bims-instec 2024-09-08 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2024–09–08
fourteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Dual function of PHF16 in reinstating homeostasis of murine intestinal epithelium after crypt regeneration.
XENTURION is a population-level multidimensional resource of xenografts and tumoroids from metastatic colorectal cancer patients.
Inflammation-induced epigenetic imprinting regulates intestinal stem cells.
Cancer drug-tolerant persister cells: from biological questions to clinical opportunities.
BRAF + EGFR +/- MEK inhibitors after immune checkpoint inhibitors in BRAF V600E mutated and deficient mismatch repair or microsatellite instability high metastatic colorectal cancer.
Consensus molecular subtyping of metastatic colorectal cancer expands biomarker-directed therapeutic benefit for patients with CMS1 and CMS2 tumors.
TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells.
HIF1A-AS2 promotes the metabolic reprogramming and progression of colorectal cancer via miR-141-3p/FOXC1 axis.
Lysophosphatidic acid signaling in the GI system.
Melatonin mitigates chemotherapy-induced small intestinal atrophy in rats and reduces cytotoxicity in murine intestinal organoids.
Patient-derived colon epithelial organoids reveal lipid-related metabolic dysfunction in pediatric ulcerative colitis.
Drosophila HNF4 acts in distinct tissues to direct a switch between lipid storage and export in the gut.
Cancer cell states: Lessons from ten years of single-cell RNA-sequencing of human tumors.
A protein expression atlas on tissue samples and cell lines from cancer patients provides insights into tumor heterogeneity and dependencies.

Dev Cell. 2024 Aug 27. pii: S1534-5807(24)00492-1. [Epub ahead of print]

Dual function of PHF16 in reinstating homeostasis of murine intestinal epithelium after crypt regeneration.

Jun-Yeong Ahn, Somi Kim, Chang Rok Kim, Ji-Hyun Lee, Jong Min Kim, Thomas M Klompstra, Yoon Ha Choi, Yoon Jeon, Yongwoo Na, Jong-Seo Kim, Yuki Okada, Ho Lee, Ik Soo Kim, Jong Kyoung Kim, Bon-Kyoung Koo, Sung Hee Baek.

  Intestinal stem cells (ISCs) are highly vulnerable to damage, being in a constant state of proliferation. Reserve stem cells repair the intestinal epithelium following damage-induced ablation of ISCs. Here, we report that the epigenetic regulator plant homology domain (PHD) finger protein 16 (PHF16) restores homeostasis of the intestinal epithelium after initial damage-induced repair. In Phf16-/Y mice, revival stem cells (revSCs) showed defects in exiting the regenerative state, and intestinal crypt regeneration failed even though revSCs were still induced in response to tissue damage, as observed by single-cell RNA sequencing (scRNA-seq). Analysis of Phf16-/Y intestinal organoids by RNA sequencing (RNA-seq) and ATAC sequencing identified that PHF16 restores homeostasis of the intestinal epithelium by inducing retinoic acid receptor (RAR)/retinoic X receptor (RXR) target genes through HBO1-mediated histone H3K14 acetylation, while at the same time counteracting YAP/TAZ activity by ubiquitination of CDC73. Together, our findings demonstrate the importance of timely suppression of regenerative activity by PHF16 for the restoration of gut homeostasis after acute tissue injury.

Keywords:  CDC73; HBO1; PHF16; RXR; YAP/TAZ; intestinal epithelium differentiation; intestinal organoids; intestinal regeneration; intestinal stem cells; revival stem cells

DOI:  https://doi.org/10.1016/j.devcel.2024.08.009
Nat Commun. 2024 Aug 29. 15(1): 7495

XENTURION is a population-level multidimensional resource of xenografts and tumoroids from metastatic colorectal cancer patients.

