bims-cagime 2024-01-07 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2024‒01‒07
thirty-one papers selected by
Kıvanç Görgülü, Technical University of Munich

Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease.
Lipid Peroxidation Drives Liquid-Liquid Phase Separation and Disrupts Raft Protein Partitioning in Biological Membranes.
Macrophages reprogramming driven by cancer-associated fibroblasts under FOLFIRINOX treatment correlates with shorter survival in pancreatic cancer.
EGFR-activated myofibroblasts promote metastasis of pancreatic cancer.
Glycine homeostasis requires reverse SHMT flux.
KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo.
Validation of dual energy X-ray absorptiometry for longitudinal quantification of tumor burden in a murine model of pancreatic ductal adenocarcinoma.
ROR2 regulates cellular plasticity in pancreatic neoplasia and adenocarcinoma.
DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas.
Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.
Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance.
Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.
Targeting cancer-associated fibroblast autophagy renders pancreatic cancer eradicable with immunochemotherapy by inhibiting adaptive immune resistance.
Amino acid intake strategies define pluripotent cell states.
Coupling Liquid Phases in 3D Condensates and 2D Membranes: Successes, Challenges, and Tools.
cytoviewer: an R/Bioconductor package for interactive visualization and exploration of highly multiplexed imaging data.
Segmentation of cellular ultrastructures on sparsely labeled 3D electron microscopy images using deep learning.
Dietary approaches for exploiting metabolic vulnerabilities in cancer.
Cellular harmonics for the morphology-invariant analysis of molecular organization at the cell surface.
Curvature sensing lipid dynamics in a mitochondrial inner membrane model.
Lysosome identity crisis: Phosphoinositides and mTORC1 negotiate lysosomal behavior.
Experimental determination and mathematical modeling of standard shapes of forming autophagosomes.
Proximity labeling reveals dynamic changes in the SQSTM1 protein network.
Pancreatic Cancer Action Network's SPARK: A Cloud-Based Patient Health Data and Analytics Platform for Pancreatic Cancer.
Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice.
Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD.
Cell size homeostasis is tightly controlled throughout the cell cycle.
Impact of aspirin on cancer incidence.
Engineering self-propelled tumor-infiltrating CAR T cells using synthetic velocity receptors.
Association of exercise with pan-cancer incidence and overall survival.
MAPS: pathologist-level cell type annotation from tissue images through machine learning.

Nat Cancer. 2024 Jan 04.

Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease.

Josef Leibold, Kaloyan M Tsanov, Corina Amor, Yu-Jui Ho, Francisco J Sánchez-Rivera, Judith Feucht, Timour Baslan, Hsuan-An Chen, Sha Tian, Janelle Simon, Alexandra Wuest, John E Wilkinson, Scott W Lowe.

Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models. Here we developed methods to somatically introduce different oncogenic lesions directly into the murine gastric epithelium. Genotypic configurations observed in patients produced metastatic gastric cancers that recapitulated the histological, molecular and clinical features of all nonviral molecular subtypes of the human disease. Applying this platform to both wild-type and immunodeficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells, which produced distinct patterns of metastasis that were mirrored in patients. Our results establish a highly portable platform for generating autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts.

DOI: https://doi.org/10.1038/s43018-023-00686-w
J Am Chem Soc. 2024 Jan 03.

Lipid Peroxidation Drives Liquid-Liquid Phase Separation and Disrupts Raft Protein Partitioning in Biological Membranes.

Muthuraj Balakrishnan, Anne K Kenworthy.

The peroxidation of membrane lipids by free radicals contributes to aging, numerous diseases, and ferroptosis, an iron-dependent form of cell death. Peroxidation changes the structure and physicochemical properties of lipids, leading to bilayer thinning, altered fluidity, and increased permeability of membranes in model systems. Whether and how lipid peroxidation impacts the lateral organization of proteins and lipids in biological membranes, however, remains poorly understood. Here, we employ cell-derived giant plasma membrane vesicles (GPMVs) as a model to investigate the impact of lipid peroxidation on ordered membrane domains, often termed membrane rafts. We show that lipid peroxidation induced by the Fenton reaction dramatically enhances the phase separation propensity of GPMVs into coexisting liquid-ordered (Lo) and liquid-disordered (Ld) domains and increases the relative abundance of the disordered phase. Peroxidation also leads to preferential accumulation of peroxidized lipids and 4-hydroxynonenal (4-HNE) adducts in the disordered phase, decreased lipid packing in both Lo and Ld domains, and translocation of multiple classes of raft proteins out of ordered domains. These findings indicate that the peroxidation of plasma membrane lipids disturbs many aspects of membrane rafts, including their stability, abundance, packing, and protein and lipid composition. We propose that these disruptions contribute to the pathological consequences of lipid peroxidation during aging and disease and thus serve as potential targets for therapeutic intervention.

DOI: https://doi.org/10.1021/jacs.3c10132
Cell Commun Signal. 2024 Jan 02. 22(1): 1

Macrophages reprogramming driven by cancer-associated fibroblasts under FOLFIRINOX treatment correlates with shorter survival in pancreatic cancer.

Zainab Hussain, Thomas Bertran, Pascal Finetti, Eugenie Lohmann, Emilie Mamessier, Ghislain Bidaut, François Bertucci, Moacyr Rego, Richard Tomasini.

  BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a clinically challenging cancer, mainly due to limited therapeutic options and the presence of a highly prominent tumor microenvironment (TME), facilitating tumor progression. The TME is predominated by heterogeneous populations of cancer-associated fibroblasts (CAFs) and tumor associated macrophages (TAMs), in constant communication with each other and with tumor cells, influencing many tumoral abilities such as therapeutic resistance. However how the crosstalk between CAFs and macrophages evolves following chemotherapeutic treatment remains poorly understood, limiting our capacity to halt therapeutic resistance.METHODS: We combined biological characterization of macrophages indirectly cocultured with human PDAC CAFs, under FOLFIRINOX treatment, with mRNAseq analyses of such macrophages and evaluated the relevance of the specific gene expression signature in a large series of primary PDAC patients to search for correlation with overall survival (OS) after FOLFIRINOX chemotherapy.
RESULTS: Firstly, we demonstrated that CAFs polarize naïve and M1 macrophages towards an M2-like phenotype with a specific increase of CD200R and CD209 M2 markers. Then, we demonstrated that CAFs counteract the pro-inflammatory phenotype induced by the FOLFIRINOX on Macrophages. Indeed, we highlighted that, under FOLFIRINOX, CAFs limit the FOLFIRINOX-induced cell death of macrophages and further reinforce their M2 phenotype as well as their immunosuppressive impact through specific chemokines production. Finally, we revealed that under FOLFIRINOX CAFs drive a specific macrophage gene expression signature involving SELENOP and GOS2 that correlates with shortened OS in FOLFIRINOX-treated PDAC patients.
CONCLUSION: Our study provides insight into the complex interactions between TME cells under FOLFIRINOX treatment. It suggests potential novel candidates that could be used as therapeutic targets in combination with FOLFIRINOX to prevent and alleviate TME influx on therapeutic resistance as well as biomarkers to predict FOLFIRINOX response in PDAC patients. Video Abstract.

Keywords:  Chemoresistance; FOLFIRINOX; Intercellular communication; Pancreatic cancer; Tumor-associated macrophages; cancer-associated fibroblasts

DOI:  https://doi.org/10.1186/s12964-023-01388-7
Cancer Cell. 2023 Dec 19. pii: S1535-6108(23)00430-0. [Epub ahead of print]

EGFR-activated myofibroblasts promote metastasis of pancreatic cancer.

Gianluca Mucciolo, Joaquín Araos Henríquez, Muntadher Jihad, Sara Pinto Teles, Judhell S Manansala, Wenlong Li, Sally Ashworth, Eloise G Lloyd, Priscilla S W Cheng, Weike Luo, Akanksha Anand, Ashley Sawle, Anna Piskorz, Giulia Biffi.

  Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Cancer-associated fibroblasts (CAFs) are recognized potential therapeutic targets, but poor understanding of these heterogeneous cell populations has limited the development of effective treatment strategies. We previously identified transforming growth factor beta (TGF-β) as a main driver of myofibroblastic CAFs (myCAFs). Here, we show that epidermal growth factor receptor/Erb-B2 receptor (EGFR/ERBB2) signaling is induced by TGF-β in myCAFs through an autocrine process mediated by amphiregulin. Inhibition of this EGFR/ERBB2-signaling network in PDAC organoid-derived cultures and mouse models differentially impacts distinct CAF subtypes, providing insights into mechanisms underpinning their heterogeneity. Remarkably, EGFR-activated myCAFs promote PDAC metastasis in mice, unmasking functional significance in myCAF heterogeneity. Finally, analyses of other cancer datasets suggest that these processes might operate in other malignancies. These data provide functional relevance to myCAF heterogeneity and identify a candidate target for preventing tumor invasion in PDAC.

Keywords:  Amphiregulin; EGFR/ERBB2 signaling; TGF-β signaling; cancer-associated fibroblasts; metastasis; myCAFs; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2023.12.002
Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00452-7. [Epub ahead of print]36(1): 103-115.e4

Glycine homeostasis requires reverse SHMT flux.

Matthew J McBride, Craig J Hunter, Zhaoyue Zhang, Tara TeSlaa, Xincheng Xu, Gregory S Ducker, Joshua D Rabinowitz.

  The folate-dependent enzyme serine hydroxymethyltransferase (SHMT) reversibly converts serine into glycine and a tetrahydrofolate-bound one-carbon unit. Such one-carbon unit production plays a critical role in development, the immune system, and cancer. Using rodent models, here we show that the whole-body SHMT flux acts to net consume rather than produce glycine. Pharmacological inhibition of whole-body SHMT1/2 and genetic knockout of liver SHMT2 elevated circulating glycine levels up to eight-fold. Stable-isotope tracing revealed that the liver converts glycine to serine, which is then converted by serine dehydratase into pyruvate and burned in the tricarboxylic acid cycle. In response to diets deficient in serine and glycine, de novo biosynthetic flux was unaltered, but SHMT2- and serine-dehydratase-mediated catabolic flux was lower. Thus, glucose-derived serine synthesis is largely insensitive to systemic demand. Instead, circulating serine and glycine homeostasis is maintained through variable consumption, with liver SHMT2 a major glycine-consuming enzyme.

Keywords:  SHMT; amino acid metabolism; folate cycle; glycine; hepatic clearance; homeostasis; serine

DOI:  https://doi.org/10.1016/j.cmet.2023.12.001
Nat Commun. 2024 Jan 02. 15(1): 100

KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo.

Arafath K Najumudeen, Sigrid K Fey, Laura M Millett, Catriona A Ford, Kathryn Gilroy, Nuray Gunduz, Rachel A Ridgway, Eve Anderson, Douglas Strathdee, William Clark, Colin Nixon, Jennifer P Morton, Andrew D Campbell, Owen J Sansom.

Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-type Kras in the context of oncogenic Kras. Deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-type Kras upon tumour initiation, progression and therapeutic response in Kras mutant CRC.

DOI: https://doi.org/10.1038/s41467-023-44342-4
PLoS One. 2024 ;19(1): e0292196

Validation of dual energy X-ray absorptiometry for longitudinal quantification of tumor burden in a murine model of pancreatic ductal adenocarcinoma.

Zachary R Sechrist, Grace Lee, Edward M Schwarz, Calvin L Cole.

