bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒01‒17
eighteen papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology
  1. Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation.
  2. ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer.
  3. Interplay between desmoglein2 and hypoxia controls metastasis in breast cancer.
  4. KNSTRN promotes tumorigenesis and gemcitabine resistance by activating AKT in bladder cancer.
  5. Targeting metastatic cancer.
  6. Myeloid-derived suppressor cells promote lung cancer metastasis by CCL11 to activate ERK and AKT signaling and induce epithelial-mesenchymal transition in tumor cells.
  7. Prolactin receptor-driven combined luminal and epithelial differentiation in breast cancer restricts plasticity, stemness, tumorigenesis and metastasis.
  8. Crizotinib Resistance Mediated by Autophagy Is Higher in the Stem-Like Cell Subset in ALK-Positive Anaplastic Large Cell Lymphoma, and This Effect Is MYC-Dependent.
  9. The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair.
  10. (Oligo)metastasis as a spectrum of disease.
  11. Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation.
  12. Carbon nano-onion-mediated dual targeting of P-selectin and P-glycoprotein to overcome cancer drug resistance.
  13. Epigenetic and post-transcriptional modulation of SOS1 can promote breast cancer metastasis through obesity-activated c-Met signaling in African American women.
  14. STIM1 Mediates Calcium-dependent Epigenetic Reprogramming in Pancreatic Cancer.
  15. Clinical Proteomics of Metastatic Melanoma Reveals Profiles of Organ-Specificity and Treatment Resistance.
  16. Deciphering the Role of Ca2+ Signalling in Cancer Metastasis: From the Bench to the Bedside.
  17. Concerted roles of PTEN and ATM in controlling hematopoietic stem cell fitness and dormancy.
  18. Multiomics characterization of low-grade serous ovarian carcinoma identifies potential biomarkers of MEK inhibitor sensitivity and therapeutic vulnerability.
  1. Cancer Cell. 2020 Dec 31. pii: S1535-6108(20)30660-7. [Epub ahead of print]
    Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation.
    Yansen Xiao, Min Cong, Jiatao Li, Dasa He, Qiuyao Wu, Pu Tian, Yuan Wang, Shuaixi Yang, Chenxi Liang, Yajun Liang, Jili Wen, Yingjie Liu, Wenqian Luo, Xianzhe Lv, Yunfei He, Dong-Dong Cheng, Tianhao Zhou, Wenjing Zhao, Peiyuan Zhang, Xue Zhang, Yichuan Xiao, Youcun Qian, Hongxia Wang, Qiang Gao, Qing-Cheng Yang, Qifeng Yang, Guohong Hu.
      Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1β (IL-1β) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1β axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.
    Keywords:  Cathespin C; breast cancer; lung metastasis; metastatic niche; neutrophil; neutrophil extracellular trap
    DOI:  https://doi.org/10.1016/j.ccell.2020.12.012
  2. Genes Dev. 2021 Jan 14.
    ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer.
    Vinee Purohit, Lidong Wang, Huibin Yang, Jiufeng Li, Gina M Ney, Erica R Gumkowski, Akash J Vaidya, Annie Wang, Amit Bhardwaj, Ende Zhao, Igor Dolgalev, Andrea Zamperone, Ethan V Abel, Marina Pasca Di Magliano, Howard C Crawford, Daniel Diolaiti, Thales Y Papagiannakopoulos, Costas A Lyssiotis, Diane M Simeone.
      Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.
    Keywords:  ATDC (Trim29); chemotherapeutic resistance; pancreatic cancer; tumor growth and invasion
    DOI:  https://doi.org/10.1101/gad.344184.120
  3. Proc Natl Acad Sci U S A. 2021 Jan 19. pii: e2014408118. [Epub ahead of print]118(3):
    Interplay between desmoglein2 and hypoxia controls metastasis in breast cancer.
    Po-Hao Chang, Min-Che Chen, Ya-Ping Tsai, Grace Y T Tan, Pang-Hung Hsu, Yung-Ming Jeng, Yi-Fang Tsai, Muh-Hwa Yang, Wendy W Hwang-Verslues.
      Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters, and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process, as down-regulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial-mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the polycomb repressive complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a mechanism by which hypoxia drives metastasis.