Simonetta M Leto, Elena Grassi, Marco Avolio, Valentina Vurchio, Francesca Cottino, Martina Ferri, Eugenia R Zanella, Sofia Borgato, Giorgio Corti, Laura di Blasio, Desiana Somale, Marianela Vara-Messler, Francesco Galimi, Francesco Sassi, Barbara Lupo, Irene Catalano, Marika Pinnelli, Marco Viviani, Luca Sperti, Alfredo Mellano, Alessandro Ferrero, Caterina C Zingaretti, Alberto Puliafito, Luca Primo, Andrea Bertotti, Livio Trusolino.

The breadth and depth at which cancer models are interrogated contribute to the successful clinical translation of drug discovery efforts. In colorectal cancer (CRC), model availability is limited by a dearth of large-scale collections of patient-derived xenografts (PDXs) and paired tumoroids from metastatic disease, where experimental therapies are typically tested. Here we introduce XENTURION, an open-science resource offering a platform of 128 PDX models from patients with metastatic CRC, along with matched PDX-derived tumoroids. Multidimensional omics analyses indicate that tumoroids retain extensive molecular fidelity with parental PDXs. A tumoroid-based trial with the anti-EGFR antibody cetuximab reveals variable sensitivities that are consistent with clinical response biomarkers, mirror tumor growth changes in matched PDXs, and recapitulate EGFR genetic deletion outcomes. Inhibition of adaptive signals upregulated by EGFR blockade increases the magnitude of cetuximab response. These findings illustrate the potential of large living biobanks, providing avenues for molecularly informed preclinical research in oncology.

DOI: https://doi.org/10.1038/s41467-024-51909-2
Cell Stem Cell. 2024 Aug 24. pii: S1934-5909(24)00292-3. [Epub ahead of print]

Inflammation-induced epigenetic imprinting regulates intestinal stem cells.

Dongchang Zhao, Visweswaran Ravikumar, Tyler J Leach, Daniel Kraushaar, Emma Lauder, Lu Li, Yaping Sun, Katherine Oravecz-Wilson, Evan T Keller, Fengju Chen, Laure Maneix, Robert R Jenq, Robert Britton, Katherine Y King, Ana E Santibanez, Chad J Creighton, Arvind Rao, Pavan Reddy.

  It remains unknown whether and how intestinal stem cells (ISCs) adapt to inflammatory exposure and whether the adaptation leaves scars that will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5+ ISCs in well-defined clinically relevant models of acute gastrointestinal graft-versus-host disease (GI GVHD). Utilizing single-cell transcriptomics, as well as organoid, metabolic, epigenomic, and in vivo models, we found that Lgr5+ ISCs undergo metabolic changes that lead to the accumulation of succinate, which reprograms their epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures and also in vivo following serial transplantation. Furthermore, ISCs demonstrated a reduced capacity for in vivo regeneration despite resolution of the initial inflammatory exposure, demonstrating the persistence of the maladaptive impact induced by the inflammatory encounter. Thus, inflammation imprints the epigenome of ISCs in a manner that persists and affects their sensitivity to adapt to future stress or challenges.

Keywords:  allogeneic hematopoietic stem cell transplantation; epigenetics; epithelial cell memory; graft-versus-host disease; intestinal stem cells; intestine organoids; metabolism; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.stem.2024.08.006
Nat Rev Cancer. 2024 Sep 02.

Cancer drug-tolerant persister cells: from biological questions to clinical opportunities.

Mariangela Russo, Mengnuo Chen, Elisa Mariella, Haoning Peng, Sumaiyah K Rehman, Elena Sancho, Alberto Sogari, Tzen S Toh, Nathalie Q Balaban, Eduard Batlle, Rene Bernards, Mathew J Garnett, Matthew Hangauer, Eleonora Leucci, Jean-Christophe Marine, Catherine A O'Brien, Yaara Oren, E Elizabeth Patton, Caroline Robert, Susan M Rosenberg, Shensi Shen, Alberto Bardelli.

