bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022–05–01
25 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. The Genetic Evolution of Metastasis.
  2. Phenotypic plasticity during metastatic colonization.
  3. Tracking dormant disseminated tumour cells.
  4. NR2F1 is a barrier to dissemination of early stage breast cancer cells.
  5. Exosomal miR-4466 from nicotine-activated neutrophils promotes tumor cell stemness and metabolism in lung cancer metastasis.
  6. Functional genetic screen identifies ITPR3/calcium/RELB axis as a driver of colorectal cancer metastatic liver colonization.
  7. Reservoirs of resistance.
  8. Colorectal cancer develops inherent radiosensitivity that can be predicted using patient-derived organoids.
  9. The myogenesis program drives clonal selection and drug resistance in rhabdomyosarcoma.
  10. Long noncoding RNA TLNC1 promotes the growth and metastasis of liver cancer via inhibition of p53 signaling.
  11. Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors.
  12. Leukotrienes promote stem cell self-renewal and chemoresistance in acute myeloid leukemia.
  13. The translational challenges of precision oncology.
  14. Quiescent Breast Cancer Cells Are Resistant to T-cell Killing.
  15. Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs.
  16. Integrated analysis of single-cell and bulk RNA sequencing data reveals a pan-cancer stemness signature predicting immunotherapy response.
  17. Calcium channel blockers potentiate gemcitabine chemotherapy  in pancreatic cancer.
  18. An EHMT2/NFYA-ALDH2 signaling axis modulates the RAF pathway to regulate paclitaxel resistance in lung cancer.
  19. Addition of interleukin-2 overcomes resistance to neoadjuvant CTLA4 and PD1 blockade in ex vivo patient tumors.
  20. The oncogene-dependent resistance to reprogramming unveils cancer therapeutic targets.
  21. A saturation mutagenesis screen uncovers resistant and sensitizing secondary KRAS mutations to clinical KRASG12C inhibitors.
  22. Reduced chromatin accessibility correlates with resistance to Notch activation.
  23. Pro-ferroptotic fatty acid metabolism renders cancer cells immunogenic.
  24. β-Hydroxybutyrate suppresses colorectal cancer.
  25. Navicixizumab plus Paclitaxel Shows Clinical Benefit in Platinum-Resistant Ovarian Cancer.
  1. Cancer Res. 2022 Apr 26. OF1-OF9
    The Genetic Evolution of Metastasis.
    Aljosja Rogiers, Irene Lobon, Lavinia Spain, Samra Turajlic.
      Cancer is an evolutionary process that is characterized by the emergence of multiple genetically distinct populations or clones within the primary tumor. Intratumor heterogeneity provides a substrate for the selection of adaptive clones, such as those that lead to metastasis. Comparative molecular studies of primary tumors and metastases have identified distinct genomic features associated with the development of metastases. In this review, we discuss how these insights could inform clinical decision-making and uncover rational antimetastasis treatment strategies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3863
  2. Trends Cell Biol. 2022 Apr 25. pii: S0962-8924(22)00079-4. [Epub ahead of print]
    Phenotypic plasticity during metastatic colonization.
    Charly Jehanno, Milica Vulin, Veronica Richina, Federica Richina, Mohamed Bentires-Alj.
      Most solid cancer-related deaths result from metastasis, a multistep process in which cancer cells exit the primary site, intravasate into the bloodstream, extravasate, and colonize distant organs. Colonization is facilitated by clonal selection and the high phenotypic plasticity of cancer cells that creates reversible switching of cellular states. Cancer cell plasticity leads to intratumor heterogeneity and fitness, yielding cells with molecular and cellular programs that facilitate survival and colonization. While cancer cell plasticity is sometimes limited to the process of epithelial-to-mesenchymal transition (EMT), recent studies have broadened its definition. Plasticity arises from both cell-intrinsic and cell-extrinsic factors and is a major obstacle to efficacious anti-cancer therapies. Here, we discuss the multifaceted notion of cancer cell plasticity associated with metastatic colonization.
    Keywords:  EMT; colonization; dormancy; metastasis; microenvironment; plasticity
    DOI:  https://doi.org/10.1016/j.tcb.2022.03.007
  3. Nat Rev Cancer. 2022 Apr 25.
    Tracking dormant disseminated tumour cells.
    Ana Luísa Correia.
      
    DOI:  https://doi.org/10.1038/s41568-022-00480-3
  4. Cancer Res. 2022 Apr 26. pii: canres.4145.2021. [Epub ahead of print]
    NR2F1 is a barrier to dissemination of early stage breast cancer cells.