Noninvasive imaging is central to preclinical, in vivo models of pancreatic ductal adenocarcinoma (PDAC). While bioluminescent imaging (BLI) is a gold standard, its signal is dependent on the metabolic activity of tumor cells. In contrast, dual energy X-ray absorptiometry (DEXA) is a direct measure of body composition. Thus, we aimed to assess its potential for longitudinal quantification of tumor burden versus BLI. We utilized the KCKO murine model of PDAC and subjected tumor-bearing (n = 20) and non-tumor control (NTC) (n = 10) animals to weekly BLI and DEXA measurements for up to 10 weeks. While BLI detected tumors at 1-week, it failed to detect tumor growth, displayed a decreasing trend overtime (slope = -9.0x108; p = 0.0028), and terminal signal did not correlate with ex vivo tumor mass (r = 0.01853; p = 0.6286). In contrast, DEXA did not detect elevated changes in abdominal cavity lean mass until week 2 post inoculation and tumors were not visible until week 3, but successfully quantified a tumor growth trend (slope = 0.7322; p<0.0001), and strongly correlated with final tumor mass (r = 0.9351; p<0.0001). These findings support the use of BLI for initial tumor engraftment and persistence but demonstrate the superiority of DEXA for longitudinal tumor burden studies. As tumor detection by DEXA is not restricted to luciferase expressing models, future studies to assess its value in various cancer models and as an in vivo outcome measure of treatment efficacy are warranted.

DOI: https://doi.org/10.1371/journal.pone.0292196
bioRxiv. 2023 Dec 14. pii: 2023.12.13.571566. [Epub ahead of print]

ROR2 regulates cellular plasticity in pancreatic neoplasia and adenocarcinoma.

Simone Benitz, Alexander Steep, Malak Nasser, Jonathan Preall, Ujjwal M Mahajan, Holly McQuithey, Ian Loveless, Erick T Davis, Hui-Ju Wen, Daniel W Long, Thomas Metzler, Samuel Zwernik, Michaela Louw, Donald Rempinski, Daniel Salas-Escabillas, Sydney Brender, Linghao Song, Ling Huang, Zhenyu Zhang, Nina Steele, Ivonne Regel, Filip Bednar, Howard C Crawford.

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells to precancerous lesions to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We found that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia (SPEM)-like identity. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that was largely persistent upon progression to carcinoma. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition.

DOI: https://doi.org/10.1101/2023.12.13.571566
Autophagy. 2024 Jan 03. 1-17

DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas.

Gamze Bildik, Joshua P Gray, Weiqun Mao, Hailing Yang, Rumeysa Ozyurt, Vivian R Orellana, Olivier De Wever, Mark S Carey, Robert C Bast, Zhen Lu.

  Pancreatic ductal adenocarcinoma (PDAC) and low-grade ovarian cancer (LGSOC) are characterized by the prevalence of KRAS oncogene mutations. DIRAS3 is the first endogenous non-RAS protein that heterodimerizes with RAS, disrupts RAS clustering, blocks RAS signaling, and inhibits cancer cell growth. Here, we found that DIRAS3-mediated KRAS inhibition induces ROS-mediated apoptosis in PDAC and LGSOC cells with KRAS mutations, but not in cells with wild-type KRAS, by downregulating NFE2L2/Nrf2 transcription, reducing antioxidants, and inducing oxidative stress. DIRAS3 also induces cytoprotective macroautophagy/autophagy that may protect mutant KRAS cancer cells from oxidative stress, by inhibiting mutant KRAS, activating the STK11/LKB1-PRKAA/AMPK pathway, increasing lysosomal CDKN1B/p27 localization, and inducing autophagic gene expression. Treatment with chloroquine or the novel dimeric chloroquine analog DC661 significantly enhances DIRAS3-mediated inhibition of mutant KRAS tumor cell growth in vitro and in vivo. Taken together, our study demonstrates that DIRAS3 plays a critical role in regulating mutant KRAS-driven oncogenesis in PDAC and LGSOC.Abbreviations: AFR: autophagic flux reporter; ATG: autophagy related; CQ: chloroquine; DCFDA: 2'-7'-dichlorodihydrofluorescein diacetate; DIRAS3: DIRAS family GTPase 3; DOX: doxycycline; KRAS: KRAS proto-oncogene, LGSOC: low-grade serous ovarian cancer; MiT/TFE: microphthalmia family of transcription factors; NAC: N-acetylcysteine; PDAC: pancreatic ductal adenocarcinoma; ROS: reactive oxygen species; TFEB: transcription factor EB.

Keywords:  Autophagy; DIRAS3; KRAS; LGSOC; PDAC; chloroquine

DOI:  https://doi.org/10.1080/15548627.2023.2299516
Cell Rep. 2023 Dec 30. pii: S2211-1247(23)01640-6. [Epub ahead of print]43(1): 113629

Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.

Dimitris Karagiannis, Warren Wu, Albert Li, Makiko Hayashi, Xiao Chen, Michaela Yip, Vaibhav Mangipudy, Xinjing Xu, Francisco J Sánchez-Rivera, Yadira M Soto-Feliciano, Jiangbin Ye, Thales Papagiannakopoulos, Chao Lu.

  The interplay between metabolism and chromatin signaling is implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway, which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen, we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDACs). This association is observed across cultured cells, mouse models, and patient-derived xenografts. Integrative epigenomic, transcriptomic, and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors.

Keywords:  CP: Cancer; HDAC inhibitors; NRF2 pathway; cancer epigenetics; cancer metabolism; cancer targeted therapy; epigenetic reprogramming; lung cancer

DOI:  https://doi.org/10.1016/j.celrep.2023.113629
Nat Commun. 2024 Jan 02. 15(1): 79

Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance.

Hyemin Lee, Amber Horbath, Lavanya Kondiparthi, Jitendra Kumar Meena, Guang Lei, Shayani Dasgupta, Xiaoguang Liu, Li Zhuang, Pranavi Koppula, Mi Li, Iqbal Mahmud, Bo Wei, Philip L Lorenzi, Khandan Keyomarsi, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan.

