bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2024‒11‒03
twenty-two papers selected by
Xiao Qin, University of Oxford
  1. Progressive plasticity during colorectal cancer metastasis.
  2. Spatiotemporal lineage tracing reveals the dynamic spatial architecture of tumor growth and metastasis.
  3. Polyclonality overcomes fitness barriers in Apc-driven tumorigenesis.
  4. Ultra-precise 3D maps of cancer cells unlock secrets of how tumours grow.
  5. Statistical inference with a manifold-constrained RNA velocity model uncovers cell cycle speed modulations.
  6. Tumour atlases enable researchers to navigate through cancers.
  7. Temporal recording of mammalian development and precancer.
  8. Single-Cell Transcriptomics Reveals Cellular Heterogeneity and Drivers in Serrated Pathway-Driven Colorectal Cancer Progression.
  9. Assembloid models of cell-cell interaction to study tissue and disease biology.
  10. scLTdb: a comprehensive single-cell lineage tracing database.
  11. Multiparameter imaging reveals clinically relevant cancer cell-stroma interaction dynamics in head and neck cancer.
  12. Defining the transcriptional lineages of breast cancer subtypes.
  13. Stemness in solid malignancies: coping with immune attack.
  14. Mapping metastatic breast cancer complexity through single-cell and spatial profiling.
  15. A multi-modal single-cell and spatial expression map of metastatic breast cancer biopsies across clinicopathological features.
  16. Tumour evolution and microenvironment interactions in 2D and 3D space.
  17. More People in Their 40s Being Screened for Colorectal Cancer Under New Recommendation.
  18. Polyclonal-to-monoclonal transition in colorectal precancerous evolution.
  19. Highly Multiplexed Tissue Imaging in Precision Oncology and Translational Cancer Research.
  20. The present and future of the Cancer Dependency Map.
  21. A cross-species foundation model for single cells.
  22. Building an Organ-Wide Macroscopic View of Cancer Hallmarks.
  1. Nature. 2024 Oct 30.
    Progressive plasticity during colorectal cancer metastasis.
    A R Moorman, E K Benitez, F Cambuli, Q Jiang, A Mahmoud, M Lumish, S Hartner, S Balkaran, J Bermeo, S Asawa, C Firat, A Saxena, F Wu, A Luthra, C Burdziak, Y Xie, V Sgambati, K Luckett, Y Li, Z Yi, I Masilionis, K Soares, E Pappou, R Yaeger, P Kingham, W Jarnagin, P Paty, M R Weiser, L Mazutis, M D'Angelica, J Shia, J Garcia-Aguilar, T Nawy, T J Hollmann, R Chaligné, F Sanchez-Vega, R Sharma, D Pe'er, K Ganesh.
      As cancers progress, they become increasingly aggressive-metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death1,2. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance3-5. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1 as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1 licenses non-canonical reprogramming.
    DOI:  https://doi.org/10.1038/s41586-024-08150-0
  2. bioRxiv. 2024 Oct 24. pii: 2024.10.21.619529. [Epub ahead of print]
    Spatiotemporal lineage tracing reveals the dynamic spatial architecture of tumor growth and metastasis.
    Matthew G Jones, Dawei Sun, Kyung Hoi Joseph Min, William N Colgan, Luyi Tian, Jackson A Weir, Victor Z Chen, Luke W Koblan, Kathryn E Yost, Nicolas Mathey-Andrews, Andrew J C Russell, Robert R Stickels, Karol S Balderrama, William M Rideout, Howard Y Chang, Tyler Jacks, Fei Chen, Jonathan S Weissman, Nir Yosef, Dian Yang.
