bims-cagime 2022-01-09 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2022‒01‒09
twenty-nine papers selected by
Kıvanç Görgülü
Technical University of Munich

The SWI/SNF chromatin remodeling assemblies BAF and PBAF differentially regulate cell cycle exit and cellular invasion in vivo.
Biochemical characterization of the interaction between KRAS and Argonaute 2.
Loss of p19Arf Promotes Fibroblast Survival During Leucine Deprivation.
Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness.
Pharmacological CDK4/6 inhibition reveals a p53-dependent senescent state with restricted toxicity.
Diet, lipids, and antitumor immunity.
Loss of Rnf43 accelerates Kras-mediated neoplasia and remodels the tumor immune microenvironment in pancreatic adenocarcinoma.
PIONEER-Panc: a platform trial for phase II randomized investigations of new and emerging therapies for localized pancreatic cancer.
Sensei: how many samples to tell a change in cell type abundance?
Behavioural immune landscapes of inflammation.
SPOP mutations promote p62/SQSTM1-dependent autophagy and Nrf2 activation in prostate cancer.
Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition.
Glucose starvation induces a switch in the histone acetylome for activation of gluconeogenic and fat metabolism genes.
Extracellular matrix guidance of autophagy: a mechanism regulating cancer growth.
Vessel co-option and angiotropic extravascular migratory metastasis: a continuum of tumour growth and spread?
ASO Visual Abstract: Sarcopenia as a Predictor of Survival in Patients with Pancreatic Adenocarcinoma After Pancreatectomy.
Central nervous system regeneration.
Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.
Emerging roles of epithelial-mesenchymal plasticity in invasion-metastasis cascade and therapy resistance.
Impact of somatic mutations on clinical and pathologic outcomes in borderline resectable and locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and stereotactic body radiotherapy followed by surgical resection.
scDALI: modeling allelic heterogeneity in single cells reveals context-specific genetic regulation.
Pancreatic fibrosis, acinar atrophy and chronic inflammation in surgical specimens associated with survival in patients with resectable pancreatic ductal adenocarcinoma.
The proprotein convertase furin in cancer: more than an oncogene.
Clinical development of metabolic inhibitors for oncology.
Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis.
Senescent immune cells release grancalcin to promote skeletal aging.
Bak Core Dimer Focusses Triacylglycerides in the Membrane.
Cell maturation: Hallmarks, triggers, and manipulation.
Machine learning-driven multiscale modeling reveals lipid-dependent dynamics of RAS signaling proteins.

PLoS Genet. 2022 Jan 04. 18(1): e1009981

The SWI/SNF chromatin remodeling assemblies BAF and PBAF differentially regulate cell cycle exit and cellular invasion in vivo.

Jayson J Smith, Yutong Xiao, Nithin Parsan, Taylor N Medwig-Kinney, Michael A Q Martinez, Frances E Q Moore, Nicholas J Palmisano, Abraham Q Kohrman, Mana Chandhok Delos Reyes, Rebecca C Adikes, Simeiyun Liu, Sydney A Bracht, Wan Zhang, Kailong Wen, Paschalis Kratsios, David Q Matus.

Chromatin remodelers such as the SWI/SNF complex coordinate metazoan development through broad regulation of chromatin accessibility and transcription, ensuring normal cell cycle control and cellular differentiation in a lineage-specific and temporally restricted manner. Mutations in genes encoding the structural subunits of chromatin, such as histone subunits, and chromatin regulating factors are associated with a variety of disease mechanisms including cancer metastasis, in which cancer co-opts cellular invasion programs functioning in healthy cells during development. Here we utilize Caenorhabditis elegans anchor cell (AC) invasion as an in vivo model to identify the suite of chromatin agents and chromatin regulating factors that promote cellular invasiveness. We demonstrate that the SWI/SNF ATP-dependent chromatin remodeling complex is a critical regulator of AC invasion, with pleiotropic effects on both G0 cell cycle arrest and activation of invasive machinery. Using targeted protein degradation and enhanced RNA interference (RNAi) vectors, we show that SWI/SNF contributes to AC invasion in a dose-dependent fashion, with lower levels of activity in the AC corresponding to aberrant cell cycle entry and increased loss of invasion. Our data specifically implicate the SWI/SNF BAF assembly in the regulation of the G0 cell cycle arrest in the AC, whereas the SWI/SNF PBAF assembly promotes AC invasion via cell cycle-independent mechanisms, including attachment to the basement membrane (BM) and activation of the pro-invasive fos-1/FOS gene. Together these findings demonstrate that the SWI/SNF complex is necessary for two essential components of AC invasion: arresting cell cycle progression and remodeling the BM. The work here provides valuable single-cell mechanistic insight into how the SWI/SNF assemblies differentially contribute to cellular invasion and how SWI/SNF subunit-specific disruptions may contribute to tumorigeneses and cancer metastasis.

DOI: https://doi.org/10.1371/journal.pgen.1009981
Biochem Biophys Rep. 2022 Mar;29 101191

Biochemical characterization of the interaction between KRAS and Argonaute 2.

Jessica J Waninger, Tyler S Beyett, Varun V Gadkari, Ronald F Siebenaler, Carson Kenum, Sunita Shankar, Brandon T Ruotolo, Arul M Chinnaiyan, John J G Tesmer.

Oncogenic mutations in KRAS result in a constitutively active, GTP-bound form that in turn activates many proliferative pathways. However, because of its compact and simple architecture, directly targeting KRAS with small molecule drugs has been challenging. Another approach is to identify targetable proteins that interact with KRAS. Argonaute 2 (AGO2) was recently identified as a protein that facilitates RAS-driven oncogenesis. Whereas previous studies described the in vivo effect of AGO2 on cancer progression in cells harboring mutated KRAS, here we sought to examine their direct interaction using purified proteins. We show that full length AGO2 co-immunoprecipitates with KRAS using purified components, however, a complex between FL AGO2 and KRAS could not be isolated. We also generated a smaller N-terminal fragment of AGO2 (NtAGO2) which is believed to represent the primary binding site of KRAS. A complex with NtAGO2 could be detected via ion-mobility mass spectrometry and size exclusion chromatography. However, the data suggest that the interaction of KRAS with purified AGO2 (NtAGO2 or FL AGO2) is weak and likely requires additional cellular components or proteo-forms of AGO2 that are not readily available in our purified assay systems. Future studies are needed to determine what conformation or modifications of AGO2 are necessary to enrich KRAS association and regulate its activities.