The emergence of drug resistance is the most substantial challenge to the effectiveness of anticancer therapies. Orthogonal approaches have revealed that a subset of cells, known as drug-tolerant 'persister' (DTP) cells, have a prominent role in drug resistance. Although long recognized in bacterial populations which have acquired resistance to antibiotics, the presence of DTPs in various cancer types has come to light only in the past two decades, yet several aspects of their biology remain enigmatic. Here, we delve into the biological characteristics of DTPs and explore potential strategies for tracking and targeting them. Recent findings suggest that DTPs exhibit remarkable plasticity, being capable of transitioning between different cellular states, resulting in distinct DTP phenotypes within a single tumour. However, defining the biological features of DTPs has been challenging, partly due to the complex interplay between clonal dynamics and tissue-specific factors influencing their phenotype. Moreover, the interactions between DTPs and the tumour microenvironment, including their potential to evade immune surveillance, remain to be discovered. Finally, the mechanisms underlying DTP-derived drug resistance and their correlation with clinical outcomes remain poorly understood. This Roadmap aims to provide a comprehensive overview of the field of DTPs, encompassing past achievements and current endeavours in elucidating their biology. We also discuss the prospect of future advancements in technologies in helping to unveil the features of DTPs and propose novel therapeutic strategies that could lead to their eradication.

DOI: https://doi.org/10.1038/s41568-024-00737-z
Eur J Cancer. 2024 Aug 22. pii: S0959-8049(24)00946-8. [Epub ahead of print]210 114290

BRAF + EGFR +/- MEK inhibitors after immune checkpoint inhibitors in BRAF V600E mutated and deficient mismatch repair or microsatellite instability high metastatic colorectal cancer.

Margherita Ambrosini, David Tougeron, Dominik Modest, Rosine Guimbaud, Scott Kopetz, Marie Decraecker, Stefano Kim, Clelia Coutzac, Geraldine Perkins, Emily Alouani, Federica Marmorino, Simon Pernot, Frank A Sinicrope, Elena Elez, Pauline Parent, Chiara Cremolini, Filippo Pietrantonio, Sara Lonardi, Claire Gallois, Julien Taieb.

   BACKGROUND: Immune checkpoint inhibitors (ICIs) are the guideline endorsed first choice for patients with deficient mismatch repair or microsatellite instability high (dMMR/MSI-H) mCRC, however a significant proportion experience primary or secondary resistance. BRAF V600E mutated (BRAFm) and dMMR/MSI-H mCRC can be treated with BRAF + EGFR inhibitors but specific data on the efficacy after progression to ICIs are missing.
METHODS: We collected consecutive patients with BRAFm dMMR/MSI-H mCRC treated from 2017 to 2024 with a combination of BRAFi+EGFRi+/-MEKi, after disease progression on ICIs. A control cohort of BRAFm pMMR/MSS mCRC patients treated with encorafenib+cetuximab+/-binimetinib from 2nd line was used.
RESULTS: dMMR/MSI-H (n = 50) BRAFm mCRC patients were more often > 70-year-old, with right-sided primary tumors, without liver but more lymphnode metastases than pMMR/MSS (n = 170). They were treated more frequently beyond 2nd line and 45 % were primary progressors to ICIs. Lower ORR (18 % versus 32 %, p = 0.09) and DCR (60 % versus 73 %, p = 0.11) was seen without reaching significance in dMMR/MSI-H as compared to pMMR/MSS patients. After a median follow-up of 14.04 months, no differences in PFS (median 5.13 versus 4.50 months, HR 0.83, 95 %CI: 0.57-1.20, p = 0.31) and OS (median 10.75 versus 9.11 months, HR 0.89, 95 %CI: 0.59-1.32, p = 0.55) were observed.
CONCLUSIONS: Our results show that BRAFm dMMR/MSI-H mCRC patients benefit from BRAFi+EGFRi+/-MEKi after progression under ICIs. Despite lower ORR and DCR, the outcome is not different from that observed in pMMR/MSS BRAFm CRC and is in line with the results of the BEACON registration trial.