      Tumor progression is driven by dynamic interactions between cancer cells and their surrounding microenvironment. Investigating the spatiotemporal evolution of tumors can provide crucial insights into how intrinsic changes within cancer cells and extrinsic alterations in the microenvironment cooperate to drive different stages of tumor progression. Here, we integrate high-resolution spatial transcriptomics and evolving lineage tracing technologies to elucidate how tumor expansion, plasticity, and metastasis co-evolve with microenvironmental remodeling in a Kras;p53 -driven mouse model of lung adenocarcinoma. We find that rapid tumor expansion contributes to a hypoxic, immunosuppressive, and fibrotic microenvironment that is associated with the emergence of pro-metastatic cancer cell states. Furthermore, metastases arise from spatially-confined subclones of primary tumors and remodel the distant metastatic niche into a fibrotic, collagen-rich microenvironment. Together, we present a comprehensive dataset integrating spatial assays and lineage tracing to elucidate how sequential changes in cancer cell state and microenvironmental structures cooperate to promote tumor progression.
    DOI:  https://doi.org/10.1101/2024.10.21.619529
  3. Nature. 2024 Oct;634(8036): 1196-1203
    Polyclonality overcomes fitness barriers in Apc-driven tumorigenesis.
    Iannish D Sadien, Sam Adler, Shenay Mehmed, Sasha Bailey, Ashley Sawle, Dominique-Laurent Couturier, Matthew Eldridge, David J Adams, Richard Kemp, Filipe C Lourenço, Douglas J Winton.
      Loss-of-function mutations in the tumour suppressor APC are an initial step in intestinal tumorigenesis1,2. APC-mutant intestinal stem cells outcompete their wild-type neighbours through the secretion of Wnt antagonists, which accelerates the fixation and subsequent rapid clonal expansion of mutants3-5. Reports of polyclonal intestinal tumours in human patients and mouse models appear at odds with this process6,7. Here we combine multicolour lineage tracing with chemical mutagenesis in mice to show that a large proportion of intestinal tumours have a multiancestral origin. Polyclonal tumours retain a structure comprising subclones with distinct Apc mutations and transcriptional states, driven predominantly by differences in KRAS and MYC signalling. These pathway-level changes are accompanied by profound differences in cancer stem cell phenotypes. Of note, these findings are confirmed by introducing an oncogenic Kras mutation that results in predominantly monoclonal tumour formation. Further, polyclonal tumours have accelerated growth dynamics, suggesting a link between polyclonality and tumour progression. Together, these findings demonstrate the role of interclonal interactions in promoting tumorigenesis through non-cell autonomous pathways that are dependent on the differential activation of oncogenic pathways between clones.
    DOI:  https://doi.org/10.1038/s41586-024-08053-0
  4. Nature. 2024 Oct 30.
    Ultra-precise 3D maps of cancer cells unlock secrets of how tumours grow.
    Miryam Naddaf.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-03539-3
  5. Nat Methods. 2024 Oct 31.
    Statistical inference with a manifold-constrained RNA velocity model uncovers cell cycle speed modulations.
    Alex R Lederer, Maxine Leonardi, Lorenzo Talamanca, Daniil M Bobrovskiy, Antonio Herrera, Colas Droin, Irina Khven, Hugo J F Carvalho, Alessandro Valente, Albert Dominguez Mantes, Pau Mulet Arabí, Luca Pinello, Felix Naef, Gioele La Manno.
      Across biological systems, cells undergo coordinated changes in gene expression, resulting in transcriptome dynamics that unfold within a low-dimensional manifold. While low-dimensional dynamics can be extracted using RNA velocity, these algorithms can be fragile and rely on heuristics lacking statistical control. Moreover, the estimated vector field is not dynamically consistent with the traversed gene expression manifold. To address these challenges, we introduce a Bayesian model of RNA velocity that couples velocity field and manifold estimation in a reformulated, unified framework, identifying the parameters of an explicit dynamical system. Focusing on the cell cycle, we implement VeloCycle to study gene regulation dynamics on one-dimensional periodic manifolds and validate its ability to infer cell cycle periods using live imaging. We also apply VeloCycle to reveal speed differences in regionally defined progenitors and Perturb-seq gene knockdowns. Overall, VeloCycle expands the single-cell RNA sequencing analysis toolkit with a modular and statistically consistent RNA velocity inference framework.
    DOI:  https://doi.org/10.1038/s41592-024-02471-8
  6. Nature. 2024 Oct 30.
    Tumour atlases enable researchers to navigate through cancers.