How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as 5-fluorouracil-resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil-resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.

DOI: https://doi.org/10.1038/s41467-023-44412-7
Nat Cancer. 2024 Jan 02.

Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.

Fuming Li, Pingyu Liu, Wen Mi, Liucheng Li, Nicole M Anderson, Nicholas P Lesner, Michelle Burrows, Jacqueline Plesset, Ariana Majer, Guanlin Wang, Jinyang Li, Lingzhi Zhu, Brian Keith, M Celeste Simon.

Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer.

DOI: https://doi.org/10.1038/s43018-023-00671-3
Autophagy. 2024 Jan 04.

Targeting cancer-associated fibroblast autophagy renders pancreatic cancer eradicable with immunochemotherapy by inhibiting adaptive immune resistance.

Xiaozhen Zhang, Mengyi Lao, Hanshen Yang, Kang Sun, Yunfei Dong, Lihong He, Xinchi Jiang, Honghui Wu, Yangwei Jiang, Muchun Li, Honggang Ying, Xinyuan Liu, Jian Xu, Yan Chen, Hanjia Zhang, Ruhong Zhou, Jianqing Gao, Xueli Bai, Tingbo Liang.

  Accumulating evidence suggests that cancer-associated fibroblast (CAF) macroautophagy/autophagy is crucial in tumor development and may be a therapeutic target for pancreatic ductal adenocarcinoma (PDAC). However, the role of CAF autophagy during immune surveillance and cancer immunotherapy is unclear. The present study revealed that the inhibition of CAF autophagy suppresses in vivo tumor development in immune-deficient xenografts. This deletion compromises anti-tumor immunity and anti-tumor efficacy both in vitro and in vivo by upregulating CD274/PDL1 levels in an immune-competent mouse model. A block in CAF autophagy reduced the production of IL6 (interleukin 6), disrupting high desmoplastic TME and decreasing USP14 expression at the transcription level in pancreatic cancer cells. We further identify USP14 as the post-translational factor responsible for downregulating CD274 expression by removing K63 linked-ubiquitination at the K280 residue. Finally, chloroquine diphosphate-loaded mesenchymal stem cell (MSC)-liposomes, by accurately targeting CAFs, inhibited CAF autophagy, improving the efficacy of immunochemotherapy to combat pancreatic cancer.

Keywords:  Adaptive immune resistance; autophagy; cancer-associated fibroblast; pancreatic ductal adenocarcinoma; programmed cell death 1 ligand 1

DOI:  https://doi.org/10.1080/15548627.2023.2300913
Nat Metab. 2024 Jan 03.

Amino acid intake strategies define pluripotent cell states.

Pavlina K Todorova, Benjamin T Jackson, Vidur Garg, Katrina I Paras, Julia S Brunner, Anna E Bridgeman, Yanyang Chen, Sanjeethan C Baksh, Jielin Yan, Anna-Katerina Hadjantonakis, Lydia W S Finley.

Mammalian preimplantation development is associated with marked metabolic robustness, and embryos can develop under a wide variety of nutrient conditions, including even the complete absence of soluble amino acids. Here we show that mouse embryonic stem cells (ESCs) capture the unique metabolic state of preimplantation embryos and proliferate in the absence of several essential amino acids. Amino acid independence is enabled by constitutive uptake of exogenous protein through macropinocytosis, alongside a robust lysosomal digestive system. Following transition to more committed states, ESCs reduce digestion of extracellular protein and instead become reliant on exogenous amino acids. Accordingly, amino acid withdrawal selects for ESCs that mimic the preimplantation epiblast. More broadly, we find that all lineages of preimplantation blastocysts exhibit constitutive macropinocytic protein uptake and digestion. Taken together, these results highlight exogenous protein uptake and digestion as an intrinsic feature of preimplantation development and provide insight into the catabolic strategies that enable embryos to sustain viability before implantation.

DOI: https://doi.org/10.1038/s42255-023-00940-6
Biophys J. 2023 Dec 29. pii: S0006-3495(23)04177-2. [Epub ahead of print]

Coupling Liquid Phases in 3D Condensates and 2D Membranes: Successes, Challenges, and Tools.

Heidi M J Weakly, Sarah L Keller.

  This review describes the major experimental challenges researchers meet when attempting to couple phase separation between membranes and condensates. Although it is well known that phase separation in a 2D membrane should affect molecules capable of forming a 3D condensate (and vice versa), few researchers have quantified the effects to date. The scarcity of these measurements is not due to lack of intense interest or effort in the field. Rather, it reflects significant experimental challenges in manipulating coupled membranes and condensates to yield quantitative values. These challenges transcend many molecular details, which means they impact a wide range of systems. This review highlights recent exciting successes in the field, and it lays out a comprehensive list of tools that address potential pitfalls for researchers who are considering coupling membranes with condensates.

Keywords:  condensate; lipid; liquid; membrane; membraneless organelle; phase separation; wetting

DOI:  https://doi.org/10.1016/j.bpj.2023.12.023
BMC Bioinformatics. 2024 Jan 03. 25(1): 9

cytoviewer: an R/Bioconductor package for interactive visualization and exploration of highly multiplexed imaging data.

Lasse Meyer, Nils Eling, Bernd Bodenmiller.