DOI: https://doi.org/10.1016/j.bbrep.2021.101191
Biol Open. 2022 Jan 07. pii: bio.058728. [Epub ahead of print]

Loss of p19Arf Promotes Fibroblast Survival During Leucine Deprivation.

Kerry C Roby, Allyson Lieberman, Bang-Jin Kim, Nicole Zaragoza Rodríguez, Jessica M Posimo, Tiffany Tsang, Ioannis I Verginadis, Ellen Puré, Donita C Brady, Constantinos Koumenis, Sandra Ryeom.

  Fibroblasts are quiescent and tumor suppressive in nature but become activated in wound healing and cancer. The response of fibroblasts to cellular stress has not been extensively investigated however the p53 tumor suppressor has been shown to be activated in fibroblasts during nutrient deprivation. Since the p19 Alternative reading frame (p19Arf) tumor suppressor is a key regulator of p53 activation during oncogenic stress, we investigated the role of p19Arf in fibroblasts during nutrient deprivation. Here we show that prolonged leucine deprivation resulted in increased expression and nuclear localization of p19Arf, triggering apoptosis in primary murine adult lung fibroblasts (ALFs). In contrast, the absence of p19Arf during long-term leucine deprivation resulted in increased ALF proliferation, migration and survival through upregulation of the Integrated Stress Response pathway and increased autophagic flux. Our data implicates a new role for p19Arf in response to nutrient deprivation.

Keywords:   p19Arf ; Autophagy; Fibroblast; Integrated Stress Response; Leucine Deprivation

DOI:  https://doi.org/10.1242/bio.058728
Cell Metab. 2022 Jan 04. pii: S1550-4131(21)00620-3. [Epub ahead of print]34(1): 90-105.e7

Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness.

Pravat Kumar Parida, Mauricio Marquez-Palencia, Vidhya Nair, Akash K Kaushik, Kangsan Kim, Jessica Sudderth, Eduardo Quesada-Diaz, Ambar Cajigas, Vamsidhara Vemireddy, Paula I Gonzalez-Ericsson, Melinda E Sanders, Bret C Mobley, Kenneth Huffman, Sunati Sahoo, Prasanna Alluri, Cheryl Lewis, Yan Peng, Robert M Bachoo, Carlos L Arteaga, Ariella B Hanker, Ralph J DeBerardinis, Srinivas Malladi.

  HER2+ breast cancer patients are presented with either synchronous (S-BM), latent (Lat), or metachronous (M-BM) brain metastases. However, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ remains unknown. Here, employing brain metastatic models, we show that metabolic diversity and plasticity within brain-tropic cells determine metastatic fitness. Lactate secreted by aggressive metastatic cells or lactate supplementation to mice bearing Lat cells limits innate immunosurveillance and triggers overt metastasis. Attenuating lactate metabolism in S-BM impedes metastasis, while M-BM adapt and survive as residual disease. In contrast to S-BM, Lat and M-BM survive in equilibrium with innate immunosurveillance, oxidize glutamine, and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Moreover, xCT expression is significantly higher in matched M-BM brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Inhibiting xCT function attenuates residual disease and recurrence in these preclinical models.

Keywords:  HER2; breast cancer brain metastasis; immune surveillance; late recurrences; metabolism; metastasis; metastatic dormancy; metastatic latency; redox homeostasis; relapse

DOI:  https://doi.org/10.1016/j.cmet.2021.12.001
EMBO J. 2022 Jan 05. e108946

Pharmacological CDK4/6 inhibition reveals a p53-dependent senescent state with restricted toxicity.

Boshi Wang, Marta Varela-Eirin, Simone M Brandenburg, Alejandra Hernandez-Segura, Thijmen van Vliet, Elisabeth M Jongbloed, Saskia M Wilting, Naoko Ohtani, Agnes Jager, Marco Demaria.

  Cellular senescence is a state of stable growth arrest and a desired outcome of tumor suppressive interventions. Treatment with many anti-cancer drugs can cause premature senescence of non-malignant cells. These therapy-induced senescent cells can have pro-tumorigenic and pro-disease functions via activation of an inflammatory secretory phenotype (SASP). Inhibitors of cyclin-dependent kinases 4/6 (CDK4/6i) have recently proven to restrain tumor growth by activating a senescence-like program in cancer cells. However, the physiological consequence of exposing the whole organism to pharmacological CDK4/6i remains poorly characterized. Here, we show that exposure to CDK4/6i induces non-malignant cells to enter a premature state of senescence dependent on p53. We observe in mice and breast cancer patients that the CDK4/6i-induced senescent program activates only a partial SASP enriched in p53 targets but lacking pro-inflammatory and NF-κB-driven components. We find that CDK4/6i-induced senescent cells do not acquire pro-tumorigenic and detrimental properties but retain the ability to promote paracrine senescence and undergo clearance. Our results demonstrate that SASP composition is exquisitely stress-dependent and a predictor for the biological functions of different senescence subsets.

Keywords:  CDK4/6 inhibitors; SASP; cellular senescence; chemotherapy; p53

DOI:  https://doi.org/10.15252/embj.2021108946
Cell Mol Immunol. 2022 Jan 05.

Diet, lipids, and antitumor immunity.

Hannah Prendeville, Lydia Lynch.