Keywords:  BRAF mutation; Cetuximab; Deficient mismatch repair; Encorafenib; Immune checkpoint inhibitors; Metastatic colorectal cancer; Microsatellite instability high

DOI:  https://doi.org/10.1016/j.ejca.2024.114290
Br J Cancer. 2024 Sep 04.

Consensus molecular subtyping of metastatic colorectal cancer expands biomarker-directed therapeutic benefit for patients with CMS1 and CMS2 tumors.

Saikat Chowdhury, Joanne Xiu, Jennifer R Ribeiro, Theodore Nicolaides, Jian Zhang, W Michael Korn, Kelsey A Poorman, Heinz-Josef Lenz, John L Marshall, Matthew J Oberley, George W Sledge, David Spetzler, Scott Kopetz, John Paul Shen.

BACKGROUND: We developed a whole transcriptome sequencing (WTS)-based Consensus Molecular Subtypes (CMS) classifier using FFPE tissue and investigated its prognostic and predictive utility in a large clinico-genomic database of CRC patients (n = 24,939).
METHODS: The classifier was trained against the original CMS datasets using an SVM model and validated in an independent blinded TCGA dataset (88.0% accuracy). Kaplan-Meier estimates of overall survival (OS) and time-on-treatment (TOT) were calculated for each CMS (p < 0.05 considered significant).
RESULTS: CMS2 tumors were enriched on left-side of colon and conferred the longest median OS. In RAS-wildtype mCRC, left-sided tumors and CMS2 classification were associated with longer TOT with anti-EGFR antibodies (cetuximab and panitumumab). When restricting to only CMS2, there was no significant difference in TOT between right- versus left-sided tumors. CMS1 tumors were associated with a longer median TOT with pembrolizumab relative to other CMS groups, even when analyzing only microsatellite stable (MSS) tumors.
DISCUSSION: A WTS-based CMS classifier allowed investigation of a large multi-institutional clinico-genomic mCRC cohort, suggesting anti-EGFR therapy benefit for right-sided RAS-WT CMS2 tumors and immune checkpoint inhibitor benefit for MSS CMS1. Routine CMS classification of CRC provides important treatment associations that should be further investigated.

DOI: https://doi.org/10.1038/s41416-024-02826-0
J Mol Med (Berl). 2024 Aug 29.

TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells.

Giuseppina Bruno, Michele Pietrafesa, Fabiana Crispo, Annamaria Piscazzi, Francesca Maddalena, Guido Giordano, Vincenza Conteduca, Marianna Garofoli, Almudena Porras, Franca Esposito, Matteo Landriscina.

  Metabolic rewiring promotes cancer cell adaptation to a hostile microenvironment, representing a hallmark of cancer. This process involves mitochondrial function and is mechanistically linked to the balance between mitochondrial biogenesis (MB) and mitophagy. The molecular chaperone TRAP1 is overexpressed in 60-70% of human colorectal cancers (CRC) and its over-expression correlates with poor clinical outcome, being associated with many cancer cell functions (i.e. adaptation to stress, protection from apoptosis and drug resistance, protein synthesis quality control, metabolic rewiring from glycolysis to mitochondrial respiration and vice versa). Here, the potential new role of TRAP1 in regulating mitochondrial dynamics was investigated in CRC cell lines and human CRCs. Our results revealed an inverse correlation between TRAP1 and mitochondrial-encoded respiratory chain proteins both at transcriptional and translational levels. Furthermore, TRAP1 silencing is associated with increased mitochondrial mass and mitochondrial DNA copy number (mtDNA-CN) as well as enhanced MB through PGC-1α/TFAM signalling pathway, promoting the formation of new functioning mitochondria and, likely, underlying the metabolic shift towards oxidative phosphorylation. These results suggest an involvement of TRAP1 in regulating MB process in human CRC cells. KEY MESSAGES: TRAP1 inversely correlates with protein-coding mitochondrial gene expression in CRC cells and tumours. TRAP1 silencing correlates with increased mitochondrial mass and mtDNA copy number in CRC cells. TRAP1 silencing favours mitochondrial biogenesis in CRC cells.