    Carolina Rodriguez-Tirado, Nupura Kale, Maria J Carlini, Nitisha Shrivastava, Alcina A Rodrigues, Bassem Khalil, Jose J Bravo-Cordero, Melissa Alexander, Jiayi Ji, Yan Hong, Fariba Behbod, Maria Soledad Sosa.
      Cancer cells can disseminate during very early and sometimes asymptomatic stages of tumor progression. Though biological barriers to tumorigenesis have been identified and characterized, the mechanisms that limit early dissemination remain largely unknown. We report here that the orphan nuclear receptor NR2F1/COUP-TF1 serves as a barrier to early dissemination. NR2F1 expression was decreased in patient ductal carcinoma in situ (DCIS) samples. High-resolution intravital imaging of HER2+ early stage cancer cells revealed that loss of function of NR2F1 increased in vivo dissemination and was accompanied by decreased E-cadherin expression, activation of WNT-dependent β-catenin signaling, disorganized laminin 5 deposition, and increased expression of EMT genes such as TWIST1, ZEB1, and PRRX1. Furthermore, downregulation of NR2F1 promoted a hybrid luminal/basal phenotype. NR2F1 expression was positively regulated by p38α signaling and repressed by HER2 and WNT4 pathways. Lastly, early cancer cells with NR2F1LOW/PRRX1HIGH staining were observed in DCIS samples. Together, these findings reveal the existence of an inhibitory mechanism of dissemination regulated by NR2F1 in early stage breast cancer cells.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-4145
  5. Oncogene. 2022 Apr 23.
    Exosomal miR-4466 from nicotine-activated neutrophils promotes tumor cell stemness and metabolism in lung cancer metastasis.
    Abhishek Tyagi, Shih-Ying Wu, Sambad Sharma, Kerui Wu, Dan Zhao, Ravindra Deshpande, Ravi Singh, Wencheng Li, Umit Topaloglu, Jimmy Ruiz, Kounosuke Watabe.
      Smoking is associated with lung cancer and has a profound impact on tumor immunity. Nicotine, the addictive and non-carcinogenic smoke component, influences various brain cells and the immune system. However, how long-term use of nicotine affects brain metastases is poorly understood. We, therefore, examined the mechanism by which nicotine promotes lung cancer brain metastasis. In this study, we conducted a retrospective analysis of 810 lung cancer patients with smoking history and assessed brain metastasis. We found that current smoker's lung cancer patients have significantly higher brain metastatic incidence compared to the never smokers. We also found that chronic nicotine exposure recruited STAT3-activated N2-neutrophils within the brain pre-metastatic niche and secreted exosomal miR-4466 which promoted stemness and metabolic switching via SKI/SOX2/CPT1A axis in the tumor cells in the brain thereby enabling metastasis. Importantly, exosomal miR-4466 levels were found to be elevated in serum/urine of cancer-free subjects with a smoking history and promote tumor growth in vivo, suggesting that exosomal miR-4466 may serve as a promising prognostic biomarker for predicting increased risk of metastatic disease among smoker(s). Our findings suggest a novel pro-metastatic role of nicotine-induced N2-neutrophils in the progression of brain metastasis. We also demonstrated that inhibiting nicotine-induced STAT3-mediated neutrophil polarization effectively abrogated brain metastasis in vivo. Our results revealed a novel mechanistic insight on how chronic nicotine exposure contributes to worse clinical outcome of metastatic lung cancer and implicated the risk of using nicotine gateway for smoking cessation in cancer patients.
    DOI:  https://doi.org/10.1038/s41388-022-02322-w
  6. Dev Cell. 2022 Apr 27. pii: S1534-5807(22)00250-7. [Epub ahead of print]
    Functional genetic screen identifies ITPR3/calcium/RELB axis as a driver of colorectal cancer metastatic liver colonization.
    Ryan H Moy, Alexander Nguyen, Jia Min Loo, Norihiro Yamaguchi, Christina M Kajba, Balaji Santhanam, Benjamin N Ostendorf, Y Gloria Wu, Saeed Tavazoie, Sohail F Tavazoie.
      Metastatic colonization is the primary cause of death from colorectal cancer (CRC). We employed genome-scale in vivo short hairpin RNA (shRNA) screening and validation to identify 26 promoters of CRC liver colonization. Among these genes, we identified a cluster that contains multiple targetable genes, including ITPR3, which promoted liver-metastatic colonization and elicited similar downstream gene expression programs. ITPR3 is a caffeine-sensitive inositol 1,4,5-triphosphate (IP3) receptor that releases calcium from the endoplasmic reticulum and enhanced metastatic colonization by inducing expression of RELB, a transcription factor that is associated with non-canonical NF-κB signaling. Genetic, cell biological, pharmacologic, and clinical association studies revealed that ITPR3 and RELB drive CRC colony formation by promoting cell survival upon substratum detachment or hypoxic exposure. RELB was sufficient to drive colonization downstream of ITPR3. Our findings implicate the ITPR3/calcium/RELB axis in CRC metastatic colony formation and uncover multiple clinico-pathologically associated targetable proteins as drivers of CRC metastatic colonization.