    Keywords:  HIF1α; breast cancer; circulating tumor cells (CTCs); desmoglein2 (DSG2); metastasis
    DOI:  https://doi.org/10.1073/pnas.2014408118
  4. Oncogene. 2021 Jan 15.
    KNSTRN promotes tumorigenesis and gemcitabine resistance by activating AKT in bladder cancer.
    Yaoyi Xiong, Lingao Ju, Lushun Yuan, Liang Chen, Gang Wang, Huimin Xu, Tianchen Peng, Yongwen Luo, Yu Xiao, Xinghuan Wang.
      KNSTRN is a component of the mitotic spindle, which was rarely investigated in tumorigenesis. AKT plays an essential role in tumorigenesis by modulating the phosphorylation of various substrates. The activation of AKT is regulated by PTEN and PIP3. Here, we prove KNSTRN is positively correlated with malignancy of bladder cancer and KNSTRN activates AKT phosphorylation at Thr308 and Ser473. More importantly, our study reveals that both KNSTRN and PTEN interact with PH domain of AKT at cell membrane. The amount of KNSTRN interacted with AKT is negatively related to PTEN. Furthermore, PIP3 pull-down assay proves that KNSTRN promoted AKT movement to PIP3. These data suggest KNSTRN may activate AKT phosphorylation by promoting AKT movement to PIP3 and alleviating PTEN suppression. Based on the activation of AKT phosphorylation, our study demonstrates that KNSTRN promotes bladder cancer metastasis and gemcitabine resistance in vitro and in vivo. Meanwhile, the effect of KNSTRN on tumorigenesis and gemcitabine resistance could be restored by AKT specific inhibitor MK2206 or AKT overexpression. In conclusion, we identify an oncogene KNSTRN that promotes tumorigenesis and gemcitabine resistance by activating AKT phosphorylation and may serve as a therapeutic target in bladder cancer.
    DOI:  https://doi.org/10.1038/s41388-020-01634-z
  5. Nat Med. 2021 01;27(1): 34-44
    Targeting metastatic cancer.
    Karuna Ganesh, Joan Massagué.
      Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. Recent work has uncovered the unique biology of metastasis-initiating cells that results in tumor growth in distant organs, evasion of immune surveillance and co-option of metastatic microenvironments. Here we review recent progress that is enabling therapeutic advances in treating both micro- and macrometastases. Such insights were gained from cancer sequencing, mechanistic studies and clinical trials, including of immunotherapy. These studies reveal both the origins and nature of metastases and identify new opportunities for developing more effective strategies to target metastatic relapse and improve patient outcomes.
    DOI:  https://doi.org/10.1038/s41591-020-01195-4
  6. Oncogene. 2021 Jan 15.
    Myeloid-derived suppressor cells promote lung cancer metastasis by CCL11 to activate ERK and AKT signaling and induce epithelial-mesenchymal transition in tumor cells.
    Shouheng Lin, Xuchao Zhang, Guohua Huang, Lin Cheng, Jiang Lv, Diwei Zheng, Simiao Lin, Suna Wang, Qiting Wu, Youguo Long, Baiheng Li, Wei Wei, Pentao Liu, Duanqing Pei, Yangqiu Li, Zhesheng Wen, Shuzhong Cui, Peng Li, Xiaofang Sun, Yilong Wu, Yao Yao.
      Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune activities and facilitate cancer progression. Although the concept of immunosuppressive MDSCs is well established, the mechanism that MDSCs regulate non-small cell lung cancer (NSCLC) progression through the paracrine signals is still lacking. Here, we reported that the infiltration of MDSCs within NSCLC tissues was associated with the progression of cancer status, and was positively correlated with the Patient-derived xenograft model establishment, and poor patient prognosis. Intratumoral MDSCs directly promoted NSCLC metastasis and highly expressed chemokines that promote NSCLC cells invasion, including CCL11. CCL11 was capable of activating the AKT and ERK signaling pathways to promote NSCLC metastasis through the epithelial-mesenchymal transition (EMT) process. Moreover, high expression of CCL11 was associated with a poor prognosis in lung cancer as well as other types of cancer. Our findings underscore that MDSCs produce CCL11 to promote NSCLC metastasis via activation of ERK and AKT signaling and induction of EMT, suggesting that the MDSCs-CCL11-ERK/AKT-EMT axis contains potential targets for NSCLC metastasis treatment.