      
    Keywords:  Biological techniques; Cancer; Computational biology and bioinformatics
    DOI:  https://doi.org/10.1038/d41586-024-03498-9
  7. Nature. 2024 Oct;634(8036): 1187-1195
    Temporal recording of mammalian development and precancer.
    Mirazul Islam, Yilin Yang, Alan J Simmons, Vishal M Shah, Krushna Pavan Musale, Yanwen Xu, Naila Tasneem, Zhengyi Chen, Linh T Trinh, Paola Molina, Marisol A Ramirez-Solano, Iannish D Sadien, Jinzhuang Dou, Andrea Rolong, Ken Chen, Mark A Magnuson, Jeffrey C Rathmell, Ian G Macara, Douglas J Winton, Qi Liu, Hamim Zafar, Reza Kalhor, George M Church, Martha J Shrubsole, Robert J Coffey, Ken S Lau.
      Temporal ordering of cellular events offers fundamental insights into biological phenomena. Although this is traditionally achieved through continuous direct observations1,2, an alternative solution leverages irreversible genetic changes, such as naturally occurring mutations, to create indelible marks that enables retrospective temporal ordering3-5. Using a multipurpose, single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo, with incorporation of cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during mouse embryonic development, unconventional developmental relationships between cell types and new epithelial progenitor states by their unique genetic histories. Analysis of mouse adenomas, coupled to multiomic and single-cell profiling of human precancers, with clonal analysis of 418 human polyps, demonstrated the occurrence of polyclonal initiation in 15-30% of colonic precancers, showing their origins from multiple normal founders. Our study presents a multimodal framework that lays the foundation for in vivo recording, integrating synthetic or natural indelible genetic changes with single-cell analyses, to explore the origins and timing of development and tumorigenesis in mammalian systems.
    DOI:  https://doi.org/10.1038/s41586-024-07954-4
  8. Int J Mol Sci. 2024 Oct 11. pii: 10944. [Epub ahead of print]25(20):
    Single-Cell Transcriptomics Reveals Cellular Heterogeneity and Drivers in Serrated Pathway-Driven Colorectal Cancer Progression.
    Jiahui Wang, Yu Zhang, Xinyi Chen, Qi Sheng, Junluo Yang, Yuyao Zhu, Yuhang Wang, Fangrong Yan, Jingya Fang.
      Serrated lesions are common precancerous pathways in colorectal cancer (CRC), but the process by which they progress to malignancy remains unclear. We aimed to elucidate this progression through a single-cell RNA landscape. We conducted single-cell RNA sequencing on three normal colonic tissues and fifteen SLs (including HPs, SSLs, SSLD, and TSAs) and integrated these data with datasets containing tumor samples. We identified three invasive malignant epithelial cell subtypes related to CRC progression: SLC1, SLC2, and tumor cell. SLC1, specific to SSLs, is involved in cell proliferation and shows a continuum of malignancy in gene expression. TSA-specific SLC2 exhibited FOXQ1 upregulation and active EMT, indicating invasiveness. The trajectory analysis showed that HPs do not progress to cancer, and different SL types are linked to the MSI status of advanced CRCs. We validated molecular drivers in premalignant lesions and later carcinogenesis. In the tumor microenvironment, CAF and pre-CAF fibroblast subtypes associated with progression were identified. During the premalignant stage, SLC1 triggered CD8+ T cell responses, while at the advanced stage, CAFs promoted tumor invasion and metastasis via FN1-CD44, influencing tumor progression and the treatment response. Our findings highlight transcriptional changes across serrated pathway stages, aiding in early CRC diagnosis and treatment.
    Keywords:  cancer progression; colorectal cancer; precancerous lesions; scRNA-seq; serrated pathway
    DOI:  https://doi.org/10.3390/ijms252010944
  9. Cell Stem Cell. 2024 Oct 24. pii: S1934-5909(24)00360-6. [Epub ahead of print]
    Assembloid models of cell-cell interaction to study tissue and disease biology.
    Massimo M Onesto, Ji-Il Kim, Sergiu P Pasca.