    Keywords:  ITPR3; RELB; calcium; colorectal cancer; hypoxia; metastasis; non-canonical NF-κB
    DOI:  https://doi.org/10.1016/j.devcel.2022.04.010
  7. Nat Rev Immunol. 2022 Apr 27.
    Reservoirs of resistance.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-022-00729-w
  8. Cancer Res. 2022 Apr 26. pii: canres.4128.2021. [Epub ahead of print]
    Colorectal cancer develops inherent radiosensitivity that can be predicted using patient-derived organoids.
    Kuo-Shun Hsu, Mohammad Adileh, Maria Laura Martin, Vladimir Makarov, Jiapeng Chen, Chao Wu, Sahra Bodo, Stefan Klingler, Charles-Etienne Gabriel Sauvé, Bryan C Szeglin, J Joshua Smith, Zvi Fuks, Nadeem Riaz, Timothy A Chan, Makoto Nishimura, Philip B Paty, Richard Kolesnick.
      Identifying colorectal cancer patient populations responsive to chemotherapy or chemoradiation therapy before surgery remains a challenge. Recently validated mouse protocols for organoid irradiation employ the single hit multi-target (SHMT) algorithm, which yields a single value, the D0, as a measure of inherent tissue radiosensitivity. Here we translate these protocols to human tissue to evaluate radioresponsiveness of patient-derived organoids (PDOs) generated from normal human intestines and rectal tumors of patients undergoing neoadjuvant therapy. While PDOs from adenomas with a logarithmically-expanded Lgr5+-intestinal stem cell population retain the radioresistant phenotype of normal colorectal PDOs, malignant transformation yields PDOs from a large patient subpopulation displaying marked radiosensitivity due to reduced homologous recombination-mediated DNA repair. A proof-of-principle pilot clinical trial demonstrated that rectal cancer patient responses to neoadjuvant chemoradiation, including complete response, correlate closely with their PDO D0 values. Overall, upon transformation to colorectal adenocarcinoma, broad radiation sensitivity occurs in a large subset of patients that can be identified using SHMT analysis of PDO radiation responses.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-4128
  9. Dev Cell. 2022 Apr 18. pii: S1534-5807(22)00243-X. [Epub ahead of print]
    The myogenesis program drives clonal selection and drug resistance in rhabdomyosarcoma.
    Anand G Patel, Xiang Chen, Xin Huang, Michael R Clay, Natalia Komorova, Matthew J Krasin, Alberto Pappo, Heather Tillman, Brent A Orr, Justina McEvoy, Brittney Gordon, Kaley Blankenship, Colleen Reilly, Xin Zhou, Jackie L Norrie, Asa Karlstrom, Jiyang Yu, Dominik Wodarz, Elizabeth Stewart, Michael A Dyer.
      Rhabdomyosarcoma (RMS) is a pediatric cancer with features of skeletal muscle; patients with unresectable or metastatic RMS fare poorly due to high rates of disease recurrence. Here, we use single-cell and single-nucleus RNA sequencing to show that RMS tumors recapitulate the spectrum of embryonal myogenesis. Using matched patient samples from a clinical trial and orthotopic patient-derived xenografts (O-PDXs), we show that chemotherapy eliminates the most proliferative component with features of myoblasts within embryonal RMS; after treatment, the immature population with features of paraxial mesoderm expands to reconstitute the developmental hierarchy of the original tumor. We discovered that this paraxial mesoderm population is dependent on EGFR signaling and is sensitive to EGFR inhibitors. Taken together, these data serve as a proof of concept that targeting each developmental state in embryonal RMS is an effective strategy for improving outcomes by preventing disease recurrence.
    Keywords:  cancer recurrence; muscle development; sarcoma; single-cell biology; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.devcel.2022.04.003
  10. Mol Cancer. 2022 Apr 27. 21(1): 105
    Long noncoding RNA TLNC1 promotes the growth and metastasis of liver cancer via inhibition of p53 signaling.
    Kefei Yuan, Jiang Lan, Lin Xu, Xuping Feng, Haotian Liao, Kunlin Xie, Hong Wu, Yong Zeng.
       BACKGROUND: Long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in cancer development and progression. However, their biological roles and function mechanisms in liver cancer remain largely unknown.