    DOI:  https://doi.org/10.1038/s41388-020-01605-4
  7. Oncogenesis. 2021 Jan 14. 10(1): 10
    Prolactin receptor-driven combined luminal and epithelial differentiation in breast cancer restricts plasticity, stemness, tumorigenesis and metastasis.
    Anwar Shams, Najat Binothman, Julien Boudreault, Ni Wang, Fuad Shams, Dana Hamam, Jun Tian, Alaa Moamer, Meiou Dai, Jean-Jacques Lebrun, Suhad Ali.
      Dedifferentiation increased cellular plasticity and stemness are established derivers of tumor heterogeneity, metastasis and therapeutic failure resulting in incurable cancers. Therefore, it is essential to decipher pro/forward-differentiation mechanisms in cancer that may serve as therapeutic targets. We found that interfering with expression of the receptor for the lactogenic hormone prolactin (PRLR) in breast cancer cells representative of the luminal and epithelial breast cancer subtypes (hormone receptor positive (HR+) and HER2-enriched (HER2-E) resulted in loss of their differentiation state, enriched for stem-like cell subpopulations, and increased their tumorigenic capacity in a subtype-specific manner. Loss of PRLR expression in HR+ breast cancer cells caused their dedifferentiation generating a mesenchymal-basal-like phenotype enriched in CD44+ breast cancer stem-like cells (BCSCs) showing high tumorigenic and metastatic capacities and resistance to anti-hormonal therapy. Whereas loss of PRLR expression in HER2-E breast cancer cells resulted in loss of their luminal differentiation yet enriched for epithelial ALDH+ BCSC population showing elevated HER2-driven tumorigenic, multi-organ metastatic spread, and resistance to anti-HER2 therapy. Collectively, this study defines PRLR as a driver of precise luminal and epithelial differentiation limiting cellular plasticity, stemness, and tumorigenesis and emphasizing the function of pro/forward-differentiation pathways as a foundation for the discovery of anti-cancer therapeutic targets.
    DOI:  https://doi.org/10.1038/s41389-020-00297-5
  8. Cancers (Basel). 2021 Jan 07. pii: E181. [Epub ahead of print]13(2):
    Crizotinib Resistance Mediated by Autophagy Is Higher in the Stem-Like Cell Subset in ALK-Positive Anaplastic Large Cell Lymphoma, and This Effect Is MYC-Dependent.
    Chuquan Shang, Bardes Hassan, Moinul Haque, Yuqi Song, Jing Li, Dongzhe Liu, Eva Lipke, Will Chen, Sylvie Giuriato, Raymond Lai.
      Previously it was shown that autophagy contributes to crizotinib resistance in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). We asked if autophagy is equally important in two distinct subsets of ALK + ALCL, namely Reporter Unresponsive (RU) and Reporter Responsive (RR), of which RR cells display stem-like properties. Autophagic flux was assessed with a fluorescence tagged LC3 reporter and immunoblots to detect endogenous LC3 alongside chloroquine, an autophagy inhibitor. The stem-like RR cells displayed significantly higher autophagic response upon crizotinib treatment. Their exaggerated autophagic response is cytoprotective against crizotinib, as inhibition of autophagy using chloroquine or shRNA against BECN1 or ATG7 led to a decrease in their viability. In contrast, autophagy inhibition in RU resulted in minimal changes. Since the differential protein expression of MYC is a regulator of the RU/RR dichotomy and is higher in RR cells, we asked if MYC regulates the autophagy-mediated cytoprotective effect. Inhibition of MYC in RR cells using shRNA significantly blunted crizotinib-induced autophagic response and effectively suppressed this cytoprotective effect. In conclusion, stem-like RR cells respond with rapid and intense autophagic flux which manifests with crizotinib resistance. For the first time, we have highlighted the direct role of MYC in regulating autophagy and its associated chemoresistance phenotype in ALK + ALCL stem-like cells.
    Keywords:  ALK + ALCL; MYC; autophagy; cancer stem-like cells; chloroquine; crizotinib; resistance
    DOI:  https://doi.org/10.3390/cancers13020181
  9. Nat Commun. 2021 Jan 15. 12(1): 401
    The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair.
