bims-instec 2024-04-21 papers

bims-instec

Biomed News

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

Issue of 2024–04–21
fiveteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Amino acid transporter SLC7A5 regulates cell proliferation and secretary cell differentiation and distribution in the mouse intestine.
Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells.
Tumor Organoids: The Era of Personalized Medicine.
Enteroendocrine Cell Loss Drives Small Intestinal Hypomotility in Colitis.
How ceramides affect the development of colon cancer: from normal colon to carcinoma.
Loss of Paneth cells dysregulates gut ILC subsets and enhances weight gain response to high fat diet in a mouse model.
Colorectal cancer cells with stably expressed SIRT3 demonstrate proliferating retardation by Wnt/β-catenin cascade inactivation.
Colorectal Cancer Stem Cell Biomarkers: Biological Traits and Prognostic Insights.
Arachidonic acid released by PIK3CA mutant tumor cells triggers malignant transformation of colonic epithelium by inducing chromatin remodeling.
Tumor endothelial cell-derived Sfrp1 supports the maintenance of cancer stem cells via Wnt signaling.
Differentiation of intestinal stem cells toward goblet cells under systemic iron overload stress are associated with inhibition of Notch signaling pathway and ferroptosis.
Environmentally dependent and independent control of 3D cell shape.
Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer.
Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer.
PERCEPTION predicts patient response and resistance to treatment using single-cell transcriptomics of their tumors.

Int J Biol Sci. 2024 ;20(6): 2187-2201

Amino acid transporter SLC7A5 regulates cell proliferation and secretary cell differentiation and distribution in the mouse intestine.

Lingyu Bao, Liezhen Fu, Yijun Su, Zuojia Chen, Zhaoyi Peng, Lulu Sun, Frank J Gonzalez, Chuan Wu, Hongen Zhang, Bingyin Shi, Yun-Bo Shi.

  The intestine is critical for not only processing nutrients but also protecting the organism from the environment. These functions are mainly carried out by the epithelium, which is constantly being self-renewed. Many genes and pathways can influence intestinal epithelial cell proliferation. Among them is mTORC1, whose activation increases cell proliferation. Here, we report the first intestinal epithelial cell (IEC)-specific knockout (ΔIEC) of an amino acid transporter capable of activating mTORC1. We show that the transporter, SLC7A5, is highly expressed in mouse intestinal crypt and Slc7a5ΔIEC reduces mTORC1 signaling. Surprisingly, adult Slc7a5ΔIEC intestinal crypts have increased cell proliferation but reduced mature Paneth cells. Goblet cells, the other major secretory cell type in the small intestine, are increased in the crypts but reduced in the villi. Analyses with scRNA-seq and electron microscopy have revealed dedifferentiation of Paneth cells in Slc7a5ΔIEC mice, leading to markedly reduced secretory granules with little effect on Paneth cell number. Thus, SLC7A5 likely regulates secretory cell differentiation to affect stem cell niche and indirectly regulate cell proliferation.

Keywords:  amino acid transporter; intestine; mTORC1 signaling pathway; organ homeostasis; stem cell

DOI:  https://doi.org/10.7150/ijbs.94297
Nat Commun. 2024 Apr 18. 15(1): 3363

Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells.

Sefora Conti, Valeria Venturini, Adrià Cañellas-Socias, Carme Cortina, Juan F Abenza, Camille Stephan-Otto Attolini, Emily Middendorp Guerra, Catherine K Xu, Jia Hui Li, Leone Rossetti, Giorgio Stassi, Pere Roca-Cusachs, Alba Diz-Muñoz, Verena Ruprecht, Jochen Guck, Eduard Batlle, Anna Labernadie, Xavier Trepat.

Colorectal cancer (CRC) tumors are composed of heterogeneous and plastic cell populations, including a pool of cancer stem cells that express LGR5. Whether these distinct cell populations display different mechanical properties, and how these properties might contribute to metastasis is poorly understood. Using CRC patient derived organoids (PDOs), we find that compared to LGR5- cells, LGR5+ cancer stem cells are stiffer, adhere better to the extracellular matrix (ECM), move slower both as single cells and clusters, display higher nuclear YAP, show a higher survival rate in response to mechanical confinement, and form larger transendothelial gaps. These differences are largely explained by the downregulation of the membrane to cortex attachment proteins Ezrin/Radixin/Moesin (ERMs) in the LGR5+ cells. By analyzing single cell RNA-sequencing (scRNA-seq) expression patterns from a patient cohort, we show that this downregulation is a robust signature of colorectal tumors. Our results show that LGR5- cells display a mechanically dynamic phenotype suitable for dissemination from the primary tumor whereas LGR5+ cells display a mechanically stable and resilient phenotype suitable for extravasation and metastatic growth.