    METHODS: RNA-seq was performed with clinical hepatoma tissues and paired adjacent normal liver tissues to identify differentially expressed lncRNAs. qPCR was utilized to examine the expression levels of lncRNAs. We studied the function of TLNC1 in cell growth and metastasis of hepatoma with both cell and mouse models. RNA-seq, RNA pull-down coupled with mass spectrometry, RNA immunoprecipitation, dual luciferase reporter assay, and surface plasmon resonance analysis were used to analyze the functional mechanism of TLNC1.
    RESULTS: Based on the intersection of our own RNA-seq, TCGA RNA-seq, and TCGA survival analysis data, TLNC1 was identified as a potential tumorigenic lncRNA of liver cancer. TLNC1 significantly enhanced the growth and metastasis of hepatoma cells both in vitro and in vivo. TLNC1 exerted its tumorigenic function through interaction with TPR and inducing the TPR-mediated transportation of p53 from nucleus to cytoplasm, thus repressing the transcription of p53 target genes and finally contributing to the progression of liver cancer.
    CONCLUSIONS: TLNC1 is a promising prognostic factor of liver cancer, and the TLNC1-TPR-p53 axis can serve as a potential therapeutic target for hepatoma treatment.
    Keywords:  Liver cancer; TLNC1; TPR; lncRNA; p53
    DOI:  https://doi.org/10.1186/s12943-022-01578-w
  11. Nat Cancer. 2022 Apr;3(4): 418-436
    Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors.
    Bram Herpers, Berina Eppink, Mark I James, Carme Cortina, Adrià Cañellas-Socias, Sylvia F Boj, Xavier Hernando-Momblona, Dominik Glodzik, Rob C Roovers, Marc van de Wetering, Carina Bartelink-Clements, Vanessa Zondag-van der Zande, Jara García Mateos, Kuan Yan, Lucia Salinaro, Abdul Basmeleh, Szabolcs Fatrai, David Maussang, Jeroen J Lammerts van Bueren, Irene Chicote, Garazi Serna, Laia Cabellos, Lorena Ramírez, Paolo Nuciforo, Ramon Salazar, Cristina Santos, Alberto Villanueva, Camille Stephan-Otto Attolini, Elena Sancho, Hector G Palmer, Josep Tabernero, Michael R Stratton, John de Kruif, Ton Logtenberg, Hans Clevers, Leo S Price, Robert G J Vries, Eduard Batlle, Mark Throsby.
      Patient-derived organoids (PDOs) recapitulate tumor architecture, contain cancer stem cells and have predictive value supporting personalized medicine. Here we describe a large-scale functional screen of dual-targeting bispecific antibodies (bAbs) on a heterogeneous colorectal cancer PDO biobank and paired healthy colonic mucosa samples. More than 500 therapeutic bAbs generated against Wingless-related integration site (WNT) and receptor tyrosine kinase (RTK) targets were functionally evaluated by high-content imaging to capture the complexity of PDO responses. Our drug discovery strategy resulted in the generation of MCLA-158, a bAb that specifically triggers epidermal growth factor receptor degradation in leucine-rich repeat-containing G-protein-coupled receptor 5-positive (LGR5+) cancer stem cells but shows minimal toxicity toward healthy LGR5+ colon stem cells. MCLA-158 exhibits therapeutic properties such as growth inhibition of KRAS-mutant colorectal cancers, blockade of metastasis initiation and suppression of tumor outgrowth in preclinical models for several epithelial cancer types.
    DOI:  https://doi.org/10.1038/s43018-022-00359-0
  12. Leukemia. 2022 Apr 23.
    Leukotrienes promote stem cell self-renewal and chemoresistance in acute myeloid leukemia.
    Alec W Stranahan, Iryna Berezniuk, Sohini Chakraborty, Faye Feller, Mona Khalaj, Christopher Y Park.
      Acute myeloid leukemia (AML) is characterized by poor clinical outcomes due to high rates of relapse following standard-of-care induction chemotherapy. While many pathogenic drivers have been described in AML, our understanding of the molecular mechanisms mediating chemotherapy resistance remains poor. Therefore, we sought to identify resistance genes to induction therapy in AML and elucidated ALOX5 as a novel mediator of resistance to anthracycline-based therapy. ALOX5 is transcriptionally upregulated in AML patient blasts in comparison to normal hematopoietic stem/progenitor cells (HSPCs) and ALOX5 mRNA, and protein expression is increased in response to induction therapy. In vitro, and in vivo genetic, and pharmacologic perturbation studies confirm that ALOX5 positively regulates the leukemogenic potential of AML LSCs, and its loss does not significantly affect the function of normal HSPCs. ALOX5 mediates resistance to daunorubicin (DNR) and promotes AML cell survival and maintenance through its leukotriene (LT) synthetic capacity, specifically via modulating the synthesis of LTB4 and its binding to LTB receptor (BLTR). Our study reveals a previously unrecognized role of LTs in AML pathogenesis and chemoresistance, whereby inhibition of ALOX5 mediated LTB4 synthesis and function could be combined with standard chemotherapy, to enhance the overall therapeutic efficacy in AML.