  Tumour growth and dissemination is largely dependent on nutrient availability. It has recently emerged that the tumour microenvironment is rich in a diverse array of lipids that increase in abundance with tumour progression and play a role in promoting tumour growth and metastasis. Here, we describe the pro-tumorigenic roles of lipid uptake, metabolism and synthesis and detail the therapeutic potential of targeting lipid metabolism in cancer. Additionally, we highlight new insights into the distinct immunosuppressive effects of lipids in the tumour microenvironment. Lipids threaten an anti-tumour environment whereby metabolic adaptation to lipid metabolism is linked to immune dysfunction. Finally, we describe the differential effects of commondietary lipids on cancer growth which may uncover a role for specific dietary regimens in association with traditional cancer therapies. Understanding the relationship between dietary lipids, tumour, and immune cells is important in the context of obesity which may reveal a possibility to harness the diet in the treatment of cancers.

Keywords:  Lipids; anti-tumour immunity; cancer; obesity; β-oxidation

DOI:  https://doi.org/10.1038/s41423-021-00781-x
Gastroenterology. 2021 Dec 29. pii: S0016-5085(21)04169-X. [Epub ahead of print]

Loss of Rnf43 accelerates Kras-mediated neoplasia and remodels the tumor immune microenvironment in pancreatic adenocarcinoma.

Abdel Nasser Hosein, Gita Dangol, Takashi Okumura, Jason Roszik, Kimal Rajapakshe, Megan Siemann, Mohamed Zaid, Bidyut Ghosh, Maria Monberg, Paola A Guerrero, Aatur Singhi, Cara L Haymaker, Hans Clevers, Lotfi Abou-Elkacem, Sonja M Woermann, Anirban Maitra.

  BACKGROUND: RNF43 is an E3 ubiquitin ligase that is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC) and precursor cystic neoplasms of the pancreas. The impact of RNF43 mutations on PDAC is poorly understood and autochthonous models have not been sufficiently characterized. In this study we describe a genetically engineered mouse model (GEMM) of PDAC with conditional expression of oncogenic Kras and deletion of the catalytic domain of Rnf43 in exocrine cells.METHODS: We generated Ptf1a-Cre;LSL-KrasG12D;Rnf43flox/flox (KRC) and Ptf1a-Cre; LSL-KrasG12D (KC) mice and animal survival was assessed. KRC mice were sacrificed at 2 months, 4 months and at moribund status followed by analysis of pancreata by single cell RNA sequencing (scRNAseq). Comparative analyses between moribund KRC and a moribund Kras/Tp53 driven PDAC GEMM (KPC) was performed. Cell lines were isolated from KRC and KC tumors and interrogated by cytokine array analyses, ATAC-seq and in vitro drug assays. KRC GEMMs were also treated with an anti-CTLA4 neutralizing antibody with treatment response measured by magnetic response imaging.
RESULTS: We demonstrate that KRC mice display a marked increase in incidence of high-grade cystic lesions of the pancreas and PDAC compared to KC. Importantly, KRC mice have a significantly decreased survival compared to KC mice. By use of scRNAseq we demonstrated that KRC tumor progression is accompanied by a decrease in macrophages, as well as an increase in T and B lymphocytes with evidence of increased immune checkpoint molecule expression and affinity maturation, respectively. This was in stark contrast to the tumor immune microenvironment observed in the KPC PDAC GEMM. Furthermore, expression of the chemokine, CXCL5, was found to be specifically decreased in KRC cancer cells by means of epigenetic regulation and emerged as a putative candidate for mediating the unique KRC immune landscape.
CONCLUSIONS: The KRC GEMM establishes RNF43 as a bona fide tumor suppressor gene in PDAC. This GEMM features a markedly different immune microenvironment compared to previously reported PDAC GEMMs and puts forth a rationale for an immunotherapy approach in this subset of PDAC cases.

Keywords:  KRAS; genetically engineered mouse models; pancreatic cancer; single cell RNA sequencing; tumor suppressor gene

DOI:  https://doi.org/10.1053/j.gastro.2021.12.273
BMC Cancer. 2022 Jan 03. 22(1): 14

PIONEER-Panc: a platform trial for phase II randomized investigations of new and emerging therapies for localized pancreatic cancer.

Julia E Douglas, Suyu Liu, Junsheng Ma, Robert A Wolff, Shubham Pant, Anirban Maitra, Eric P Tamm, Priya Bhosale, Matthew H G Katz, Gauri R Varadhachary, Eugene J Koay.

  BACKGROUND: Personalized and effective treatments for pancreatic ductal adenocarcinoma (PDAC) continue to remain elusive. Novel clinical trial designs that enable continual and rapid evaluation of novel therapeutics are needed. Here, we describe a platform clinical trial to address this unmet need.METHODS: This is a phase II study using a Bayesian platform design to evaluate multiple experimental arms against a control arm in patients with PDAC. We first separate patients into three clinical stage groups of localized PDAC (resectable, borderline resectable, and locally advanced disease), and further divide each stage group based on treatment history (treatment naïve or previously treated). The clinical stage and treatment history therefore define 6 different cohorts, and each cohort has one control arm but may have one or more experimental arms running simultaneously. Within each cohort, adaptive randomization rules are applied and patients will be randomized to either an experimental arm or the control arm accordingly. The experimental arm(s) of each cohort are only compared to the applicable cohort specific control arm. Experimental arms may be added independently to one or more cohorts during the study. Multiple correlative studies for tissue, blood, and imaging are also incorporated.
DISCUSSION: To date, PDAC has been treated as a single disease, despite knowledge that there is substantial heterogeneity in disease presentation and biology. It is recognized that the current approach of single arm phase II trials and traditional phase III randomized studies are not well-suited for more personalized treatment strategies in PDAC. The PIONEER Panc platform clinical trial is designed to overcome these challenges and help advance our treatment strategies for this deadly disease.
TRIAL REGISTRATION: This study is approved by the Institutional Review Board (IRB) of MD Anderson Cancer Center, IRB-approved protocol 2020-0075. The PIONEER trial is registered at the US National Institutes of Health (ClinicalTrials.gov) NCT04481204 .

Keywords:  Borderline resectable; FOLFIRINOX; Gemcitabine/nab-paclitaxel; Locally advanced; PIONEER; Pancreatic cancer; Pancreatic ductal adenocarcinoma (PDAC); Phase II; Randomized platform trial; Resectable

DOI:  https://doi.org/10.1186/s12885-021-09095-7
BMC Bioinformatics. 2022 Jan 04. 23(1): 2

Sensei: how many samples to tell a change in cell type abundance?