    Ayesha A Shafi, Chris M McNair, Jennifer J McCann, Mohammed Alshalalfa, Anton Shostak, Tesa M Severson, Yanyun Zhu, Andre Bergman, Nicolas Gordon, Amy C Mandigo, Saswati N Chand, Peter Gallagher, Emanuela Dylgjeri, Talya S Laufer, Irina A Vasilevskaya, Matthew J Schiewer, Michael Brunner, Felix Y Feng, Wilbert Zwart, Karen E Knudsen.
      Mechanisms regulating DNA repair processes remain incompletely defined. Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage stabilizes CRY1 in cancer (in vitro, in vivo, and human tumors ex vivo), which proves critical for efficient DNA repair. Further mechanistic investigation shows that stabilized CRY1 temporally regulates expression of genes required for homologous recombination. Collectively, these findings reveal that CRY1 is hormone-induced in tumors, is further stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation. These studies identify the circadian factor CRY1 as pro-tumorigenic and nominate CRY1 as a new therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-020-20513-5
  10. Cancer Res. 2021 Jan 15. pii: canres.3337.2020. [Epub ahead of print]
    (Oligo)metastasis as a spectrum of disease.
    Stanley I Gutiontov, Sean P Pitroda, Phuoc T Tran, Ralph R Weichselbaum.
      Cancer metastasis is the leading cause of cancer-related mortality, and most patients with metastases from solid tumors have historically been considered incurable. Here we discuss the evolution of our understanding of the oligometastatic state with an emphasis on the view that cancer metastasis represents a spectrum of disease. We highlight several recently published prospective clinical trials demonstrating improvements in cancer-specific outcomes with the utilization of metastasis-directed local therapies. We discuss biological aspects of oligometastases including genetic, epigenetic, and immune determinants of the metastatic spectrum. Finally, we propose future considerations regarding clinical trial design for patients with oligometastatic disease.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3337
  11. EMBO Mol Med. 2021 Jan 13. e12627
    Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation.
    Xinyuan Tong, Yueqing Chen, Xinsheng Zhu, Yi Ye, Yun Xue, Rui Wang, Yijun Gao, Wenjing Zhang, Weiqiang Gao, Lei Xiao, Haiquan Chen, Peng Zhang, Hongbin Ji.
      Growing evidence supports that LKB1-deficient KRAS-driven lung tumors represent a unique therapeutic challenge, displaying strong cancer plasticity that promotes lineage conversion and drug resistance. Here we find that murine lung tumors from the KrasLSL-G12D/+ ; Lkb1flox/flox (KL) model show strong plasticity, which associates with up-regulation of stem cell pluripotency genes such as Nanog. Deletion of Nanog in KL model initiates a gastric differentiation program and promotes mucinous lung tumor growth. We find that NANOG is not expressed at a meaningful level in human lung adenocarcinoma (ADC), as well as in human lung invasive mucinous adenocarcinoma (IMA). Gastric differentiation involves activation of Notch signaling, and perturbation of Notch pathway by the γ-secretase inhibitor LY-411575 remarkably impairs mucinous tumor formation. In contrast to non-mucinous tumors, mucinous tumors are resistant to phenformin treatment. Such therapeutic resistance could be overcome through combined treatments with LY-411575 and phenformin. Overall, we uncover a previously unappreciated plasticity of LKB1-deficient tumors and identify the Nanog-Notch axis in regulating gastric differentiation, which holds important therapeutic implication for the treatment of mucinous lung cancer.
    Keywords:   Nanog ; LKB1; Notch; drug resistance; gastric differentiation
    DOI:  https://doi.org/10.15252/emmm.202012627
  12. Nat Commun. 2021 01 12. 12(1): 312
    Carbon nano-onion-mediated dual targeting of P-selectin and P-glycoprotein to overcome cancer drug resistance.
    Hai Wang, Yutong Liang, Yue Yin, Jie Zhang, Wen Su, Alisa M White, Bin Jiang, Jiangsheng Xu, Yuntian Zhang, Samantha Stewart, Xiongbin Lu, Xiaoming He.