    DOI:  https://doi.org/10.1038/s41375-022-01579-0
  13. Cancer Cell. 2022 Apr 21. pii: S1535-6108(22)00164-7. [Epub ahead of print]
    The translational challenges of precision oncology.
    Oriol Pich, Chris Bailey, Thomas B K Watkins, Simone Zaccaria, Mariam Jamal-Hanjani, Charles Swanton.
      The translational challenges in the field of precision oncology are in part related to the biological complexity and diversity of this disease. Technological advances in genomics have facilitated large sequencing efforts and discoveries that have further supported this notion. In this review, we reflect on the impact of these discoveries on our understanding of several concepts: cancer initiation, cancer prevention, early detection, adjuvant therapy and minimal residual disease monitoring, cancer drug resistance, and cancer evolution in metastasis. We discuss key areas of focus for improving cancer outcomes, from biological insights to clinical application, and suggest where the development of these technologies will lead us. Finally, we discuss practical challenges to the wider adoption of molecular profiling in the clinic and the need for robust translational infrastructure.
    Keywords:  cancer evolution; cancer genomics; drug resistance
    DOI:  https://doi.org/10.1016/j.ccell.2022.04.002
  14. Cancer Discov. 2022 Apr 29. OF1
    Quiescent Breast Cancer Cells Are Resistant to T-cell Killing.
      Cancer cells that express antigen but are T cell-resistant are found to be principally quiescent.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-072
  15. Nat Cancer. 2022 Apr;3(4): 486-504
    Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs.
    Tsunaki Hongu, Maren Pein, Jacob Insua-Rodríguez, Ewgenija Gutjahr, Greta Mattavelli, Jasmin Meier, Kristin Decker, Arnaud Descot, Matthias Bozza, Richard Harbottle, Andreas Trumpp, Hans-Peter Sinn, Angela Riedel, Thordur Oskarsson.
      Disseminated cancer cells frequently lodge near vasculature in secondary organs. However, our understanding of the cellular crosstalk invoked at perivascular sites is still rudimentary. Here, we identify intercellular machinery governing formation of a pro-metastatic vascular niche during breast cancer colonization in the lung. We show that specific secreted factors, induced in metastasis-associated endothelial cells (ECs), promote metastasis in mice by enhancing stem cell properties and the viability of cancer cells. Perivascular macrophages, activated via tenascin C (TNC) stimulation of Toll-like receptor 4 (TLR4), were shown to be crucial in niche activation by secreting nitric oxide (NO) and tumor necrosis factor (TNF) to induce EC-mediated production of niche components. Notably, this mechanism was independent of vascular endothelial growth factor (VEGF), a key regulator of EC behavior and angiogenesis. However, targeting both macrophage-mediated vascular niche activation and VEGF-regulated angiogenesis resulted in added potency to curb lung metastasis in mice. Together, our findings provide mechanistic insights into the formation of vascular niches in metastasis.
    DOI:  https://doi.org/10.1038/s43018-022-00353-6
  16. Genome Med. 2022 Apr 29. 14(1): 45
    Integrated analysis of single-cell and bulk RNA sequencing data reveals a pan-cancer stemness signature predicting immunotherapy response.
    Zhen Zhang, Zi-Xian Wang, Yan-Xing Chen, Hao-Xiang Wu, Ling Yin, Qi Zhao, Hui-Yan Luo, Zhao-Lei Zeng, Miao-Zhen Qiu, Rui-Hua Xu.
       BACKGROUND: Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in cancer therapy, only a limited fraction of patients benefit from it. Cancer stemness can be the potential culprit in ICI resistance, but direct clinical evidence is lacking.
    METHODS: Publicly available scRNA-Seq datasets derived from ICI-treated patients were collected and analyzed to elucidate the association between cancer stemness and ICI response. A novel stemness signature (Stem.Sig) was developed and validated using large-scale pan-cancer data, including 34 scRNA-Seq datasets, The Cancer Genome Atlas (TCGA) pan-cancer cohort, and 10 ICI transcriptomic cohorts. The therapeutic value of Stem.Sig genes was further explored using 17 CRISPR datasets that screened potential immunotherapy targets.