      Neurodevelopment involves the migration, projection, and integration of various cell types across different regions of the nervous system. Assembloids are self-organizing systems formed by the integration of multiple organoids or cell types. Here, we outline the generation and application of assembloids. We illustrate how assembloids recapitulate critical neurodevelopmental steps, like migration, axon projection, and circuit formation, and how they are starting to provide biological insights into neuropsychiatric disorders. Additionally, we review how assembloids can be used to study properties emerging from cell-cell interactions within non-neural tissues. Overall, assembloid platforms represent a powerful tool for discovering human biology and developing therapeutics.
    Keywords:  assembloids; nervous system; organoids
    DOI:  https://doi.org/10.1016/j.stem.2024.09.017
  10. Nucleic Acids Res. 2024 Oct 29. pii: gkae913. [Epub ahead of print]
    scLTdb: a comprehensive single-cell lineage tracing database.
    Junyao Jiang, Xing Ye, Yunhui Kong, Chenyu Guo, Mingyuan Zhang, Fang Cao, Yanxiao Zhang, Weike Pei.
      Single-cell lineage tracing (scLT) is a powerful technique that integrates cellular barcoding with single-cell sequencing technologies. This new approach enables the simultaneous measurement of cell fate and molecular profiles at single-cell resolution, uncovering the gene regulatory program of cell fate determination. However, a comprehensive scLT database is not yet available. Here, we present the single-cell lineage tracing database (scLTdb, https://scltdb.com) containing 109 datasets that are manually curated and analyzed through a standard pipeline. The scLTdb provides interactive analysis modules for visualizing and re-analyzing scLT datasets, especially the comprehensive cell fate analysis and lineage relationship analysis. Importantly, scLTdb also allows users to identify fate-related gene signatures. In conclusion, scLTdb provides an interactive interface of scLT data exploration and analysis, and will facilitate the understanding of cell fate decision and lineage commitment in development and diseases.
    DOI:  https://doi.org/10.1093/nar/gkae913
  11. Cell. 2024 Oct 22. pii: S0092-8674(24)01146-2. [Epub ahead of print]
    Multiparameter imaging reveals clinically relevant cancer cell-stroma interaction dynamics in head and neck cancer.
    Karolina Punovuori, Fabien Bertillot, Yekaterina A Miroshnikova, Mirjam I Binner, Satu-Marja Myllymäki, Gautier Follain, Kai Kruse, Johannes Routila, Teemu Huusko, Teijo Pellinen, Jaana Hagström, Noemi Kedei, Sami Ventelä, Antti Mäkitie, Johanna Ivaska, Sara A Wickström.
      Epithelial tumors are characterized by abundant inter- and intra-tumor heterogeneity, which complicates diagnostics and treatment. The contribution of cancer-stroma interactions to this heterogeneity is poorly understood. Here, we report a paradigm to quantify phenotypic diversity in head and neck squamous cell carcinoma (HNSCC) with single-cell resolution. By combining cell-state markers with morphological features, we identify phenotypic signatures that correlate with clinical features, including metastasis and recurrence. Integration of tumor and stromal signatures reveals that partial epithelial-mesenchymal transition (pEMT) renders disease outcome highly sensitive to stromal composition, generating a strong prognostic and predictive signature. Spatial transcriptomics and subsequent analyses of cancer spheroid dynamics identify the cancer-associated fibroblast-pEMT axis as a nexus for intercompartmental signaling that reprograms pEMT cells into an invasive phenotype. Taken together, we establish a paradigm to identify clinically relevant tumor phenotypes and discover a cell-state-dependent interplay between stromal and epithelial compartments that drives cancer aggression.
    Keywords:  cancer; cancer biomarker; cancer stem cell; epithelial-to-mesenchyme-transition
    DOI:  https://doi.org/10.1016/j.cell.2024.09.046
  12. Nat Cancer. 2024 Oct 30.
    Defining the transcriptional lineages of breast cancer subtypes.
      
    DOI:  https://doi.org/10.1038/s43018-024-00774-5
  13. Nat Rev Cancer. 2024 Oct 25.
    Stemness in solid malignancies: coping with immune attack.
    Judith Agudo, Yuxuan Miao.