Keywords:  Colorectal cancer; Metabolism; Mitochondrial biogenesis; Peroxisome proliferation-activated receptor gamma coactivator α1-alpha; TNF receptor-associated protein 1; Transcription factor A mitochondrial

DOI:  https://doi.org/10.1007/s00109-024-02479-9
Cell Death Dis. 2024 Sep 03. 15(9): 645

HIF1A-AS2 promotes the metabolic reprogramming and progression of colorectal cancer via miR-141-3p/FOXC1 axis.

Xinyang Zhong, Yaxian Wang, Xuefeng He, Xinxin He, Zijuan Hu, Huixia Huang, Jiayu Chen, Keji Chen, Ping Wei, Senlin Zhao, Yilin Wang, Hong Zhang, Bo Feng, Dawei Li.

lncRNA can regulate tumorigenesis development and distant metastasis of colorectal cancer (CRC). However, the detailed molecular mechanisms are still largely unknown. Using RNA-sequencing data, RT-qPCR, and FISH assay, we found that HIF1A-AS2 was upregulated in CRC tissues and associated with poor prognosis. Functional experiments were performed to determine the roles of HIF1A-AS2 in tumor progression and we found that HIF1A-AS2 can promote the proliferation, metastasis, and aerobic glycolysis of CRC cells. Mechanistically, HIF1A-AS2 can promote FOXC1 expression by sponging miR-141-3p. SP1 can transcriptionally activate HIF1A-AS2. Further, HIF1A-AS2 can be packaged into exosomes and promote the malignant phenotype of recipient tumor cells. Taken together, we discovered that SP1-induced HIF1A-AS2 can promote the metabolic reprogramming and progression of CRC via miR-141-3p/FOXC1 axis. HIF1A-AS2 is a promising diagnostic marker and treatment target in CRC.

DOI: https://doi.org/10.1038/s41419-024-06958-2
Cell Mol Gastroenterol Hepatol. 2024 Sep 02. pii: S2352-345X(24)00153-X. [Epub ahead of print] 101398

Lysophosphatidic acid signaling in the GI system.

C Chris Yun, Yiran Han, Beth McConnell.

The intestinal epithelium undergoes continuous homeostatic renewal to conduct the digestion and absorption of nutrients. At the same time, the intestinal epithelial barrier separates the host from the intestinal lumen preventing systemic infection from enteric pathogens. To maintain homeostasis and epithelial functionality, stem cells, which reside in the base of intestinal crypts, generate progenitor cells that ultimately differentiate to produce an array of secretory and absorptive cells. Intestinal regeneration is regulated by niche signaling pathways, specifically, Wnt, bone morphogenetic protein, Notch, and epidermal growth factor (EGF). In addition, growth factors and other peptides have emerged as potential modulators of intestinal repair and inflammation through their roles in cellular proliferation, differentiation, migration, and survival. Lysophosphatidic acid (LPA) is such a factor that modulates the proliferation, survival, and migration of epithelial cells while also regulating trafficking of immune cells, both of which are important for tissue homeostasis. Perturbation of LPA signaling, however, have been shown to promote cancer and inflammation. This review focuses on the recent advances in LPA-mediated signaling that contribute to physiological and pathophysiological regulation of the GI system.

DOI: https://doi.org/10.1016/j.jcmgh.2024.101398
PLoS One. 2024 ;19(9): e0307414

Melatonin mitigates chemotherapy-induced small intestinal atrophy in rats and reduces cytotoxicity in murine intestinal organoids.

Karsten Peters, Ada Lerma Clavero, Fredrik Kullenberg, Maria Kopsida, David Dahlgren, Femke Heindryckx, Hans Lennernäs, Markus Sjöblom.