    RESULTS: Cancer stemness, as evaluated by CytoTRACE, was found to be significantly associated with ICI resistance in melanoma and basal cell carcinoma (both P < 0.001). Significantly negative association was found between Stem.Sig and anti-tumor immunity, while positive correlations were detected between Stem.Sig and intra-tumoral heterogenicity (ITH) / total mutational burden (TMB). Based on this signature, machine learning model predicted ICI response with an AUC of 0.71 in both validation and testing set. Remarkably, compared with previous well-established signatures, Stem.Sig achieved better predictive performance across multiple cancers. Moreover, we generated a gene list ranked by the average effect of each gene to enhance tumor immune response after genetic knockout across different CRISPR datasets. Then we matched Stem.Sig to this gene list and found Stem.Sig significantly enriched 3% top-ranked genes from the list (P = 0.03), including EMC3, BECN1, VPS35, PCBP2, VPS29, PSMF1, GCLC, KXD1, SPRR1B, PTMA, YBX1, CYP27B1, NACA, PPP1CA, TCEB2, PIGC, NR0B2, PEX13, SERF2, and ZBTB43, which were potential therapeutic targets.
    CONCLUSIONS: We revealed a robust link between cancer stemness and immunotherapy resistance and developed a promising signature, Stem.Sig, which showed increased performance in comparison to other signatures regarding ICI response prediction. This signature could serve as a competitive tool for patient selection of immunotherapy. Meanwhile, our study potentially paves the way for overcoming immune resistance by targeting stemness-associated genes.
    Keywords:  Big data analysis; Immune checkpoint therapy; Pan-cancer; Single-cell sequencing; Stemness
    DOI:  https://doi.org/10.1186/s13073-022-01050-w
  17. Proc Natl Acad Sci U S A. 2022 May 03. 119(18): e2200143119
    Calcium channel blockers potentiate gemcitabine chemotherapy  in pancreatic cancer.
    Daniel R Principe, Alexandre F Aissa, Sandeep Kumar, Thao N D Pham, Patrick W Underwood, Rakesh Nair, Rong Ke, Basabi Rana, Jose G Trevino, Hidayatullah G Munshi, Elizaveta V Benevolenskaya, Ajay Rana.
      SignificancePancreatic cancer is a leading cause of cancer-related death, in part due to incomplete responses to standard-of-care chemotherapy. In this study, using a combination of single-cell RNA sequencing and high-throughput proteomics, we identified the calcium-responsive protein calmodulin as a key mediator of resistance to the first-line chemotherapy agent gemcitabine. Inhibition of calmodulin led to the loss of gemcitabine resistance in vitro, which was recapitulated using a calcium chelator or Food and Drug Administration-approved calcium channel blockers (CCBs), including amlodipine. In animal studies, amlodipine markedly enhanced therapeutic responses to gemcitabine chemotherapy, reducing the incidence of distant metastases and extending survival. Hence, incorporating CCBs may provide a safe and effective means of improving responses to gemcitabine-based chemotherapy in pancreatic cancer patients.
    Keywords:  chemotherapy; drug resistance; gemcitabine; pancreatic cancer
    DOI:  https://doi.org/10.1073/pnas.2200143119
  18. Mol Cancer. 2022 Apr 27. 21(1): 106
    An EHMT2/NFYA-ALDH2 signaling axis modulates the RAF pathway to regulate paclitaxel resistance in lung cancer.
    Wenjing Wang, Jianmin Wang, Shuai Liu, Yong Ren, Jingyu Wang, Sen Liu, Wei Cui, Lina Jia, Xing Tang, Jingyu Yang, Chunfu Wu, Lihui Wang.
       BACKGROUND: Lung cancer is a kind of malignancy with high morbidity and mortality worldwide. Paclitaxel (PTX) is the main treatment for non-small cell lung cancer (NSCLC), and resistance to PTX seriously affects the survival of patients. However, the underlying mechanism and potential reversing strategy need to be further explored.
    METHODS: We identified ALDH2 as a PTX resistance-related gene using gene microarray analysis. Subsequently, a series of functional analysis in cell lines, patient samples and xenograft models were performed to explore the functional role, clinical significance and the aberrant regulation mechanism of ALDH2 in PTX resistance of NSCLC. Furthermore, the pharmacological agents targeting ALDH2 and epigenetic enzyme were used to investigate the diverse reversing strategy against PTX resistance.
    RESULTS: Upregulation of ALDH2 expression is highly associated with resistance to PTX using in vitro and in vivo analyses of NSCLC cells along with clinicopathological analyses of NSCLC patients. ALDH2-overexpressing NSCLC cells exhibited significantly reduced PTX sensitivity and increased biological characteristics of malignancy in vitro and tumor growth and metastasis in vivo. EHMT2 (euchromatic histone lysine methyltransferase 2) inhibition and NFYA (nuclear transcription factor Y subunit alpha) overexpression had a cooperative effect on the regulation of ALDH2. Mechanistically, ALDH2 overexpression activated the RAS/RAF oncogenic pathway. NSCLC/PTX cells re-acquired sensitivity to PTX in vivo and in vitro when ALDH2 was inhibited by pharmacological agents, including the ALDH2 inhibitors Daidzin (DZN)/Disulfiram (DSF) and JIB04, which reverses the effect of EHMT2.