  BACKGROUND: Highly multiplexed imaging enables single-cell-resolved detection of numerous biological molecules in their spatial tissue context. Interactive visualization of multiplexed imaging data is crucial at any step of data analysis to facilitate quality control and the spatial exploration of single cell features. However, tools for interactive visualization of multiplexed imaging data are not available in the statistical programming language R.RESULTS: Here, we describe cytoviewer, an R/Bioconductor package for interactive visualization and exploration of multi-channel images and segmentation masks. The cytoviewer package supports flexible generation of image composites, allows side-by-side visualization of single channels, and facilitates the spatial visualization of single-cell data in the form of segmentation masks. As such, cytoviewer improves image and segmentation quality control, the visualization of cell phenotyping results and qualitative validation of hypothesis at any step of data analysis. The package operates on standard data classes of the Bioconductor project and therefore integrates with an extensive framework for single-cell and image analysis. The graphical user interface allows intuitive navigation and little coding experience is required to use the package. We showcase the functionality and biological application of cytoviewer by analysis of an imaging mass cytometry dataset acquired from cancer samples.
CONCLUSIONS: The cytoviewer package offers a rich set of features for highly multiplexed imaging data visualization in R that seamlessly integrates with the workflow for image and single-cell data analysis. It can be installed from Bioconductor via https://www.bioconductor.org/packages/release/bioc/html/cytoviewer.html . The development version and further instructions can be found on GitHub at https://github.com/BodenmillerGroup/cytoviewer .

Keywords:  Imaging-mass-cytometry; Multiplexed-imaging; R; Single-cell; Spatial; Visualization

DOI:  https://doi.org/10.1186/s12859-023-05546-z
Front Bioinform. 2023 ;3 1308708

Segmentation of cellular ultrastructures on sparsely labeled 3D electron microscopy images using deep learning.

Archana Machireddy, Guillaume Thibault, Kevin G Loftis, Kevin Stoltz, Cecilia E Bueno, Hannah R Smith, Jessica L Riesterer, Joe W Gray, Xubo Song.

  Focused ion beam-scanning electron microscopy (FIB-SEM) images can provide a detailed view of the cellular ultrastructure of tumor cells. A deeper understanding of their organization and interactions can shed light on cancer mechanisms and progression. However, the bottleneck in the analysis is the delineation of the cellular structures to enable quantitative measurements and analysis. We mitigated this limitation using deep learning to segment cells and subcellular ultrastructure in 3D FIB-SEM images of tumor biopsies obtained from patients with metastatic breast and pancreatic cancers. The ultrastructures, such as nuclei, nucleoli, mitochondria, endosomes, and lysosomes, are relatively better defined than their surroundings and can be segmented with high accuracy using a neural network trained with sparse manual labels. Cell segmentation, on the other hand, is much more challenging due to the lack of clear boundaries separating cells in the tissue. We adopted a multi-pronged approach combining detection, boundary propagation, and tracking for cell segmentation. Specifically, a neural network was employed to detect the intracellular space; optical flow was used to propagate cell boundaries across the z-stack from the nearest ground truth image in order to facilitate the separation of individual cells; finally, the filopodium-like protrusions were tracked to the main cells by calculating the intersection over union measure for all regions detected in consecutive images along z-stack and connecting regions with maximum overlap. The proposed cell segmentation methodology resulted in an average Dice score of 0.93. For nuclei, nucleoli, and mitochondria, the segmentation achieved Dice scores of 0.99, 0.98, and 0.86, respectively. The segmentation of FIB-SEM images will enable interpretative rendering and provide quantitative image features to be associated with relevant clinical variables.

Keywords:  cell boundary; deep neural network; electron microscopy; segmentation; subcellular ultrastructure

DOI:  https://doi.org/10.3389/fbinf.2023.1308708
Biochim Biophys Acta Rev Cancer. 2023 Dec 27. pii: S0304-419X(23)00211-1. [Epub ahead of print] 189062

Dietary approaches for exploiting metabolic vulnerabilities in cancer.

Otília Menyhárt, Balázs Győrffy.

  Renewed interest in tumor metabolism sparked an enthusiasm for dietary interventions to prevent and treat cancer. Changes in diet impact circulating nutrient levels in the plasma and the tumor microenvironment, and preclinical studies suggest that dietary approaches, including caloric and nutrient restrictions, can modulate tumor initiation, progression, and metastasis. Cancers are heterogeneous in their metabolic dependencies and preferred energy sources and can be addicted to glucose, fructose, amino acids, or lipids for survival and growth. This dependence is influenced by tumor type, anatomical location, tissue of origin, aberrant signaling, and the microenvironment. This review summarizes nutrient dependencies and the related signaling pathway activations that provide targets for nutritional interventions. We examine popular dietary approaches used as adjuvants to anticancer therapies, encompassing caloric restrictions, including time-restricted feeding, intermittent fasting, fasting-mimicking diets (FMDs), and nutrient restrictions, notably the ketogenic diet. Despite promising results, much of the knowledge on dietary restrictions comes from in vitro and animal studies, which may not accurately reflect real-life situations. Further research is needed to determine the optimal duration, timing, safety, and efficacy of dietary restrictions for different cancers and treatments. In addition, well-designed human trials are necessary to establish the link between specific metabolic vulnerabilities and targeted dietary interventions. However, low patient compliance in clinical trials remains a significant challenge.

Keywords:  Caloric restriction; Dietary intervention; Fasting-mimicking diet; Ketogenic diet; cancer metabolism

DOI:  https://doi.org/10.1016/j.bbcan.2023.189062
Nat Comput Sci. 2023 Sep;3(9): 777-788

Cellular harmonics for the morphology-invariant analysis of molecular organization at the cell surface.

Hanieh Mazloom-Farsibaf, Qiongjing Zou, Rebecca Hsieh, Gaudenz Danuser, Meghan K Driscoll.

The spatiotemporal organization of membrane-associated molecules is central to the regulation of cellular signals. Powerful new microscopy techniques enable the three-dimensional visualization of localization and activation of these molecules; however, the quantitative interpretation and comparison of molecular organization on the three-dimensional cell surface remains challenging because cells themselves vary greatly in morphology. Here we introduce u-signal3D, a framework to assess the spatial scales of molecular organization at the cell surface in a cell-morphology-invariant manner. We validated the framework by analyzing synthetic signaling patterns painted onto observed cell morphologies, as well as measured distributions of cytoskeletal and signaling molecules. To demonstrate the framework's versatility, we further compared the spatial organization of cell surface signals both within, and between, cell populations, and powered an upstream machine-learning-based analysis of signaling motifs.