      Immunotherapy has become a key new pillar of cancer treatment, and this has sparked interest in understanding mechanisms of cancer immune evasion. It has long been appreciated that cancers are constituted by heterogeneous populations of tumour cells. This feature is often fuelled by specialized cells that have molecular programs resembling tissue stem cells. Although these cancer stem cells (CSCs) have capacity for unlimited self-renewal and differentiation, it is increasingly evident that some CSCs are capable of achieving remarkable immune resistance. Given that most immunotherapy regiments have overlooked CSC-specific immune-evasive mechanisms, many current treatment strategies often lead to cancer relapse. This Review focuses on advancements in understanding how CSCs in solid tumours achieve their unique immune-evasive properties, enabling them to drive tumour regrowth. Moreover, as cancers often arise from tissue stem cells that acquired oncogenic mutations, we discuss how tissue stem cells undergoing malignant transformation activate intrinsic immune-evasive mechanisms and establish close interactions with suppressive immune cells to escape immune surveillance. In addition, we summarize how in advanced disease stages, CSCs often hijack features of normal stem cells to resist antitumour immunity. Finally, we provide insights in how to design a new generation of cancer immunotherapies to ensure elimination of CSCs.
    DOI:  https://doi.org/10.1038/s41568-024-00760-0
  14. Nat Med. 2024 Oct 30.
    Mapping metastatic breast cancer complexity through single-cell and spatial profiling.
      
    DOI:  https://doi.org/10.1038/s41591-024-03308-9
  15. Nat Med. 2024 Oct 30.
    A multi-modal single-cell and spatial expression map of metastatic breast cancer biopsies across clinicopathological features.
    Johanna Klughammer, Daniel L Abravanel, Åsa Segerstolpe, Timothy R Blosser, Yury Goltsev, Yi Cui, Daniel R Goodwin, Anubhav Sinha, Orr Ashenberg, Michal Slyper, Sébastien Vigneau, Judit Jané-Valbuena, Shahar Alon, Chiara Caraccio, Judy Chen, Ofir Cohen, Nicole Cullen, Laura K DelloStritto, Danielle Dionne, Janet Files, Allison Frangieh, Karla Helvie, Melissa E Hughes, Stephanie Inga, Abhay Kanodia, Ana Lako, Colin MacKichan, Simon Mages, Noa Moriel, Evan Murray, Sara Napolitano, Kyleen Nguyen, Mor Nitzan, Rebecca Ortiz, Miraj Patel, Kathleen L Pfaff, Caroline B M Porter, Asaf Rotem, Sarah Strauss, Robert Strasser, Aaron R Thorner, Madison Turner, Isaac Wakiro, Julia Waldman, Jingyi Wu, Jorge Gómez Tejeda Zañudo, Diane Zhang, Nancy U Lin, Sara M Tolaney, Eric P Winer, Edward S Boyden, Fei Chen, Garry P Nolan, Scott J Rodig, Xiaowei Zhuang, Orit Rozenblatt-Rosen, Bruce E Johnson, Aviv Regev, Nikhil Wagle.
      Although metastatic disease is the leading cause of cancer-related deaths, its tumor microenvironment remains poorly characterized due to technical and biospecimen limitations. In this study, we assembled a multi-modal spatial and cellular map of 67 tumor biopsies from 60 patients with metastatic breast cancer across diverse clinicopathological features and nine anatomic sites with detailed clinical annotations. We combined single-cell or single-nucleus RNA sequencing for all biopsies with a panel of four spatial expression assays (Slide-seq, MERFISH, ExSeq and CODEX) and H&E staining of consecutive serial sections from up to 15 of these biopsies. We leveraged the coupled measurements to provide reference points for the utility and integration of different experimental techniques and used them to assess variability in cell type composition and expression as well as emerging spatial expression characteristics across clinicopathological and methodological diversity. Finally, we assessed spatial expression and co-localization features of macrophage populations, characterized three distinct spatial phenotypes of epithelial-to-mesenchymal transition and identified expression programs associated with local T cell infiltration versus exclusion, showcasing the potential of clinically relevant discovery in such maps.