    CONCLUSION: Our findings suggest that ALDH2 status can help predict patient response to PTX therapy and ALDH2 inhibition may be a promising strategy to overcome PTX resistance in the clinic.
    Keywords:  ALDH2; EHMT2; Non-small cell lung cancer; Paclitaxel resistance; RAS/RAF pathway
    DOI:  https://doi.org/10.1186/s12943-022-01579-9
  19. Sci Transl Med. 2022 Apr 27. 14(642): eabj9779
    Addition of interleukin-2 overcomes resistance to neoadjuvant CTLA4 and PD1 blockade in ex vivo patient tumors.
    Paulien Kaptein, Celia Jacoberger-Foissac, Petros Dimitriadis, Paula Voabil, Marjolein de Bruijn, Simone Brokamp, Irene Reijers, Judith Versluis, Gahyathiri Nallan, Hannah Triscott, Elizabeth McDonald, Joshua Tay, Georgina V Long, Christian U Blank, Daniela S Thommen, Michele W L Teng.
      Neoadjuvant immunotherapy with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) + anti-programmed cell death protein 1 (PD1) monoclonal antibodies has demonstrated remarkable pathological responses and relapse-free survival in ~80% of patients with clinically detectable stage III melanoma. However, about 20% of the treated patients do not respond. In pretreatment biopsies of patients with melanoma, we found that resistance to neoadjuvant CTLA4 + PD1 blockade was associated with a low CD4/interleukin-2 (IL-2) gene signature. Ex vivo, addition of IL-2 to CTLA4 + PD1 blockade induced T cell activation and deep immunological responses in anti-CTLA4 + anti-PD1-resistant human tumor specimens. In the 4T1.2 breast cancer mouse model of neoadjuvant immunotherapy, triple combination of anti-CTLA4 + anti-PD1 + IL-2 cured almost twice as many mice as compared with dual checkpoint inhibitor therapy. This improved efficacy was due to the expansion of tumor-specific CD8+ T cells and improved proinflammatory cytokine polyfunctionality of both CD4+ and CD8+ T effector cells and regulatory T cells. Depletion studies suggested that CD4+ T cells were critical for priming of CD8+ T cell immunity against 4T1.2 and helped in the expansion of tumor-specific CD8+ T cells early after neoadjuvant triple immunotherapy. Our results suggest that the addition of IL-2 can overcome resistance to neoadjuvant anti-CTLA4 + anti-PD1, providing the rationale for testing this combination as a neoadjuvant therapy in patients with early-stage cancer.
    DOI:  https://doi.org/10.1126/scitranslmed.abj9779
  20. Cell Rep. 2022 Apr 26. pii: S2211-1247(22)00482-X. [Epub ahead of print]39(4): 110721
    The oncogene-dependent resistance to reprogramming unveils cancer therapeutic targets.
    Kenji Ito, Kohei Nagata, Sho Ohta, Yutaka Matsuda, Tomoyo Ukai, Ichiro Yasuda, Akira Ota, Ryota Kobayashi, Mio Kabata, Nao Sankoda, Tatsuya Maeda, Knut Woltjen, Liying Yang, Reo Maruyama, Ryohei Katayama, Takuya Yamamoto, Yasuhiro Yamada.
      The resistance to transcription factor-mediated reprogramming into pluripotent stem cells is one of the distinctive features of cancer cells. Here we dissect the profiles of reprogramming factor binding and the subsequent transcriptional response in cancer cells to reveal its underlying mechanisms. Using clear cell sarcomas (CCSs), we show that the driver oncogene EWS/ATF1 misdirects the reprogramming factors to cancer-specific enhancers and thereby impairs the transcriptional response toward pluripotency that is otherwise provoked. Sensitization to the reprogramming cue is observed in other cancer types when the corresponding oncogenic signals are pharmacologically inhibited. Exploiting this oncogene dependence of the transcriptional "stiffness," we identify mTOR signaling pathways downstream of EWS/ATF1 and discover that inhibiting mTOR activity substantially attenuates the propagation of CCS cells in vitro and in vivo. Our results demonstrate that the early transcriptional response to cell fate perturbations can be a faithful readout to identify effective therapeutics targets in cancer cells.