Shaoheng Liang, Jason Willis, Jinzhuang Dou, Vakul Mohanty, Yuefan Huang, Eduardo Vilar, Ken Chen.

  Cellular heterogeneity underlies cancer evolution and metastasis. Advances in single-cell technologies such as single-cell RNA sequencing and mass cytometry have enabled interrogation of cell type-specific expression profiles and abundance across heterogeneous cancer samples obtained from clinical trials and preclinical studies. However, challenges remain in determining sample sizes needed for ascertaining changes in cell type abundances in a controlled study. To address this statistical challenge, we have developed a new approach, named Sensei, to determine the number of samples and the number of cells that are required to ascertain such changes between two groups of samples in single-cell studies. Sensei expands the t-test and models the cell abundances using a beta-binomial distribution. We evaluate the mathematical accuracy of Sensei and provide practical guidelines on over 20 cell types in over 30 cancer types based on knowledge acquired from the cancer cell atlas (TCGA) and prior single-cell studies. We provide a web application to enable user-friendly study design via https://kchen-lab.github.io/sensei/table_beta.html .

Keywords:  Cell type abundance; Clinical trial; Sample size estimation; Single-cell profiling; Tissue heterogeneity

DOI:  https://doi.org/10.1186/s12859-021-04526-5
Nature. 2022 Jan 05.

Behavioural immune landscapes of inflammation.

Georgiana Crainiciuc, Miguel Palomino-Segura, Miguel Molina-Moreno, Jon Sicilia, David G Aragones, Jackson Liang Yao Li, Rodrigo Madurga, José M Adrover, Alejandra Aroca-Crevillén, Sandra Martin-Salamanca, Alfonso Serrano Del Valle, Sandra D Castillo, Heidi C E Welch, Oliver Soehnlein, Mariona Graupera, Fátima Sánchez-Cabo, Alexander Zarbock, Thomas E Smithgall, Mauro Di Pilato, Thorsten R Mempel, Pierre-Louis Tharaux, Santiago F González, Angel Ayuso-Sacido, Lai Guan Ng, Gabriel F Calvo, Iván González-Díaz, Fernando Díaz-de-María, Andrés Hidalgo.

Transcriptional and proteomic profiling of individual cells have revolutionized interpretation of biological phenomena by providing cellular landscapes of healthy and diseased tissues1,2. These approaches, however, do not describe dynamic scenarios in which cells continuously change their biochemical properties and downstream 'behavioural' outputs3-5. Here we used 4D live imaging to record tens to hundreds of morpho-kinetic parameters describing the dynamics of individual leukocytes at sites of active inflammation. By analysing more than 100,000 reconstructions of cell shapes and tracks over time, we obtained behavioural descriptors of individual cells and used these high-dimensional datasets to build behavioural landscapes. These landscapes recognized leukocyte identities in the inflamed skin and trachea, and uncovered a continuum of neutrophil states inside blood vessels, including a large, sessile state that was embraced by the underlying endothelium and associated with pathogenic inflammation. Behavioural screening in 24 mouse mutants identified the kinase Fgr as a driver of this pathogenic state, and interference with Fgr protected mice from inflammatory injury. Thus, behavioural landscapes report distinct properties of dynamic environments at high cellular resolution.

DOI: https://doi.org/10.1038/s41586-021-04263-y
Cell Death Differ. 2022 Jan 06.

SPOP mutations promote p62/SQSTM1-dependent autophagy and Nrf2 activation in prostate cancer.

Qing Shi, Xiaofeng Jin, Pingzhao Zhang, Qian Li, Zeheng Lv, Yan Ding, Huiying He, Yijun Wang, Yuanlong He, Xiaying Zhao, Shi-Min Zhao, Yao Li, Kun Gao, Chenji Wang.

p62/SQSTM1 is a selective autophagy receptor that drives ubiquitinated cargos towards autophagic degradation. This receptor is also a stress-induced scaffold protein that helps cells to cope with oxidative stress through activation of the Nrf2 pathway. Functional disorders of p62 are closely associated with multiple neurodegenerative diseases and cancers. The gene encoding the E3 ubiquitin ligase substrate-binding adapter SPOP is frequently mutated in prostate cancer (PCa), but the molecular mechanisms underlying how SPOP mutations contribute to PCa tumorigenesis remain poorly understood. Here, we report that cytoplasmic SPOP binds and induces the non-degradative ubiquitination of p62 at residue K420 within the UBA domain. This protein modification decreases p62 puncta formation, liquid phase condensation, dimerization, and ubiquitin-binding capacity, thereby suppressing p62-dependent autophagy. Moreover, we show that SPOP relieves p62-mediated Keap1 sequestration, which ultimately decreases Nrf2-mediated transcriptional activation of antioxidant genes. We further show that PCa-associated SPOP mutants lose the capacity to ubiquitinate p62 and instead promote autophagy and the redox response in a dominant-negative manner. Thus, our findings indicate oncogenic roles of autophagy and Nrf2 activation in the tumorigenesis of SPOP-mutated PCa.

DOI: https://doi.org/10.1038/s41418-021-00913-w
J Clin Invest. 2022 Jan 06. pii: e155523. [Epub ahead of print]

Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition.

Yihsuan S Tsai, Mark G Woodcock, Salma H Azam, Leigh B Thorne, Krishna L Kanchi, Joel S Parker, Benjamin G Vincent, Chad V Pecot.