    DOI:  https://doi.org/10.1038/s41591-024-03215-z
  16. Nature. 2024 Oct;634(8036): 1178-1186
    Tumour evolution and microenvironment interactions in 2D and 3D space.
    Chia-Kuei Mo, Jingxian Liu, Siqi Chen, Erik Storrs, Andre Luiz N Targino da Costa, Andrew Houston, Michael C Wendl, Reyka G Jayasinghe, Michael D Iglesia, Cong Ma, John M Herndon, Austin N Southard-Smith, Xinhao Liu, Jacqueline Mudd, Alla Karpova, Andrew Shinkle, S Peter Goedegebuure, Abdurrahman Taha Mousa Ali Abdelzaher, Peng Bo, Lauren Fulghum, Samantha Livingston, Metin Balaban, Angela Hill, Joseph E Ippolito, Vesteinn Thorsson, Jason M Held, Ian S Hagemann, Eric H Kim, Peter O Bayguinov, Albert H Kim, Mary M Mullen, Kooresh I Shoghi, Tao Ju, Melissa A Reimers, Cody Weimholt, Liang-I Kang, Sidharth V Puram, Deborah J Veis, Russell Pachynski, Katherine C Fuh, Milan G Chheda, William E Gillanders, Ryan C Fields, Benjamin J Raphael, Feng Chen, Li Ding.
      To study the spatial interactions among cancer and non-cancer cells1, we here examined a cohort of 131 tumour sections from 78 cases across 6 cancer types by Visium spatial transcriptomics (ST). This was combined with 48 matched single-nucleus RNA sequencing samples and 22 matched co-detection by indexing (CODEX) samples. To describe tumour structures and habitats, we defined 'tumour microregions' as spatially distinct cancer cell clusters separated by stromal components. They varied in size and density among cancer types, with the largest microregions observed in metastatic samples. We further grouped microregions with shared genetic alterations into 'spatial subclones'. Thirty five tumour sections exhibited subclonal structures. Spatial subclones with distinct copy number variations and mutations displayed differential oncogenic activities. We identified increased metabolic activity at the centre and increased antigen presentation along the leading edges of microregions. We also observed variable T cell infiltrations within microregions and macrophages predominantly residing at tumour boundaries. We reconstructed 3D tumour structures by co-registering 48 serial ST sections from 16 samples, which provided insights into the spatial organization and heterogeneity of tumours. Additionally, using an unsupervised deep-learning algorithm and integrating ST and CODEX data, we identified both immune hot and cold neighbourhoods and enhanced immune exhaustion markers surrounding the 3D subclones. These findings contribute to the understanding of spatial tumour evolution through interactions with the local microenvironment in 2D and 3D space, providing valuable insights into tumour biology.
    DOI:  https://doi.org/10.1038/s41586-024-08087-4
  17. JAMA. 2024 Nov 01.
    More People in Their 40s Being Screened for Colorectal Cancer Under New Recommendation.
    Avery Orrall.
      
    DOI:  https://doi.org/10.1001/jama.2024.22058
  18. Nature. 2024 Oct 30.
    Polyclonal-to-monoclonal transition in colorectal precancerous evolution.
    Zhaolian Lu, Shanlan Mo, Duo Xie, Xiangwei Zhai, Shanjun Deng, Kantian Zhou, Kun Wang, Xueling Kang, Hao Zhang, Juanzhen Tong, Liangzhen Hou, Huijuan Hu, Xuefei Li, Da Zhou, Leo Tsz On Lee, Li Liu, Yaxi Zhu, Jing Yu, Ping Lan, Jiguang Wang, Zhen He, Xionglei He, Zheng Hu.