DOI: https://doi.org/10.1038/s41467-024-47227-2
Biochemistry (Mosc). 2024 Jan;89(Suppl 1): S127-S147

Tumor Organoids: The Era of Personalized Medicine.

Natalia V Rassomakhina, Alexandra Yu Ryazanova, Astemir R Likhov, Sergey A Bruskin, Liliya G Maloshenok, Victoria V Zherdeva.

  The strategies of future medicine are aimed to modernize and integrate quality approaches including early molecular-genetic profiling, identification of new therapeutic targets and adapting design for clinical trials, personalized drug screening (PDS) to help predict and individualize patient treatment regimens. In the past decade, organoid models have emerged as an innovative in vitro platform with the potential to realize the concept of patient-centered medicine. Organoids are spatially restricted three-dimensional clusters of cells ex vivo that self-organize into complex functional structures through genetically programmed determination, which is crucial for reconstructing the architecture of the primary tissue and organs. Currently, there are several strategies to create three-dimensional (3D) tumor systems using (i) surgically resected patient tissue (PDTOs, patient-derived tumor organoids) or (ii) single tumor cells circulating in the patient's blood. Successful application of 3D tumor models obtained by co-culturing autologous tumor organoids (PDTOs) and peripheral blood lymphocytes have been demonstrated in a number of studies. Such models simulate a 3D tumor architecture in vivo and contain all cell types characteristic of this tissue, including immune system cells and stem cells. Components of the tumor microenvironment, such as fibroblasts and immune system cells, affect tumor growth and its drug resistance. In this review, we analyzed the evolution of tumor models from two-dimensional (2D) cell cultures and laboratory animals to 3D tissue-specific tumor organoids, their significance in identifying mechanisms of antitumor response and drug resistance, and use of these models in drug screening and development of precision methods in cancer treatment.

Keywords:  3D tumor organoids; chemotherapy; immune checkpoints; immunotherapy; induced pluripotent stem cells (iPSCs); patient-derived tumor organoids (PDTOs); personalized therapy; precision medicine; programmed cell death; targeted therapy

DOI:  https://doi.org/10.1134/S0006297924140086
Cell Mol Gastroenterol Hepatol. 2024 Apr 11. pii: S2352-345X(24)00067-5. [Epub ahead of print]

Enteroendocrine Cell Loss Drives Small Intestinal Hypomotility in Colitis.

Jacques Gonzales.

DOI: https://doi.org/10.1016/j.jcmgh.2024.03.012
Pflugers Arch. 2024 Apr 18.

How ceramides affect the development of colon cancer: from normal colon to carcinoma.

Nadine Merz, Jennifer Christina Hartel, Sabine Grösch.

  The integrity of the colon and the development of colon cancer depend on the sphingolipid balance in colon epithelial cells. In this review, we summarize the current knowledge on how ceramides and their complex derivatives influence normal colon development and colon cancer development. Ceramides, glucosylceramides and sphingomyelin are essential membrane components and, due to their biophysical properties, can influence the activation of membrane proteins, affecting protein-protein interactions and downstream signalling pathways. Here, we review the cellular mechanisms known to be affected by ceramides and their effects on colon development. We also describe which ceramides are deregulated during colorectal carcinogenesis, the molecular mechanisms involved in ceramide deregulation and how this affects carcinogenesis. Finally, we review new methods that are now state of the art for studying lipid-protein interactions in the physiological environment.

Keywords:  Ceramide synthase; Colon cancer; Crypt; Hypoxia; Sphingolipid; Stem cell

DOI:  https://doi.org/10.1007/s00424-024-02960-x
bioRxiv. 2024 Apr 01. pii: 2024.03.29.587349. [Epub ahead of print]

Loss of Paneth cells dysregulates gut ILC subsets and enhances weight gain response to high fat diet in a mouse model.