DOI: https://doi.org/10.1038/s43588-023-00512-4
Commun Biol. 2024 Jan 05. 7(1): 29

Curvature sensing lipid dynamics in a mitochondrial inner membrane model.

Vinaya Kumar Golla, Kevin J Boyd, Eric R May.

Membrane curvature is essential for many cellular structures and processes, and factors such as leaflet asymmetry, lipid composition, and proteins all play important roles. Cardiolipin is the signature lipid of mitochondrial membranes and is essential for maintaining the highly curved shapes of the inner mitochondrial membrane (IMM) and the spatial arrangement of membrane proteins. In this study, we investigate the partitioning behavior of various lipids present in the IMM using coarse-grained molecular dynamics simulations. This study explores curved bilayer systems containing phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CDL) in binary and ternary component mixtures. Curvature properties such as mean and Gaussian curvatures, as well as the distribution of lipids into the various curved regions of the cristae models, are quantified. Overall, this work represents an advance beyond previous studies on lipid curvature sensing by simulating these systems in a geometry that has the morphological features and scales of curvature consistent with regions of the IMM. We find that CDL has a stronger preference for accumulating in regions of negative curvature than PE lipids, in agreement with previous results. Furthermore, we find lipid partitioning propensity is dominated by sensitivity to mean curvature, while there is a weaker correlation with Gaussian curvature.

DOI: https://doi.org/10.1038/s42003-023-05657-6
Mol Cell. 2024 Jan 04. pii: S1097-2765(23)01028-6. [Epub ahead of print]84(1): 17-19

Lysosome identity crisis: Phosphoinositides and mTORC1 negotiate lysosomal behavior.

Mélanie Mansat, Roberto J Botelho.

Ebner et al.1 discovered a nutrient-dependent molecular feedback circuit that employs mTORC1, lipid kinases, and phosphatases to generate phosphatidylinositol-3-phosphate [PI(3)P] or phosphatidylinositol-4-phosphate [PI(4)P] in a mutually exclusive manner on lysosomes, which respectively convert lysosomes into organelles that support anabolism or catabolism.

DOI: https://doi.org/10.1016/j.molcel.2023.12.009
Nat Commun. 2024 Jan 02. 15(1): 91

Experimental determination and mathematical modeling of standard shapes of forming autophagosomes.

Yuji Sakai, Satoru Takahashi, Ikuko Koyama-Honda, Chieko Saito, Noboru Mizushima.

The formation of autophagosomes involves dynamic morphological changes of a phagophore from a flat membrane cisterna into a cup-shaped intermediate and a spherical autophagosome. However, the physical mechanism behind these morphological changes remains elusive. Here, we determine the average shapes of phagophores by statistically investigating three-dimensional electron micrographs of more than 100 phagophores. The results show that the cup-shaped structures adopt a characteristic morphology; they are longitudinally elongated, and the rim is catenoidal with an outwardly recurved shape. To understand these characteristic shapes, we establish a theoretical model of the shape of entire phagophores. The model quantitatively reproduces the average morphology and reveals that the characteristic shape of phagophores is primarily determined by the relative size of the open rim to the total surface area. These results suggest that the seemingly complex morphological changes during autophagosome formation follow a stable path determined by elastic bending energy minimization.

DOI: https://doi.org/10.1038/s41467-023-44442-1
bioRxiv. 2023 Dec 13. pii: 2023.12.12.571324. [Epub ahead of print]

Proximity labeling reveals dynamic changes in the SQSTM1 protein network.

Alejandro N Rondón Ortiz, Lushuang Zhang, Peter E A Ash, Avik Basu, Sambhavi Puri, Sophie J F van der Spek, Luke Dorrian, Andrew Emili, Benjamin Wolozin.

Sequestosome1 (SQSTM1) is an autophagy receptor that mediates degrada4on of intracellular cargo, including protein aggregates, through mul4ple protein interac4ons. These interac4ons form the SQSTM1 protein network that are mediated by SQSTM1 func4onal interac4on domains, which include LIR, PB1, UBA and KIR. Despite various abempts to unravel the complexity of the SQSTM1 protein network, our understanding of the rela4onship of various components in cellular physiology and disease states con4nues to evolve. To inves4gate the SQSTM1 protein interac4on network, we performed proximity profile labeling by fusing TurboID with the human protein SQSTM1 (TurboID::SQSTM1). This chimeric protein displayed well-established SQSTM1 features including: produc4on of SQSTM1 intracellular bodies, binding to known SQSTM1 interac4ng partners via defined func4onal SQSTM1 interac4ng domains and capture of novel SQSTM1 interactors. Strikingly, aggregated tau protein altered the protein interac4on network of SQSTM1 to include many stress-associated proteins. Overall, our work reveals the dynamic landscape of the SQSTM1 protein network and offers a resource to study SQSTM1 func4on in cellular physiology and disease state. ProteomeXchange Consor4um PRIDE Submission: Submission details: Project Name: Proximity labeling reveals dynamic changes in the SQSTM1 protein network. Project accession: PXD047725 Project DOI: Not applicable.

DOI: https://doi.org/10.1101/2023.12.12.571324
JCO Clin Cancer Inform. 2024 Jan;8 e2300119

Pancreatic Cancer Action Network's SPARK: A Cloud-Based Patient Health Data and Analytics Platform for Pancreatic Cancer.

Kawther Abdilleh, Omar Khalid, Dennis Ladnier, Wenshuai Wan, Sara Seepo, Garrett Rupp, Valentin Corelj, Zelia F Worman, Divya Sain, Jack DiGiovanna, Bruce Press, Satty Chandrashekhar, Eric Collisson, Karen Y Cui, Anirban Maitra, Paul A Rejto, Kevin P White, Lynn Matrisian, Sudheer Doss.