Cancer continues to pose a significant global health challenge, with gastrointestinal (GI) cancers among the most prevalent and deadly forms. These cancers often lead to high mortality rates and demand the use of potent cytotoxic chemotherapeutics. For example, 5-fluorouracil (5-FU) forms the backbone of chemotherapy regimens for various GI cancers, including colorectal cancer. While these chemotherapeutics efficiently kill cancer cells, they frequently cause off-target effects such as chemotherapy-induced mucositis (CIM), characterized by debilitating symptoms like pain, nausea, and diarrhoea, necessitating medical intervention. In this study, we elucidated the potential of melatonin and misoprostol to reduce 5-FU-induced small intestinal mucositis. Morphological and cellular changes in the jejunum, along with colonic faecal water content were quantified in rats as markers for CIM. Additionally, the effects of melatonin were investigated in vitro on 5-FU treated murine intestinal organoids. The results showed that melatonin prevented villus atrophy in the rat jejunal mucosa and upheld cell viability in murine intestinal organoids. In contrast, misoprostol alone or in combination with melatonin did not significantly affect CIM caused by 5-FU. These in vivo and in vitro experiments provided promising insights that melatonin may be used as a preventive and/or adjuvant combination therapy to prevent and reduce CIM, holding the potential to enhance cancer treatment outcomes and improve patient quality-of-life.

DOI: https://doi.org/10.1371/journal.pone.0307414
bioRxiv. 2024 Aug 23. pii: 2024.08.22.609271. [Epub ahead of print]

Patient-derived colon epithelial organoids reveal lipid-related metabolic dysfunction in pediatric ulcerative colitis.

Babajide A Ojo, Lyong Heo, Sejal R Fox, Amanda Waddell, Maria E Moreno-Fernandez, Marielle Gibson, Tracy Tran, Ashley L Dunn, Essam I A Elknawy, Neetu Saini, Javier A López-Rivera, Senad Divanovic, Vinicio A de Jesus Perez, Michael J Rosen.

Ulcerative colitis (UC) is associated with epithelial metabolic derangements which exacerbate gut inflammation. Patient-derived organoids recapitulate complexities of the parent tissue in health and disease; however, whether colon organoids (colonoids) model the metabolic impairments in the pediatric UC epithelium is unclear. Here, we developed colonoid lines from pediatric patients with endoscopically active UC, inactive UC, and those without endoscopic or histologic evidence of colon inflammation (non-IBD controls) to interrogate functional metabolic differences in the colon epithelia. We demonstrate that colonoids from active UC patients exhibit hypermetabolic features and cellular stress, specifically during differentiation. Hypermetabolism in differentiating active UC colonoids was driven, in part, by increased proton leak, and supported by enhanced glycolytic capacity and dysregulated neutral lipid accumulation. Transcriptomic and pathway analyses indicated a role for PPAR-α in lipid-induced hypermetabolism in aUC colonoids, which was validated by PPAR-α activation in non-IBD colonoids. Accordingly, limiting neutral lipid accumulation in active UC colonoids through pharmacological inhibition of PPAR-α induced a metabolic shift towards glucose utilization, suppressed hypermetabolism and chemokine secretion, and improved markers of cellular stress and epithelial differentiation. Taken together, we reveal a role for lipid-related metabolic dysfunction in the pediatric UC epithelium and support the advancement of colonoids as a preclinical human model for testing epithelial-directed therapies against such metabolic dysfunction.

DOI: https://doi.org/10.1101/2024.08.22.609271
Cell Rep. 2024 Sep 04. pii: S2211-1247(24)01044-1. [Epub ahead of print]43(9): 114693

Drosophila HNF4 acts in distinct tissues to direct a switch between lipid storage and export in the gut.

Maximilian C Vonolfen, Fenja L Meyer Zu Altenschildesche, Hyuck-Jin Nam, Susanne Brodesser, Akos Gyenis, Jan Buellesbach, Geanette Lam, Carl S Thummel, Gilles Storelli.