Marisa R Joldrichsen, Eunsoo Kim, Haley E Steiner, Yea Ji Jeong, Christopher Premanandan, Willa Hsueh, Ouliana Ziouzenkova, Estelle Cormet-Boyaka, Prosper N Boyaka.

Obesity has been associated with dysbiosis, but innate mechanisms linking intestinal epithelial cell subsets and obesity remain poorly understood. Using mice lacking Paneth cells (Sox9 ΔIEC mice), small intestinal epithelial cells specialized in the production of antimicrobial products and cytokines, we show that dysbiosis alone does not induce obesity or metabolic disorders. Loss of Paneth cells reduced ILC3 and increased ILC2 numbers in the intestinal lamina propria. High-fat diet (HFD) induced higher weight gain and more severe metabolic disorders in Sox9 ΔIEC mice. Further, HFD enhances the number of ILC1 in the intestinal lamina propria of Sox9 ΔIEC mice and increases intestinal permeability and the accumulation of immune cells (inflammatory macrophages and T cells, and B cells) in abdominal fat tissues of obese Sox9 ΔIEC . Transplantation of fecal materials from Sox9 ΔIEC mice in germ-free mice before HFD further confirmed the regulatory role of Paneth cells for gut ILC subsets and the development of obesity.

DOI: https://doi.org/10.1101/2024.03.29.587349
Clin Exp Pharmacol Physiol. 2024 Jun;51(6): e13856

Colorectal cancer cells with stably expressed SIRT3 demonstrate proliferating retardation by Wnt/β-catenin cascade inactivation.

Tianyu Li, Leqi Fan, Yijiang Jia, Chen Xu, Wei Guo, Yuji Wang, Ye Li.

  Colorectal cancer (CRC) is a typical and lethal digestive system malignancy. In this study, we investigated the effect of sirtuin 3 (SIRT3) expression, a fidelity mitochondrial protein, on the proliferation of CRC cells and the mechanisms involved. Using the University of Alabama at Birmingham Cancer Data Analysis Portal database and the Clinical Proteomic Tumour Analysis Consortium database, we discovered that low expression of SIRT3 in CRC was a negative factor for survival prognosis (P < .05). Meanwhile, SIRT3 expression was correlated with distant metastasis and tumour, node, metastasis stage of CRC patients (P < .05). Subsequently, we observed that CRC cells with stable SIRT3 expression exhibited a significant decrease in proliferative capacities both in vitro and in vivo, compared to their counterparts (P < .05). Further investigation using western blot, immunoprecipitation and TOPflash/FOPflash assay showed the mechanism of growth retardation of these cells was highly associated with the degradation of β-catenin in cytosol, and the localization of β-catenin/α-catenin complex in the nucleus. In conclusion, our findings suggest that the inhibition of CRC cell proliferation by SIRT3 is closely associated with the inactivation of the Wnt/β-catenin signalling pathway.

Keywords:  SIRT3; Wnt/β‐catenin cascade; colorectal cancer; proliferation

DOI:  https://doi.org/10.1111/1440-1681.13856
Curr Pharm Des. 2024 Apr 15.

Colorectal Cancer Stem Cell Biomarkers: Biological Traits and Prognostic Insights.

Atena Soleimani, Nikoo Saeedi, Abdulridha Mohammed Al-Asady, Elnaz Nazari, Reyhane Hanaie, Majid Khazaei, Elnaz Ghorbani, Hamed Akbarzade, Mikhail Ryzhikov, Amir Avan, Seyed Mahdi Hasanian Mehr.

  Due to self-renewal, differentiation, and limitless proliferation properties, Cancer Stem Cells (CSCs) increase the probability of tumor development. These cells are identified by using CSC markers, which are highly expressed proteins on the cell surface of CSCs. Recently, the therapeutic application of CSCs as novel biomarkers improved both the prognosis and diagnosis outcome of colorectal Cancer. In the present review, we focused on a specific panel of colorectal CSC markers, including LGR5, ALDH, CD166, CD133, and CD44, which offers a targeted and comprehensive analysis of their functions. The selection criteria for these markersCancer were based on their established significance in Colorectal Cancer (CRC) pathogenesis and clinical outcomes, providing novel insights into the CSC biology of CRC. Through this approach, we aim to elevate understanding and stimulate further research for developing effective diagnostic and therapeutic strategies in CRC.