  The KRAS proto-oncogene is among the most frequently mutated genes in cancer, yet for 40 years it remained an elusive therapeutic target. Recently, allosteric inhibitors that covalently bind to KRAS G12C mutations have been approved for use in lung adenocarcinomas. Although responses are observed they are often short-lived, thus making in-depth characterization of the mechanisms of resistance of paramount importance. Here, we present a rapid-autopsy case of a patient who had a KRASG12C-mutant lung adenocarcinoma who initially responded to a KRAS G12C inhibitor but then rapidly developed resistance. Using deep RNA and whole exome sequencing comparing pre-treatment, post-treatment and matched normal tissues, we uncover numerous mechanisms of resistance to direct KRAS inhibition. In addition to decreased KRAS G12C mutant allele frequency in refractory tumors, we also found reactivation of the MAPK pathway despite no new mutations in KRAS or its downstream mediators. Tumor cell intrinsic and non-cell autonomous mechanisms included increased complement activation, coagulation and tumor angiogenesis, and several lines of evidence of immunologic evasion. Together, our findings reveal numerous mechanisms of resistance to current KRAS G12C inhibitors through enrichment of clonal populations, KRAS-independent downstream signaling and diverse remodeling of the tumor microenvironment.

Keywords:  Adaptive immunity; Drug therapy; Genetics; Molecular genetics; Oncology

DOI:  https://doi.org/10.1172/JCI155523
Mol Cell. 2022 Jan 06. pii: S1097-2765(21)01077-7. [Epub ahead of print]82(1): 60-74.e5

Glucose starvation induces a switch in the histone acetylome for activation of gluconeogenic and fat metabolism genes.

Wen-Chuan Hsieh, Benjamin M Sutter, Holly Ruess, Spencer D Barnes, Venkat S Malladi, Benjamin P Tu.

  Acetyl-CoA is a key intermediate situated at the intersection of many metabolic pathways. The reliance of histone acetylation on acetyl-CoA enables the coordination of gene expression with metabolic state. Abundant acetyl-CoA has been linked to the activation of genes involved in cell growth or tumorigenesis through histone acetylation. However, the role of histone acetylation in transcription under low levels of acetyl-CoA remains poorly understood. Here, we use a yeast starvation model to observe the dramatic alteration in the global occupancy of histone acetylation following carbon starvation; the location of histone acetylation marks shifts from growth-promoting genes to gluconeogenic and fat metabolism genes. This reallocation is mediated by both the histone deacetylase Rpd3p and the acetyltransferase Gcn5p, a component of the SAGA transcriptional coactivator. Our findings reveal an unexpected switch in the specificity of histone acetylation to promote pathways that generate acetyl-CoA for oxidation when acetyl-CoA is limiting.

Keywords:  Gcn5p; Rpd3p; SAGA; acetyl-CoA; environmental stress response; fat metabolism; gluconeogenesis; glucose starvation; histone acetylation; transcription

DOI:  https://doi.org/10.1016/j.molcel.2021.12.015
Open Biol. 2022 Jan;12(1): 210304

Extracellular matrix guidance of autophagy: a mechanism regulating cancer growth.

Carolyn G Chen, Renato V Iozzo.

  The extracellular matrix (ECM) exists as a dynamic network of biophysical and biochemical factors that maintain tissue homeostasis. Given its sensitivity to changes in the intra- and extracellular space, the plasticity of the ECM can be pathological in driving disease through aberrant matrix remodelling. In particular, cancer uses the matrix for its proliferation, angiogenesis, cellular reprogramming and metastatic spread. An emerging field of matrix biology focuses on proteoglycans that regulate autophagy, an intracellular process that plays both critical and contextual roles in cancer. Here, we review the most prominent autophagic modulators from the matrix and the current understanding of the cellular pathways and signalling cascades that mechanistically drive their autophagic function. We then critically assess how their autophagic functions influence tumorigenesis, emphasizing the complexities and stage-dependent nature of this relationship in cancer. We highlight novel emerging data on immunoglobulin-containing and proline-rich receptor-1, heparanase and thrombospondin 1 in autophagy and cancer. Finally, we further discuss the pro- and anti-autophagic modulators originating from the ECM, as well as how these proteoglycans and other matrix constituents specifically influence cancer progression.

Keywords:  angiogenesis; collagen VI; decorin; perlecan; proteoglycan

DOI:  https://doi.org/10.1098/rsob.210304
Br J Cancer. 2022 Jan 05.

Vessel co-option and angiotropic extravascular migratory metastasis: a continuum of tumour growth and spread?

Claire Lugassy, Peter B Vermeulen, Domenico Ribatti, Francesco Pezzella, Raymond L Barnhill.

Two fields of cancer research have emerged dealing with the biology of tumour cells localised to the abluminal vascular surface: vessel co-option (VCo), a non-angiogenic mode of tumour growth and angiotropic extravascular migratory metastasis (EVMM), a non-hematogenous mode of tumour migration and metastasis. VCo is a mechanism by which tumour cells gain access to a blood supply by spreading along existing blood vessels in order to grow locally. Angiotropic EVMM involves "pericytic mimicry" (PM), which is characterised by tumour cells continuously migrating in the place of pericytes distantly along abluminal vascular surfaces. When cancer cells are engaged in PM and EVMM, they migrate along blood vessels beyond the advancing front of the tumour to secondary sites with the formation of regional and distant metastases. In the present perspective, the authors review the current scientific literature, emphasising the analogies between embryogenesis and cancer progression, the re-activation of embryonic signals by "cancer stem cells", and the important role of laminins and epithelial-mesenchymal-transition. This perspective maintains that VCo and angiotropic EVMM constitute complementary processes and represent a continuum of cancer progression from the primary tumour to metastases and of tumour growth to EVMM, analogous to the embryonic development program.

DOI: https://doi.org/10.1038/s41416-021-01686-2
Ann Surg Oncol. 2022 Jan 08.

ASO Visual Abstract: Sarcopenia as a Predictor of Survival in Patients with Pancreatic Adenocarcinoma After Pancreatectomy.

Hadass Rom, Shlomit Tamir, Jeroen van Vugt, Yael Berger, Gali Perl, Sara Morgenstern, Ana Tovar, Baruch Brenner, Daniel Benchimol, Hanoch Kashtan, Eran Sadot.

DOI: https://doi.org/10.1245/s10434-021-11127-2
Cell. 2022 Jan 06. pii: S0092-8674(21)01284-8. [Epub ahead of print]185(1): 77-94

Central nervous system regeneration.

Supraja G Varadarajan, John L Hunyara, Natalie R Hamilton, Alex L Kolodkin, Andrew D Huberman.