  Nutrient digestion, absorption, and export must be coordinated in the gut to meet the nutritional needs of the organism. We used the Drosophila intestine to characterize the mechanisms that coordinate the fate of dietary lipids. We identified enterocytes specialized in absorbing and exporting lipids to peripheral organs. Distinct hepatocyte-like cells, called oenocytes, communicate with these enterocytes to adjust intestinal lipid storage and export. A single transcription factor, Drosophila hepatocyte nuclear factor 4 (dHNF4), supports this gut-liver axis. In enterocytes, dHNF4 maximizes dietary lipid export by preventing their sequestration in cytoplasmic lipid droplets. In oenocytes, dHNF4 promotes the expression of the insulin antagonist ImpL2 to activate Foxo and suppress lipid retention in enterocytes. Disruption of this switch between lipid storage and export is associated with intestinal inflammation, suggesting a lipidic origin for inflammatory bowel diseases. These studies establish dHNF4 as a central regulator of intestinal metabolism and inter-organ lipid trafficking.

Keywords:  CP: Metabolism; CP: Molecular biology; Drosophila; chylomicron; enterocyte; gut-liver axis; hepatocyte nuclear factor 4; inflammation; lipid; lipoprotein; metabolism; oenocyte

DOI:  https://doi.org/10.1016/j.celrep.2024.114693
Cancer Cell. 2024 Aug 28. pii: S1535-6108(24)00304-0. [Epub ahead of print]

Cancer cell states: Lessons from ten years of single-cell RNA-sequencing of human tumors.

Itay Tirosh, Mario L Suva.

Human tumors are intricate ecosystems composed of diverse genetic clones and malignant cell states that evolve in a complex tumor micro-environment. Single-cell RNA-sequencing (scRNA-seq) provides a compelling strategy to dissect this intricate biology and has enabled a revolution in our ability to understand tumor biology over the last ten years. Here we reflect on this first decade of scRNA-seq in human tumors and highlight some of the powerful insights gleaned from these studies. We first focus on computational approaches for robustly defining cancer cell states and their diversity and highlight some of the most common patterns of gene expression intra-tumor heterogeneity (eITH) observed across cancer types. We then discuss ambiguities in the field in defining and naming such eITH programs. Finally, we highlight critical developments that will facilitate future research and the broader implementation of these technologies in clinical settings.

DOI: https://doi.org/10.1016/j.ccell.2024.08.005
Nat Cancer. 2024 Sep 03.

A protein expression atlas on tissue samples and cell lines from cancer patients provides insights into tumor heterogeneity and dependencies.

Jun Li, Wei Liu, Kamalika Mojumdar, Hong Kim, Zhicheng Zhou, Zhenlin Ju, Shwetha V Kumar, Patrick Kwok-Shing Ng, Han Chen, Michael A Davies, Yiling Lu, Rehan Akbani, Gordon B Mills, Han Liang.

The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) are foundational resources in cancer research, providing extensive molecular and phenotypic data. However, large-scale proteomic data across various cancer types for these cohorts remain limited. Here, we expand upon our previous work to generate high-quality protein expression data for approximately 8,000 TCGA patient samples and around 900 CCLE cell line samples, covering 447 clinically relevant proteins, using reverse-phase protein arrays. These protein expression profiles offer profound insights into intertumor heterogeneity and cancer dependency and serve as sensitive functional readouts for somatic alterations. We develop a systematic protein-centered strategy for identifying synthetic lethality pairs and experimentally validate an interaction between protein kinase A subunit α and epidermal growth factor receptor. We also identify metastasis-related protein markers with clinical relevance. This dataset represents a valuable resource for advancing our understanding of cancer mechanisms, discovering protein biomarkers and developing innovative therapeutic strategies.

DOI: https://doi.org/10.1038/s43018-024-00817-x