Keywords:  ALDH; CD133; CD166; CD44; Cancer stem cell; Colon cancer.; LGR5

DOI:  https://doi.org/10.2174/0113816128291321240329050945
Cell Rep Med. 2024 Apr 05. pii: S2666-3791(24)00179-4. [Epub ahead of print] 101510

Arachidonic acid released by PIK3CA mutant tumor cells triggers malignant transformation of colonic epithelium by inducing chromatin remodeling.

Baoyu He, Qingli Bie, Rou Zhao, Yugang Yan, Guanjun Dong, Baogui Zhang, Sen Wang, Wenrong Xu, Dongxing Tian, Yujun Hao, Yanhua Zhang, Mingsheng Zhao, Huabao Xiong, Bin Zhang.

  Key gene mutations are essential for colorectal cancer (CRC) development; however, how the mutated tumor cells impact the surrounding normal cells to promote tumor progression has not been well defined. Here, we report that PIK3CA mutant tumor cells transmit oncogenic signals and result in malignant transformation of intestinal epithelial cells (IECs) via paracrine exosomal arachidonic acid (AA)-induced H3K4 trimethylation. Mechanistically, PIK3CA mutations sustain SGK3-FBW7-mediated stability of the cPLA2 protein, leading to the synthetic increase in AA, which is transported through exosome and accumulated in IECs. Transferred AA directly binds Menin and strengthens the interactions of Menin and MLL1/2 methyltransferase. Finally, the combination of VTP50469, an inhibitor of the Menin-MLL interaction, and alpelisib synergistically represses PDX tumors harboring PIK3CA mutations. Together, these findings unveil the metabolic link between PIK3CA mutant tumor cells and the IECs, highlighting AA as the potential target for the treatment of patients with CRC harboring PIK3CA mutations.

Keywords:  H3K4 trimethylation; Menin; PIK3CA mutations; VTP50469; arachidonic acid; cPLA2; exosome; intestinal epithelial cells; malignant transformation

DOI:  https://doi.org/10.1016/j.xcrm.2024.101510
In Vitro Cell Dev Biol Anim. 2024 Apr 16.

Tumor endothelial cell-derived Sfrp1 supports the maintenance of cancer stem cells via Wnt signaling.

Yumiko Hayashi, Masakazu Hashimoto, Katsuyoshi Takaoka, Tatsuya Takemoto, Nobuyuki Takakura, Hiroyasu Kidoya.

  Cancer stem cells (CSCs), which are critical targets for cancer therapy as they are involved in drug resistance to anticancer drugs, and metastasis, are maintained by angiocrine factors produced by particular niches that form within tumor tissue. Secreted frizzled-related protein 1 (Sfrp1) is an extracellular protein that modulates Wnt signaling. However, the cells that produce Sfrp1 in the tumor environment and its function remain unclear. We aimed to elucidate angiocrine factors related to CSC maintenance, focusing on Sfrp1. Although Sfrp1 is a Wnt pathway-related factor, its impact on tumor tissues remains unknown. We investigated the localization of Sfrp1 in tumors and found that it is expressed in some tumor vessels. Analysis of mice lacking Sfrp1 showed that tumor growth was suppressed in Sfrp1-deficient tumor tissues. Flow cytometry analysis indicated that CSCs were maintained in the early tumor growth phase in the Sfrp1 knockout (KO) mouse model of tumor-bearing cancer. However, tumor growth was inhibited in the late tumor growth phase because of the inability to maintain CSCs. Real-time PCR results from tumors of Sfrp1 KO mice showed that the expression of Wnt signaling target genes significantly decreased in the late stage of tumor growth. This suggests that Sfrp1, an angiocrine factor produced by the tumor vascular niche, is involved in Wnt signaling-mediated mechanisms in tumor tissues.

Keywords:  Angiocrine factor; Cancer stem cell; Sfrp1; Tumor endothelial cell; Wnt signaling

DOI:  https://doi.org/10.1007/s11626-024-00899-y
Redox Biol. 2024 Apr 15. pii: S2213-2317(24)00136-8. [Epub ahead of print]72 103160

Differentiation of intestinal stem cells toward goblet cells under systemic iron overload stress are associated with inhibition of Notch signaling pathway and ferroptosis.