Neurons of the mammalian central nervous system fail to regenerate. Substantial progress has been made toward identifying the cellular and molecular mechanisms that underlie regenerative failure and how altering those pathways can promote cell survival and/or axon regeneration. Here, we summarize those findings while comparing the regenerative process in the central versus the peripheral nervous system. We also highlight studies that advance our understanding of the mechanisms underlying neural degeneration in response to injury, as many of these mechanisms represent primary targets for restoring functional neural circuits.

DOI: https://doi.org/10.1016/j.cell.2021.10.029
Nat Med. 2022 Jan 06.

Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.

Anirban Das, Sumedha Sudhaman, Daniel Morgenstern, Ailish Coblentz, Jiil Chung, Simone C Stone, Noor Alsafwani, Zhihui Amy Liu, Ola Abu Al Karsaneh, Shirin Soleimani, Hagay Ladany, David Chen, Matthew Zatzman, Vanja Cabric, Liana Nobre, Vanessa Bianchi, Melissa Edwards, Lauren C Sambira Nahum, Ayse B Ercan, Arash Nabbi, Shlomi Constantini, Rina Dvir, Michal Yalon-Oren, Gadi Abebe Campino, Shani Caspi, Valerie Larouche, Alyssa Reddy, Michael Osborn, Gary Mason, Scott Lindhorst, Annika Bronsema, Vanan Magimairajan, Enrico Opocher, Rebecca Loret De Mola, Magnus Sabel, Charlotta Frojd, David Sumerauer, David Samuel, Kristina Cole, Stefano Chiaravalli, Maura Massimino, Patrick Tomboc, David S Ziegler, Ben George, An Van Damme, Nobuko Hijiya, David Gass, Rose B McGee, Oz Mordechai, Daniel C Bowers, Theodore W Laetsch, Alexander Lossos, Deborah T Blumenthal, Tomasz Sarosiek, Lee Yi Yen, Jeffrey Knipstein, Anne Bendel, Lindsey M Hoffman, Sandra Luna-Fineman, Stefanie Zimmermann, Isabelle Scheers, Kim E Nichols, Michal Zapotocky, Jordan R Hansford, John M Maris, Peter Dirks, Michael D Taylor, Abhaya V Kulkarni, Manohar Shroff, Derek S Tsang, Anita Villani, Wei Xu, Melyssa Aronson, Carol Durno, Adam Shlien, David Malkin, Gad Getz, Yosef E Maruvka, Pamela S Ohashi, Cynthia Hawkins, Trevor J Pugh, Eric Bouffet, Uri Tabori.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

DOI: https://doi.org/10.1038/s41591-021-01581-6
Cancer Metastasis Rev. 2022 Jan 03.

Emerging roles of epithelial-mesenchymal plasticity in invasion-metastasis cascade and therapy resistance.

Minal Garg.

  Strong association of cancer incidence and its progression with mortality highlights the need to decipher the cellular and molecular mechanisms that drive tumor cells to rapidly progress to metastatic disease and therapy resistance. Epithelial-mesenchymal plasticity (EMP) emerged as a key regulator of metastatic outgrowth. It allows neoplastic epithelial cells to delaminate from their neighbors either individually or collectively, traverse the extracellular matrix (ECM) barrier, enter into the circulation, and establish distal metastases. Plasticity between epithelial and mesenchymal states and the existence of hybrid epithelial/mesenchymal (E/M) phenotypes are increasingly being reported in different tumor contexts. Small subset of cancer cells with stemness called cancer stem cells (CSCs) exhibit plasticity, possess high tumorigenic potential, and contribute to high degree of tumoral heterogeneity. EMP characterized by the presence of dynamic intermediate states is reported to be influenced by (epi)genomic reprograming, growth factor signaling, inflammation, and low oxygen generated by tumor stromal microenvironment. EMP alters the genotypic and phenotypic characteristics of tumor cells/CSCs, disrupts tissue homeostasis, induces the reprogramming of angiogenic and immune recognition functions, and renders tumor cells to survive hostile microenvironments and resist therapy. The present review summarizes the roles of EMP in tumor invasion and metastasis and provides an update on therapeutic strategies to target the metastatic and refractory cancers.

Keywords:  Epithelial-mesenchymal plasticity; Epithelial/mesenchymal (E/M) phenotypes; Metastasis; Therapeutic strategies; Tumor invasion

DOI:  https://doi.org/10.1007/s10555-021-10003-5
Radiat Oncol J. 2021 Dec;39(4): 304-314

Impact of somatic mutations on clinical and pathologic outcomes in borderline resectable and locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and stereotactic body radiotherapy followed by surgical resection.

Abhinav V Reddy, Colin S Hill, Shuchi Sehgal, Ding Ding, Amy Hacker-Prietz, Jin He, Lei Zheng, Joseph M Herman, Jeffrey Meyer, Amol K Narang.

  PURPOSE: The purpose of this study was to determine if somatic mutations are associated with clinical and pathologic outcomes in patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) who were treated with neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT).MATERIALS AND METHODS: Patients treated with neoadjuvant chemotherapy and SBRT followed by surgical resection from August 2016 to January 2019 and who underwent next generation sequencing of their primary tumor were included in the study. Next-generation sequencing was performed either in-house with a Solid Tumor Panel or with FoundationOne CDx. Univariate (UVA) and multivariable analyses (MVA) were performed to determine associations between somatic mutations and pathologic and clinical outcomes.
RESULTS: Thirty-five patients were included in the study. Chemotherapy consisted of modified FOLFIRINOX, gemcitabine and nab-paclitaxel, or gemcitabine and capecitabine. Patients were treated with SBRT in 33 Gy in 5 fractions. On UVA and MVA, tumors with KRAS G12V mutation demonstrated better pathologic tumor regression grade (TRG) to neoadjuvant therapy when compared to tumors with other KRAS mutations (odds ratio = 0.087; 95% confidence interval [CI], 0.009-0.860; p = 0.036). On UVA and MVA, mutations in NOTCH1/2 were associated with worse overall survival (hazard ratio [HR] = 4.15; 95% CI, 1.57-10.95; p = 0.004) and progression-free survival (HR = 3.61; 95% CI, 1.41-9.28; p = 0.008). On UVA, only mutations in NOTCH1/2 were associated with inferior distant metastasis-free survival (HR = 3.38; 95% CI, 1.25-9.16; p = 0.017).
CONCLUSION: In BRPC and LAPC, the KRAS G12V mutation was associated with better TRG following chemotherapy and SBRT. Additionally, NOTCH1/2 mutations were associated with worse overall survival, distant metastasis-free survival, and progression-free survival.