    Keywords:  CP: Cancer; MyoD1; OSKM; cancer cell identity; cancer therapeutics; driver oncogenic signal; reprogramming; resistance to reprogramming; transcriptional response
    DOI:  https://doi.org/10.1016/j.celrep.2022.110721
  21. Proc Natl Acad Sci U S A. 2022 May 03. 119(18): e2120512119
    A saturation mutagenesis screen uncovers resistant and sensitizing secondary KRAS mutations to clinical KRASG12C inhibitors.
    Siyu Feng, Marinella G Callow, Jean-Philippe Fortin, Zia Khan, David Bray, Mike Costa, Zhen Shi, Weiru Wang, Marie Evangelista.
      SignificanceKRASG12C inhibitors have demonstrated promising efficacy in non-small-cell lung cancer patients harboring the KRASG12C mutation. However, the mechanism of resistance remains to be fully understood. To understand the consequences of single amino acid changes within KRASG12C, we conducted a saturation mutagenesis screen of the KRASG12C protein and assessed the mutational impact on drug sensitivity. Not only did our screen reveal resistant hits that were identified from patients' samples (V8L, C12F, R68S, H95D, H95R, and Y96C), but we also discovered variants that sensitize the inhibition. Furthermore, we examined the human genetics databases and identified germline or somatic KRAS mutations that appear among the strong resistance hits. Our study positions future drug discovery targeting KRASG12C toward focusing on inhibitors preserving potency against resistance mutations at key residues.
    Keywords:  KRASG12C; adagrasib; drug resistance; mutagenesis screen; sotorasib
    DOI:  https://doi.org/10.1073/pnas.2120512119
  22. Nat Commun. 2022 Apr 25. 13(1): 2210
    Reduced chromatin accessibility correlates with resistance to Notch activation.
    Jelle van den Ameele, Robert Krautz, Seth W Cheetham, Alex P A Donovan, Oriol Llorà-Batlle, Rebecca Yakob, Andrea H Brand.
      The Notch signalling pathway is a master regulator of cell fate transitions in development and disease. In the brain, Notch promotes neural stem cell (NSC) proliferation, regulates neuronal migration and maturation and can act as an oncogene or tumour suppressor. How NOTCH and its transcription factor RBPJ activate distinct gene regulatory networks in closely related cell types in vivo remains to be determined. Here we use Targeted DamID (TaDa), requiring only thousands of cells, to identify NOTCH and RBPJ binding in NSCs and their progeny in the mouse embryonic cerebral cortex in vivo. We find that NOTCH and RBPJ associate with a broad network of NSC genes. Repression of NSC-specific Notch target genes in intermediate progenitors and neurons correlates with decreased chromatin accessibility, suggesting that chromatin compaction may contribute to restricting NOTCH-mediated transactivation.
    DOI:  https://doi.org/10.1038/s41467-022-29834-z
  23. Trends Cancer. 2022 Apr 22. pii: S2405-8033(22)00089-9. [Epub ahead of print]
    Pro-ferroptotic fatty acid metabolism renders cancer cells immunogenic.
    Oliver Kepp, Guido Kroemer.
      Tumor cell-intrinsic metabolic features can affect the cancer-immunity dialogue. In a recent paper published in Cancer Cell, Liao et al. demonstrate that IFNγ produced by T cells, together with arachidonic acid, can induce acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis, correlating with increased immunosurveillance and response to checkpoint blockade.
    Keywords:  PARP; immunogenic cell death; immunotherapy
    DOI:  https://doi.org/10.1016/j.trecan.2022.04.002
  24. Nature. 2022 Apr 27.
    β-Hydroxybutyrate suppresses colorectal cancer.
    Oxana Dmitrieva-Posocco, Andrea C Wong, Patrick Lundgren, Aleksandra M Golos, Hélène C Descamps, Lenka Dohnalová, Zvi Cramer, Yuhua Tian, Brian Yueh, Onur Eskiocak, Gabor Egervari, Yemin Lan, Jinping Liu, Jiaxin Fan, Jihee Kim, Bhoomi Madhu, Kai Markus Schneider, Svetlana Khoziainova, Natalia Andreeva, Qiaohong Wang, Ning Li, Emma E Furth, Will Bailis, Judith R Kelsen, Kathryn E Hamilton, Klaus H Kaestner, Shelley L Berger, Jonathan A Epstein, Rajan Jain, Mingyao Li, Semir Beyaz, Christopher J Lengner, Bryson W Katona, Sergei I Grivennikov, Christoph A Thaiss, Maayan Levy.
      Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed1. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body β-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC.
    DOI:  https://doi.org/10.1038/s41586-022-04649-6
  25. Cancer Discov. 2022 Apr 29. OF1
    Navicixizumab plus Paclitaxel Shows Clinical Benefit in Platinum-Resistant Ovarian Cancer.
      Combined navicixizumab and paclitaxel showed durable activity in patients with platinum-resistant ovarian cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-073
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