Jing Zhao, Wan Ma, Sisi Wang, Kang Zhang, Qingqing Xiong, Yunqin Li, Hong Yu, Huahua Du.

  Iron overload can lead to oxidative stress and intestinal damage and happens frequently during blood transfusions and iron supplementation. However, how iron overload influences intestinal mucosa remains unknown. Here, the aim of current study was to investigate the effects of iron overload on the proliferation and differentiation of intestinal stem cells (ISCs). An iron overload mouse model was established by intraperitoneal injection of 120 mg/kg body weight iron dextran once a fortnight for a duration of 12 weeks, and an iron overload enteroid model was produced by treatment with 3 mM or 10 mM of ferric ammonium citrate for 24 h. We found that iron overload caused damage to intestinal morphology with a 64 % reduction in villus height/crypt depth ratio, and microvilli injury in the duodenum. Iron overload mediated epithelial function by inhibiting the expression of nutrient transporters and enhancing the expression of secretory factors in the duodenum. Meanwhile, iron overload inhibited the proliferation of ISCs and regulated their differentiation into secretory mature cells, such as goblet cells, through inhibiting Notch signaling pathway both in mice and enteroid. Furthermore, iron overload caused oxidative stress and ferroptosis in intestinal epithelial cells. In addition, ferroptosis could also inhibit Notch signaling pathway, and affected the proliferation and differentiation of ISCs. These findings reveal the regulatory role of iron overload on the proliferation and differentiation of ISCs, providing a new insight into the internal mechanism of iron overload affecting intestinal health, and offering important theoretical basis for the scientific application of iron nutrition regulation.

Keywords:  Ferroptosis; ISCs; Intestinal stem cells; Iron overload; Notch signaling pathway

DOI:  https://doi.org/10.1016/j.redox.2024.103160
Cell Rep. 2024 Apr 16. pii: S2211-1247(24)00344-9. [Epub ahead of print] 114016

Environmentally dependent and independent control of 3D cell shape.

Lucas G Dent, Nathan Curry, Hugh Sparks, Vicky Bousgouni, Vincent Maioli, Sunil Kumar, Ian Munro, Francesca Butera, Ian Jones, Mar Arias-Garcia, Leo Rowe-Brown, Chris Dunsby, Chris Bakal.

  How cancer cells determine their shape in response to three-dimensional (3D) geometric and mechanical cues is unclear. We develop an approach to quantify the 3D cell shape of over 60,000 melanoma cells in collagen hydrogels using high-throughput stage-scanning oblique plane microscopy (ssOPM). We identify stereotypic and environmentally dependent changes in shape and protrusivity depending on whether a cell is proximal to a flat and rigid surface or is embedded in a soft environment. Environmental sensitivity metrics calculated for small molecules and gene knockdowns identify interactions between the environment and cellular factors that are important for morphogenesis. We show that the Rho guanine nucleotide exchange factor (RhoGEF) TIAM2 contributes to shape determination in environmentally independent ways but that non-muscle myosin II, microtubules, and the RhoGEF FARP1 regulate shape in ways dependent on the microenvironment. Thus, changes in cancer cell shape in response to 3D geometric and mechanical cues are modulated in both an environmentally dependent and independent fashion.

Keywords:  CP: Cell biology; FARP1; OPM; RhoGEF; TIAM2; cell protrusions; collagen; imaging 3D morphology; melanoma; microenvironment; oblique plane microscopy

DOI:  https://doi.org/10.1016/j.celrep.2024.114016
bioRxiv. 2024 Apr 01. pii: 2024.03.29.587381. [Epub ahead of print]

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer.

Stephen L DeAngelo, Sofia Dziechciarz, Sumeet Solanki, Myungsun Shin, Liang Zhao, Andrii Balia, Marwa O El-Derany, Nupur K Das, Cristina Castillo, Hannah N Bell, Joao A Paulo, Yuezhong Zhang, Nicholas J Rossiter, Elizabeth C McCulla, Jianping He, Indrani Talukder, Zachary T Schafer, Nouri Neamati, Joseph D Mancias, Markos Koutmos, Yatrik M Shah.