PURPOSE: Pancreatic cancer currently holds the position of third deadliest cancer in the United States and the 5-year survival rate is among the lowest for major cancers at just 12%. Thus, continued research efforts to better understand the clinical and molecular underpinnings of pancreatic cancer are critical to developing both early detection methodologies as well as improved therapeutic options. This study introduces Pancreatic Cancer Action Network's (PanCAN's) SPARK, a cloud-based data and analytics platform that integrates patient health data from the PanCAN's research initiatives and aims to accelerate pancreatic cancer research by making real-world patient health data and analysis tools easier to access and use.MATERIALS AND METHODS: The SPARK platform integrates clinical, molecular, multiomic, imaging, and patient-reported data generated from PanCAN's research initiatives. The platform is built on a cloud-based infrastructure powered by Velsera. Cohort exploration and browser capabilities are built using Velsera ARIA, a specialized product for leveraging clinicogenomic data to build cohorts, query variant information, and drive downstream association analyses. Data science and analytic capabilities are also built into the platform allowing researchers to perform simple to complex analysis.
RESULTS: Version 1 of the SPARK platform was released to pilot users, who represented diverse end users, including molecular biologists, clinicians, and bioinformaticians. Included in the pilot release of SPARK are deidentified clinical (including treatment and outcomes data), molecular, multiomic, and whole-slide pathology images for over 600 patients enrolled in PanCAN's Know Your Tumor molecular profiling service.
CONCLUSION: The pilot release of the SPARK platform introduces qualified researchers to PanCAN real-world patient health data and analytical resources in a centralized location.

DOI: https://doi.org/10.1200/CCI.23.00119
Mol Metab. 2023 Dec 30. pii: S2212-8778(23)00203-X. [Epub ahead of print]79 101869

Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice.

Alena Akhmetshina, Valentina Bianco, Ivan Bradić, Melanie Korbelius, Anita Pirchheim, Katharina B Kuentzel, Thomas O Eichmann, Helga Hinteregger, Dagmar Kolb, Hansjoerg Habisch, Laura Liesinger, Tobias Madl, Wolfgang Sattler, Branislav Radović, Simon Sedej, Ruth Birner-Gruenberger, Nemanja Vujić, Dagmar Kratky.

  OBJECTIVE: Lysosomal acid lipase (LAL) is the only enzyme known to hydrolyze cholesteryl esters (CE) and triacylglycerols in lysosomes at an acidic pH. Despite the importance of lysosomal hydrolysis in skeletal muscle (SM), research in this area is limited. We hypothesized that LAL may play an important role in SM development, function, and metabolism as a result of lipid and/or carbohydrate metabolism disruptions.RESULTS: Mice with systemic LAL deficiency (Lal-/-) had markedly lower SM mass, cross-sectional area, and Feret diameter despite unchanged proteolysis or protein synthesis markers in all SM examined. In addition, Lal-/- SM showed increased total cholesterol and CE concentrations, especially during fasting and maturation. Regardless of increased glucose uptake, expression of the slow oxidative fiber marker MYH7 was markedly increased in Lal-/-SM, indicating a fiber switch from glycolytic, fast-twitch fibers to oxidative, slow-twitch fibers. Proteomic analysis of the oxidative and glycolytic parts of the SM confirmed the transition between fast- and slow-twitch fibers, consistent with the decreased Lal-/- muscle size due to the "fiber paradox". Decreased oxidative capacity and ATP concentration were associated with reduced mitochondrial function of Lal-/- SM, particularly affecting oxidative phosphorylation, despite unchanged structure and number of mitochondria. Impairment in muscle function was reflected by increased exhaustion in the treadmill peak effort test in vivo.
CONCLUSION: We conclude that whole-body loss of LAL is associated with a profound remodeling of the muscular phenotype, manifested by fiber type switch and a decline in muscle mass, most likely due to dysfunctional mitochondria and impaired energy metabolism, at least in mice.

Keywords:  Energy metabolism; LAL; LAL deficiency; Lal-deficient mouse; Muscle proteomics

DOI:  https://doi.org/10.1016/j.molmet.2023.101869
Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00464-3. [Epub ahead of print]36(1): 116-129.e7

Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD.

Alia Ghrayeb, Alexandra C Finney, Bella Agranovich, Daniel Peled, Sumit Kumar Anand, M Peyton McKinney, Mahasen Sarji, Dongshan Yang, Natan Weissman, Shani Drucker, Sara Isabel Fernandes, Jonatan Fernández-García, Kyle Mahan, Zaid Abassi, Lin Tan, Philip L Lorenzi, James Traylor, Jifeng Zhang, Ifat Abramovich, Y Eugene Chen, Oren Rom, Inbal Mor, Eyal Gottlieb.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.

Keywords:  MASLD; SHMT; acetaminophen hepatotoxicity; glutathione; glycine; one-carbon metabolism; xenobiotic

DOI:  https://doi.org/10.1016/j.cmet.2023.12.013
PLoS Biol. 2024 Jan;22(1): e3002453

Cell size homeostasis is tightly controlled throughout the cell cycle.

Xili Liu, Jiawei Yan, Marc W Kirschner.