Keywords:  KRAS genes; Mutations; Notch proteins; Pancreatic cancer; Stereotactic body radiotherapy

DOI:  https://doi.org/10.3857/roj.2021.00815
Genome Biol. 2022 Jan 06. 23(1): 8

scDALI: modeling allelic heterogeneity in single cells reveals context-specific genetic regulation.

Tobias Heinen, Stefano Secchia, James P Reddington, Bingqing Zhao, Eileen E M Furlong, Oliver Stegle.

  While it is established that the functional impact of genetic variation can vary across cell types and states, capturing this diversity remains challenging. Current studies using bulk sequencing either ignore this heterogeneity or use sorted cell populations, reducing discovery and explanatory power. Here, we develop scDALI, a versatile computational framework that integrates information on cellular states with allelic quantifications of single-cell sequencing data to characterize cell-state-specific genetic effects. We apply scDALI to scATAC-seq profiles from developing F1 Drosophila embryos and scRNA-seq from differentiating human iPSCs, uncovering heterogeneous genetic effects in specific lineages, developmental stages, or cell types.

Keywords:  Single-cell, Regulatory genomics, Statistical methods

DOI:  https://doi.org/10.1186/s13059-021-02593-8
BMC Cancer. 2022 Jan 03. 22(1): 23

Pancreatic fibrosis, acinar atrophy and chronic inflammation in surgical specimens associated with survival in patients with resectable pancreatic ductal adenocarcinoma.

Taija Korpela, Ari Ristimäki, Marianne Udd, Tiina Vuorela, Harri Mustonen, Caj Haglund, Leena Kylänpää, Hanna Seppänen.

  BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, is increasing in incidence. However, the stromal reaction pathophysiology and its role in PDAC development remain unknown. We, therefore, investigated the potential role of histological chronic pancreatitis findings and chronic inflammation on surgical PDAC specimens and disease-specific survival (DSS).METHODS: Between 2000 and 2016, we retrospectively enrolled 236 PDAC patients treated with curative-intent pancreatic surgery at Helsinki University Hospital. All pancreatic transection margin slides were re-reviewed and histological findings were evaluated applying international guidelines.
RESULTS: DSS among patients with no fibrosis, acinar atrophy or chronic inflammation identified on pathology slides was significantly better than DSS among patients with fibrosis, acinar atrophy and chronic inflammation [median survival: 41.8 months, 95% confidence interval (CI) 26.0-57.6 vs. 20.6 months, 95% CI 10.3-30.9; log-rank test p = 0.001]. Multivariate analysis revealed that Ca 19-9 > 37 kU/l [hazard ratio (HR) 1.48, 95% CI 1.02-2.16], lymph node metastases N1-2 (HR 1.71, 95% CI 1.16-2.52), tumor size > 30 mm (HR 1.47, 95% CI 1.04-2.08), the combined effect of fibrosis and acinar atrophy (HR 1.91, 95% CI 1.27-2.88) and the combined effect of fibrosis, acinar atrophy and chronic inflammation (HR 1.63, 95% CI 1.03-2.58) independently served as unfavorable prognostic factors for DSS. However, we observed no significant associations between tumor size (> 30 mm) and the degree of perilobular fibrosis (p = 0.655), intralobular fibrosis (p = 0.587), acinar atrophy (p = 0.584) or chronic inflammation (p = 0.453).
CONCLUSIONS: Our results indicate that the pancreatic stroma is associated with PDAC patients' DSS. Additionally, the more severe the fibrosis, acinar atrophy and chronic inflammation, the worse the impact on DSS, thereby warranting further studies investigating stroma-targeted therapies.

Keywords:  Chronic pancreatitis; Pancreatic cancer; Stroma; Tumor–stroma interactions

DOI:  https://doi.org/10.1186/s12885-021-09080-0
Oncogene. 2022 Jan 07.

The proprotein convertase furin in cancer: more than an oncogene.

Zongsheng He, Abdel-Majid Khatib, John W M Creemers.

Furin is the first discovered proprotein convertase member and is present in almost all mammalian cells. Therefore, by regulating the maturation of a wide range of proproteins, Furin expression and/or activity is involved in various physiological and pathophysiological processes ranging from embryonic development to carcinogenesis. Since many of these protein precursors are involved in initiating and maintaining the hallmarks of cancer, Furin has been proposed as a potential target for treating several human cancers. In contrast, other studies have revealed that some types of cancer do not benefit from Furin inhibition. Therefore, understanding the heterogeneous functions of Furin in cancer will provide important insights into the design of effective strategies targeting Furin in cancer treatment. Here, we present recent advances in understanding how Furin expression and activity are regulated in cancer cells and their influences on the activity of Furin substrates in carcinogenesis. Furthermore, we discuss how Furin represses tumorigenic properties of several cancer cells and why Furin inhibition leads to aggressive phenotypes in other tumors. Finally, we summarize the clinical applications of Furin inhibition in treating human cancers.

DOI: https://doi.org/10.1038/s41388-021-02175-9
J Clin Invest. 2022 Jan 04. pii: e148550. [Epub ahead of print]132(1):

Clinical development of metabolic inhibitors for oncology.

Kathryn M Lemberg, Sadakatali S Gori, Takashi Tsukamoto, Rana Rais, Barbara S Slusher.

Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each agent, we evaluate the preclinical studies demonstrating antitumor and TME effects and review ongoing clinical trials. The goal of this Review is to provide an overview of the landscape of metabolic inhibitors in clinical development for oncology.