      Unravelling the origin and evolution of precancerous lesions is crucial for effectively preventing malignant transformation, yet our current knowledge remains limited1-3. Here we used a base editor-enabled DNA barcoding system4 to comprehensively map single-cell phylogenies in mouse models of intestinal tumorigenesis induced by inflammation or loss of the Apc gene. Through quantitative analysis of high-resolution phylogenies including 260,922 single cells from normal, inflamed and neoplastic intestinal tissues, we identified tens of independent cell lineages undergoing parallel clonal expansions within each lesion. We also found polyclonal origins of human sporadic colorectal polyps through bulk whole-exome sequencing and single-gland whole-genome sequencing. Genomic and clinical data support a model of polyclonal-to-monoclonal transition, with monoclonal lesions representing a more advanced stage. Single-cell RNA sequencing revealed extensive intercellular interactions in early polyclonal lesions, but there was significant loss of interactions during monoclonal transition. Therefore, our data suggest that colorectal precancer is often founded by many different lineages and highlight their cooperative interactions in the earliest stages of cancer formation. These findings provide insights into opportunities for earlier intervention in colorectal cancer.
    DOI:  https://doi.org/10.1038/s41586-024-08133-1
  19. Cancer Discov. 2024 Nov 01. 14(11): 2071-2088
    Highly Multiplexed Tissue Imaging in Precision Oncology and Translational Cancer Research.
    Alina Bollhagen, Bernd Bodenmiller.
      Precision oncology tailors treatment strategies to a patient's molecular and health data. Despite the essential clinical value of current diagnostic methods, hematoxylin and eosin morphology, immunohistochemistry, and gene panel sequencing offer an incomplete characterization. In contrast, highly multiplexed tissue imaging allows spatial analysis of dozens of markers at single-cell resolution enabling analysis of complex tumor ecosystems; thereby it has the potential to advance our understanding of cancer biology and supports drug development, biomarker discovery, and patient stratification. We describe available highly multiplexed imaging modalities, discuss their advantages and disadvantages for clinical use, and potential paths to implement these into clinical practice. Significance: This review provides guidance on how high-resolution, multiplexed tissue imaging of patient samples can be integrated into clinical workflows. It systematically compares existing and emerging technologies and outlines potential applications in the field of precision oncology, thereby bridging the ever-evolving landscape of cancer research with practical implementation possibilities of highly multiplexed tissue imaging into routine clinical practice.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1165
  20. Nat Rev Cancer. 2024 Oct 28.
    The present and future of the Cancer Dependency Map.
    Rand Arafeh, Tsukasa Shibue, Joshua M Dempster, William C Hahn, Francisca Vazquez.
      Despite tremendous progress in the past decade, the complex and heterogeneous nature of cancer complicates efforts to identify new therapies and therapeutic combinations that achieve durable responses in most patients. Further advances in cancer therapy will rely, in part, on the development of targeted therapeutics matched with the genetic and molecular characteristics of cancer. The Cancer Dependency Map (DepMap) is a large-scale data repository and research platform, aiming to systematically reveal the landscape of cancer vulnerabilities in thousands of genetically and molecularly annotated cancer models. DepMap is used routinely by cancer researchers and translational scientists and has facilitated the identification of several novel and selective therapeutic strategies for multiple cancer types that are being tested in the clinic. However, it is also clear that the current version of DepMap is not yet comprehensive. In this Perspective, we review (1) the impact and current uses of DepMap, (2) the opportunities to enhance DepMap to overcome its current limitations, and (3) the ongoing efforts to further improve and expand DepMap.
    DOI:  https://doi.org/10.1038/s41568-024-00763-x
  21. Cell Res. 2024 Oct 31.
    A cross-species foundation model for single cells.
    Korbinian Traeuble, Matthias Heinig.
      
    DOI:  https://doi.org/10.1038/s41422-024-01045-9
  22. Cancer Discov. 2024 Nov 01. 14(11): 2041-2046
    Building an Organ-Wide Macroscopic View of Cancer Hallmarks.
    Suling Liu, Yuan Wang, Jiawen Feng, Zhihua Liu, Shengtao Zhou.
      Despite an increasingly detailed understanding of cancer hallmarks at molecular or atomic resolution, most studies, however, fall short of investigating the systemic interactions of cancer with the human body. We propose to investigate the hallmarks of cancer from an organ-wide macroscopic view, discuss the challenges in preclinical and clinical research to study the cross-organ regulation of cancer together with potential directions to overcome these challenges, and foresee how this holistic view may be translated into more effective therapies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0833
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