA-sequencing of plasma cells from 26 patients at varying disease stages and 9 healthy donors. In silico dissection and comparison of normal and transformed plasma cells from the same bone marrow biopsy enables discovery of patient-specific transcriptional changes. Using Non-Negative Matrix Factorization, we discover 15 gene expression signatures which represent transcriptional modules relevant to myeloma biology, and identify a signature that is uniformly lost in abnormal cells across disease stages. Finally, we demonstrate that tumors contain heterogeneous subpopulations expressing distinct transcriptional patterns. Our findings characterize transcriptomic alterations present at the earliest stages of myeloma, providing insight into the molecular underpinnings of disease initiation.

DOI: https://doi.org/10.1038/s41467-022-33944-z

Nat Commun. 2022 Nov 18. 13(1): 7014

Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions.

Karl-Uwe Reusswig, Julia Bittmann, Martina Peritore, Mathilde Courtes, Benjamin Pardo, Michael Wierer, Matthias Mann, Boris Pfander.

DNA replicates once per cell cycle. Interfering with the regulation of DNA replication initiation generates genome instability through over-replication and has been linked to early stages of cancer development. Here, we engineer genetic systems in budding yeast to induce unscheduled replication in a G1-like cell cycle state. Unscheduled G1 replication initiates at canonical S-phase origins. We quantifiy the composition of replisomes in G1- and S-phase and identified firing factors, polymerase α, and histone supply as factors that limit replication outside S-phase. G1 replication per se does not trigger cellular checkpoints. Subsequent replication during S-phase, however, results in over-replication and leads to chromosome breaks and chromosome-wide, strand-biased occurrence of RPA-bound single-stranded DNA, indicating head-to-tail replication collisions as a key mechanism generating genome instability upon G1 replication. Low-level, sporadic induction of G1 replication induces an identical response, indicating findings from synthetic systems are applicable to naturally occurring scenarios of unscheduled replication initiation.

DOI: https://doi.org/10.1038/s41467-022-34379-2

Nature. 2022 Nov 16.

Colon tumour cell death causes mTOR dependence by paracrine P2X4 stimulation.

Solid cancers exhibit a dynamic balance between cell death and proliferation ensuring continuous tumour maintenance and growth1,2. Increasing evidence links enhanced cancer cell apoptosis to paracrine activation of cells in the tumour microenvironment initiating tissue repair programs that support tumour growth3,4, yet the direct effects of dying cancer cells on neighbouring tumour epithelia and how this paracrine effect potentially contributes to therapy resistance are unclear. Here we demonstrate that chemotherapy-induced tumour cell death in patient-derived colorectal tumour organoids causes ATP release triggering P2X4 (also known as P2RX4) to mediate an mTOR-dependent pro-survival program in neighbouring cancer cells, which renders surviving tumour epithelia sensitive to mTOR inhibition. The induced mTOR addiction in persisting epithelial cells is due to elevated production of reactive oxygen species and subsequent increased DNA damage in response to the death of neighbouring cells. Accordingly, inhibition of the P2X4 receptor or direct mTOR blockade prevents induction of S6 phosphorylation and synergizes with chemotherapy to cause massive cell death induced by reactive oxygen species and marked tumour regression that is not seen when individually applied. Conversely, scavenging of reactive oxygen species prevents cancer cells from becoming reliant on mTOR activation. Collectively, our findings show that dying cancer cells establish a new dependency on anti-apoptotic programs in their surviving neighbours, thereby creating an opportunity for combination therapy in P2X4-expressing epithelial tumours.

DOI: https://doi.org/10.1038/s41586-022-05426-1