DOI: https://doi.org/10.1172/JCI148550
Sci Adv. 2022 Jan 07. 8(1): eabl4150

Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis.

William Dion, Heather Ballance, Jane Lee, Yinghong Pan, Saad Irfan, Casey Edwards, Michelle Sun, Jing Zhang, Xin Zhang, Silvia Liu, Bokai Zhu.

[Figure: see text].

DOI: https://doi.org/10.1126/sciadv.abl4150
Cell Metab. 2022 Jan 04. pii: S1550-4131(21)00622-7. [Epub ahead of print]34(1): 184-185

Senescent immune cells release grancalcin to promote skeletal aging.

Chang-Jun Li, Ye Xiao, Yu-Chen Sun, Wen-Zhen He, Ling Liu, Mei Huang, Chen He, Min Huang, Kai-Xuan Chen, Jing Hou, Xu Feng, Tian Su, Qi Guo, Yan Huang, Hui Peng, Mi Yang, Guang-Hui Liu, Xiang-Hang Luo.

DOI: https://doi.org/10.1016/j.cmet.2021.12.003
Biophys J. 2021 Dec 30. pii: S0006-3495(21)03998-9. [Epub ahead of print]

Bak Core Dimer Focusses Triacylglycerides in the Membrane.

Nicholas A Smith, Ahmad Z Wardak, Angus D Cowan, Peter M Colman, Peter E Czabotar, Brian J Smith.

Apoptosis, the intrinsic programmed cell death process, is mediated by Bcl-2 family members Bak and Bax. Activation via formation of symmetric core dimers, and oligomerization on the mitochondrial outer membrane (MOM) leads to permeabilization and cell death. Whilst this process is linked to the MOM, the role of the membrane in facilitating such pores is poorly understood. We recently described Bak core domain dimers, revealing lipid binding sites and an initial role for lipids in oligomerization. Here, we describe simulations that identified localized clustering and interaction of triacylglycerides (TAG) with a minimized Bak dimer construct. Coalescence of TAG occurred beneath this Bak dimer mitigating dimer induced local membrane thinning and curvature in representative coarse-grain MOM and model membrane systems. Furthermore, the effects observed as a result of coarse-grain TAG cluster formation was concentration dependent, scaling from low physiological MOM concentrations to those found in other organelles. We find that increasing TAG concentration in liposomes mimicking the MOM demonstrated a decreasing ability of activated Bak to permeabilize these liposomes. These results suggest that the presence of TAG within a Bak-lipid membrane preserves membrane integrity and is associated with reduced membrane stress, suggesting a possible role of TAG in Bak-mediated apoptosis.

DOI: https://doi.org/10.1016/j.bpj.2021.12.043
Cell. 2021 Dec 30. pii: S0092-8674(21)01450-1. [Epub ahead of print]

Cell maturation: Hallmarks, triggers, and manipulation.

Juan R Alvarez-Dominguez, Douglas A Melton.

  How cells become specialized, or "mature," is important for cell and developmental biology. While maturity is usually deemed a terminal fate, it may be more helpful to consider maturation not as a switch but as a dynamic continuum of adaptive phenotypic states set by genetic and environment programing. The hallmarks of maturity comprise changes in anatomy (form, gene circuitry, and interconnectivity) and physiology (function, rhythms, and proliferation) that confer adaptive behavior. We discuss efforts to harness their chemical (nutrients, oxygen, and growth factors) and physical (mechanical, spatial, and electrical) triggers in vitro and in vivo and how maturation strategies may support disease research and regenerative medicine.

Keywords:  biomaterials; cell maturity; circadian rhythms; directed stem cell differentiation; energy metabolism; machine–tissue interfaces; microfluidic chips; nanotechnology; organoids; tissue anatomy and physiology

DOI:  https://doi.org/10.1016/j.cell.2021.12.012
Proc Natl Acad Sci U S A. 2022 Jan 04. pii: e2113297119. [Epub ahead of print]119(1):

Machine learning-driven multiscale modeling reveals lipid-dependent dynamics of RAS signaling proteins.

Helgi I Ingólfsson, Chris Neale, Timothy S Carpenter, Rebika Shrestha, Cesar A López, Timothy H Tran, Tomas Oppelstrup, Harsh Bhatia, Liam G Stanton, Xiaohua Zhang, Shiv Sundram, Francesco Di Natale, Animesh Agarwal, Gautham Dharuman, Sara I L Kokkila Schumacher, Thomas Turbyville, Gulcin Gulten, Que N Van, Debanjan Goswami, Frantz Jean-Francois, Constance Agamasu, De Chen, Jeevapani J Hettige, Timothy Travers, Sumantra Sarkar, Michael P Surh, Yue Yang, Adam Moody, Shusen Liu, Brian C Van Essen, Arthur F Voter, Arvind Ramanathan, Nicolas W Hengartner, Dhirendra K Simanshu, Andrew G Stephen, Peer-Timo Bremer, S Gnanakaran, James N Glosli, Felice C Lightstone, Frank McCormick, Dwight V Nissley, Frederick H Streitz.

  RAS is a signaling protein associated with the cell membrane that is mutated in up to 30% of human cancers. RAS signaling has been proposed to be regulated by dynamic heterogeneity of the cell membrane. Investigating such a mechanism requires near-atomistic detail at macroscopic temporal and spatial scales, which is not possible with conventional computational or experimental techniques. We demonstrate here a multiscale simulation infrastructure that uses machine learning to create a scale-bridging ensemble of over 100,000 simulations of active wild-type KRAS on a complex, asymmetric membrane. Initialized and validated with experimental data (including a new structure of active wild-type KRAS), these simulations represent a substantial advance in the ability to characterize RAS-membrane biology. We report distinctive patterns of local lipid composition that correlate with interfacially promiscuous RAS multimerization. These lipid fingerprints are coupled to RAS dynamics, predicted to influence effector binding, and therefore may be a mechanism for regulating cell signaling cascades.

Keywords:  RAS dynamics; RAS-membrane biology; massive parallel simulations; multiscale infrastructure; multiscale modeling

DOI:  https://doi.org/10.1073/pnas.2113297119