Ferroptosis is an iron-dependent, non-apoptotic form of cell death resulting from the accumulation of lipid peroxides. Colorectal cancer (CRC) accumulates high levels of intracellular iron and reactive oxygen species (ROS), thereby sensitizing cells to ferroptosis. The selenoprotein glutathione peroxidase (GPx4) is a key enzyme in the detoxification of lipid peroxides and can be inhibited by the compound (S)-RSL3 ([1S,3R]-RSL3). However, the stereoisomer (R)-RSL3 ([1R,3R]-RSL3), which does not inhibit GPx4, exhibits equipotent activity to (S)-RSL3 across a panel of CRC cell lines. Utilizing CRC cell lines with an inducible knockdown of GPx4, we demonstrate that (S)-RSL3 sensitivity does not align with GPx4 dependency. Subsequently, a biotinylated (S)-RSL3 was then synthesized to perform affinity purification-mass spectrometry (AP-MS), revealing that (S)-RSL3 acts as a pan-inhibitor of the selenoproteome, targeting both the glutathione and thioredoxin peroxidase systems as well as multiple additional selenoproteins. To investigate the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC, we employed further chemical and genetic approaches to disrupt selenoprotein function. The findings demonstrate that the selenoprotein inhibitor Auranofin can induce ferroptosis and/or oxidative cell death both in-vitro and in-vivo . Consistent with this data we observe that AlkBH8, a tRNA-selenocysteine methyltransferase required for the translational incorporation of selenocysteine, is essential for CRC growth. In summary, our research elucidates the complex mechanisms underlying ferroptosis in CRC and reveals that modulation of the selenoproteome provides multiple new therapeutic targets and opportunities in CRC.

DOI: https://doi.org/10.1101/2024.03.29.587381
Sci Adv. 2024 Apr 19. 10(16): eadj1987

Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer.

Laia Peruchet-Noray, Anja M Sedlmeier, Niki Dimou, Hansjörg Baurecht, Béatrice Fervers, Emma Fontvieille, Julian Konzok, Kostas K Tsilidis, Sofia Christakoudi, Anna Jansana, Reynalda Cordova, Patricia Bohmann, Michael J Stein, Andrea Weber, Stéphane Bézieau, Hermann Brenner, Andrew T Chan, Iona Cheng, Jane C Figueiredo, Koldo Garcia-Etxebarria, Victor Moreno, Christina C Newton, Stephanie L Schmit, Mingyang Song, Cornelia M Ulrich, Pietro Ferrari, Vivian Viallon, Robert Carreras-Torres, Marc J Gunter, Heinz Freisling.

It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue-specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue-specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.

DOI: https://doi.org/10.1126/sciadv.adj1987
Nat Cancer. 2024 Apr 18.

PERCEPTION predicts patient response and resistance to treatment using single-cell transcriptomics of their tumors.

Sanju Sinha, Rahulsimham Vegesna, Sumit Mukherjee, Ashwin V Kammula, Saugato Rahman Dhruba, Wei Wu, D Lucas Kerr, Nishanth Ulhas Nair, Matthew G Jones, Nir Yosef, Oleg V Stroganov, Ivan Grishagin, Kenneth D Aldape, Collin M Blakely, Peng Jiang, Craig J Thomas, Cyril H Benes, Trever G Bivona, Alejandro A Schäffer, Eytan Ruppin.

Tailoring optimal treatment for individual cancer patients remains a significant challenge. To address this issue, we developed PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology), a precision oncology computational pipeline. Our approach uses publicly available matched bulk and single-cell (sc) expression profiles from large-scale cell-line drug screens. These profiles help build treatment response models based on patients' sc-tumor transcriptomics. PERCEPTION demonstrates success in predicting responses to targeted therapies in cultured and patient-tumor-derived primary cells, as well as in two clinical trials for multiple myeloma and breast cancer. It also captures the resistance development in patients with lung cancer treated with tyrosine kinase inhibitors. PERCEPTION outperforms published state-of-the-art sc-based and bulk-based predictors in all clinical cohorts. PERCEPTION is accessible at https://github.com/ruppinlab/PERCEPTION . Our work, showcasing patient stratification using sc-expression profiles of their tumors, will encourage the adoption of sc-omics profiling in clinical settings, enhancing precision oncology tools based on sc-omics.

DOI: https://doi.org/10.1038/s43018-024-00756-7