To achieve a stable size distribution over multiple generations, proliferating cells require a means of counteracting stochastic noise in the rate of growth, the time spent in various phases of the cell cycle, and the imprecision in the placement of the plane of cell division. In the most widely accepted model, cell size is thought to be regulated at the G1/S transition, such that cells smaller than a critical size pause at the end of G1 phase until they have accumulated mass to a predetermined size threshold, at which point the cells proceed through the rest of the cell cycle. However, a model, based solely on a specific size checkpoint at G1/S, cannot readily explain why cells with deficient G1/S control mechanisms are still able to maintain a very stable cell size distribution. Furthermore, such a model would not easily account for stochastic variation in cell size during the subsequent phases of the cell cycle, which cannot be anticipated at G1/S. To address such questions, we applied computationally enhanced quantitative phase microscopy (ceQPM) to populations of cultured human cell lines, which enables highly accurate measurement of cell dry mass of individual cells throughout the cell cycle. From these measurements, we have evaluated the factors that contribute to maintaining cell mass homeostasis at any point in the cell cycle. Our findings reveal that cell mass homeostasis is accurately maintained, despite disruptions to the normal G1/S machinery or perturbations in the rate of cell growth. Control of cell mass is generally not confined to regulation of the G1 length. Instead mass homeostasis is imposed throughout the cell cycle. In the cell lines examined, we find that the coefficient of variation (CV) in dry mass of cells in the population begins to decline well before the G1/S transition and continues to decline throughout S and G2 phases. Among the different cell types tested, the detailed response of cell growth rate to cell mass differs. However, in general, when it falls below that for exponential growth, the natural increase in the CV of cell mass is effectively constrained. We find that both mass-dependent cell cycle regulation and mass-dependent growth rate modulation contribute to reducing cell mass variation within the population. Through the interplay and coordination of these 2 processes, accurate cell mass homeostasis emerges. Such findings reveal previously unappreciated and very general principles of cell size control in proliferating cells. These same regulatory processes might also be operative in terminally differentiated cells. Further quantitative dynamical studies should lead to a better understanding of the underlying molecular mechanisms of cell size control.

DOI: https://doi.org/10.1371/journal.pbio.3002453
Nat Comput Sci. 2022 May;2(5): 286

Impact of aspirin on cancer incidence.

Ananya Rastogi.

DOI: https://doi.org/10.1038/s43588-022-00259-4
bioRxiv. 2023 Dec 14. pii: 2023.12.13.571595. [Epub ahead of print]

Engineering self-propelled tumor-infiltrating CAR T cells using synthetic velocity receptors.

Adrian C Johnston, Gretchen M Alicea, Cameron C Lee, Payal V Patel, Eban A Hanna, Eduarda Vaz, André Forjaz, Zeqi Wan, Praful R Nair, Yeongseo Lim, Tina Chen, Wenxuan Du, Dongjoo Kim, Tushar D Nichakawade, Vito W Rebecca, Challice L Bonifant, Rong Fan, Ashley L Kiemen, Pei-Hsun Wu, Denis Wirtz.

Chimeric antigen receptor (CAR) T cells express antigen-specific synthetic receptors, which upon binding to cancer cells, elicit T cell anti-tumor responses. CAR T cell therapy has enjoyed success in the clinic for hematological cancer indications, giving rise to decade-long remissions in some cases. However, CAR T therapy for patients with solid tumors has not seen similar successes. Solid tumors constitute 90% of adult human cancers, representing an enormous unmet clinical need, ripe for new cell therapies. Current approaches do not solve the central problem of limited ability of therapeutic cells to migrate through the stromal matrix. We discover that T cells at low and high density display low- and high-migration phenotypes, respectively. The highly migratory phenotype is mediated by a paracrine pathway from a group of self-produced inflammatory cytokines that include IL5, TNFα, IFNγ, and IL8. We exploit this finding to "lock-in" a highly migratory phenotype by developing and expressing receptors, which we call velocity receptors (VRs). VRs target these cytokines and signal through these cytokines' cognate receptors to increase T cell motility and infiltrate lung, ovarian, and pancreatic tumors in large numbers and at doses for which control CAR T cells remain confined to the tumor periphery. In contrast to CAR therapy alone, VR-CAR T cells significantly attenuate tumor growth and extend overall survival. This work suggests that approaches to the design of immune cell receptors that focus on migration signaling will help current and future CAR cellular therapies to infiltrate deep into solid tumors.

DOI: https://doi.org/10.1101/2023.12.13.571595
Cancer Cell. 2023 Dec 27. pii: S1535-6108(23)00435-X. [Epub ahead of print]

Association of exercise with pan-cancer incidence and overall survival.

Jessica A Lavery, Paul C Boutros, Daniel Knight, Tuomas Tammela, Chaya S Moskowitz, Lee W Jones.

Lavery et al. show that the association between exercise and risk of cancer varied as a function of organ site and amount of exercise. Exercise was also associated with a longevity benefit regardless of a cancer diagnosis or not. This study further highlights the importance of exercise as an effective cancer preventive strategy.

DOI: https://doi.org/10.1016/j.ccell.2023.12.007
Nat Commun. 2024 Jan 02. 15(1): 28

MAPS: pathologist-level cell type annotation from tissue images through machine learning.

Muhammad Shaban, Yunhao Bai, Huaying Qiu, Shulin Mao, Jason Yeung, Yao Yu Yeo, Vignesh Shanmugam, Han Chen, Bokai Zhu, Jason L Weirather, Garry P Nolan, Margaret A Shipp, Scott J Rodig, Sizun Jiang, Faisal Mahmood.

Highly multiplexed protein imaging is emerging as a potent technique for analyzing protein distribution within cells and tissues in their native context. However, existing cell annotation methods utilizing high-plex spatial proteomics data are resource intensive and necessitate iterative expert input, thereby constraining their scalability and practicality for extensive datasets. We introduce MAPS (Machine learning for Analysis of Proteomics in Spatial biology), a machine learning approach facilitating rapid and precise cell type identification with human-level accuracy from spatial proteomics data. Validated on multiple in-house and publicly available MIBI and CODEX datasets, MAPS outperforms current annotation techniques in terms of speed and accuracy, achieving pathologist-level precision even for typically challenging cell types, including tumor cells of immune origin. By democratizing rapidly deployable and scalable machine learning annotation, MAPS holds significant potential to expedite advances in tissue biology and disease comprehension.

DOI: https://doi.org/10.1038/s41467-023-44188-w