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Nature Papers Present Way to Analyze Cancer Mutational Signatures, Explore Treatment Resistance in Lung Cancer, More

A framework for analyzing cancer mutational signatures is presented in Nature Cancer this week. Developed by researchers from the University of Cambridge, the framework is applied to 3,107 whole genome-sequenced primary cancers of 21 organs and reveals both known signatures and nine previously undescribed rearrangement signatures. The scientists also uncover evidence of organ-specific variation between signatures and highlight relationships with driver mutations including multiple mutational signatures of genomic instability that are contingent on TP53 dysregulation. They also discuss how uncertainty in mutational signature identification and assignment to samples affects tumor classification.

Using RNA sequencing and spatial transcriptomics, a team led by scientists from the Oncode Institute in the Netherlands report in Nature similarities between mouse gastruloids — three dimensional aggregates of embryonic stem cells — and embryos, supporting their use as model system for embryology. In their analysis, they identify a number of embryonic cell types that were not previously known to be present in gastruloids and show that key regulators of somitogenesis are expressed similarly between embryos and gastruloids. The investigators also demonstrate that gastruloids can be made to generate somites with the correct rostral-caudal patterning, which appear sequentially in an anterior-to-posterior direction over time. "In vitro mimics of development — such as gastruloids — are promising systems with which we are starting to obtain insights that could not readily be obtained with embryos," the authors write. "We therefore anticipate many applications of this system, which will help to unravel the complex processes that regulate embryogenesis."

Using single-cell RNA sequencing, a group led by researchers from the University of Texas MD Anderson Cancer Center find that treatment resistance in small cell lung cancer (SCLC) is followed by increased intratumoral heterogeneity (ITH). The findings point to multiple resistance mechanisms working together in the disease and highlight the need for combination therapies. As reported in Nature Cancer, the scientists generated circulating tumor cell (CTC)-derived xenografts from SCLC patients, sequencing both chemosensitive and chemoresistant xenografts, as well as patient CTCs. They find globally increased ITH, including heterogeneous expression of therapeutic targets and potential resistance pathways, between cellular subpopulations following treatment resistance. The findings, the study's authors write, "suggest that the window of therapeutic vulnerability in SCLC is short; thus, approaches featuring aggressive deployment of diverse strategies in the frontline and maintenance settings may be critical to conquering this devastating disease."