      The transmembrane P-glycoprotein (P-gp) pumps that efflux drugs are a major mechanism of cancer drug resistance. They are also important in protecting normal tissue cells from poisonous xenobiotics and endogenous metabolites. Here, we report a fucoidan-decorated silica-carbon nano-onion (FSCNO) hybrid nanoparticle that targets tumor vasculature to specifically release P-gp inhibitor and anticancer drug into tumor cells. The tumor vasculature targeting capability of the nanoparticle is demonstrated using multiple models. Moreover, we reveal the superior light absorption property of nano-onion in the near infrared region (NIR), which enables triggered drug release from the nanoparticle at a low NIR power. The released inhibitor selectively binds to P-gp pumps and disables their function, which improves the bioavailability of anticancer drug inside the cells. Furthermore, free P-gp inhibitor significantly increases the systemic toxicity of a chemotherapy drug, which can be resolved by delivering them with FSCNO nanoparticles in combination with a short low-power NIR laser irradiation.
    DOI:  https://doi.org/10.1038/s41467-020-20588-0
  13. Cancer Res. 2021 Jan 14. pii: canres.4031.2019. [Epub ahead of print]
    Epigenetic and post-transcriptional modulation of SOS1 can promote breast cancer metastasis through obesity-activated c-Met signaling in African American women.
    Fei Xing, Dan Zhao, Shin-Ying Wu, Abhishek Tyagi, Kerui Wu, Sambad Sharma, Yin Liu, Ravindra Deshpande, Yuezhu Wang, Jacob Cleary, Lance D Miller, Amar G Chittiboyina, Chinni Yalamanchili, Yin-Yuan Mo, Kounosuke Watabe.
      Ethnicity is considered to be one of the major risk factors in certain subtypes of breast cancer. However, the mechanism of this racial disparity remains poorly understood. Here we demonstrate that SOS1, a key regulator of Ras pathway, is highly expressed in African American (AA) breast cancer patients compared to Caucasian American (CA) patients. Because of the higher obesity rate in AA women, increased levels of SOS1 facilitated signal transduction of the c-Met pathway which was highly activated in AA breast cancer patients via HGF secreted from adipocytes. Elevated expression of SOS1 also enhanced cancer stemness through upregulation of PTTG1 and promoted M2 polarization of macrophages by CCL2 in metastatic sites. SOS1 was epigenetically regulated by a super-enhancer identified by H3K27ac in AA patients. Knockout of the super-enhancer by CRISPR in AA cell lines significantly reduced SOS1 expression. Furthermore, SOS1 was post-transcriptionally regulated by miR-483 whose expression is reduced in AA patients through histone tri-methylation (H3K27me3) on its promoter. The natural compound taxifolin suppressed signaling transduction of SOS1 by blocking the interaction between SOS1 and Grb2, suggesting a potential utility of this compound as a therapeutic agent for AA breast cancer patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-4031
  14. Cancer Res. 2021 Jan 12. pii: canres.2874.2020. [Epub ahead of print]
    STIM1 Mediates Calcium-dependent Epigenetic Reprogramming in Pancreatic Cancer.
    Ana P Kutschat, Feda H Hamdan, Xin Wang, Alexander Q Wixom, Zeynab Najafova, Christine S Gibhardt, Waltraut Kopp, Jochen Gaedcke, Philipp Ströbel, Volker Ellenrieder, Ivan Bogeski, Elisabeth Hessmann, Steven A Johnsen.
      Pancreatic Ductal Adenocarcinoma (PDAC) displays a dismal prognosis due to late diagnosis and high chemoresistance incidence. For advanced disease stages or patients with comorbidities, treatment options are limited to gemcitabine alone or in combination with other drugs. While gemcitabine resistance has been widely attributed to the levels of one of its targets, RRM1, the molecular consequences of gemcitabine resistance in PDAC remain largely elusive. Here we sought to identify genomic, epigenomic, and transcriptomic events associated with gemcitabine resistance in PDAC and their potential clinical relevance. We found that gemcitabine-resistant cells displayed a co-amplification of the adjacent RRM1 and STIM1 genes. Interestingly, RRM1, but not STIM1, was required for gemcitabine resistance, while high STIM1 levels caused an increase in cytosolic calcium concentration. Higher STIM1-dependent calcium influx led to an impaired ER stress response and a heightened NFAT activity. Importantly, these findings were confirmed in patient and patient-derived xenograft samples. Taken together, our study uncovers previously unknown biologically relevant molecular properties of gemcitabine-resistant tumors, revealing an undescribed function of STIM1 as a rheostat directing the effects of calcium signaling and controlling epigenetic cell fate determination. It further reveals the potential benefit of targeting STIM1-controlled calcium signaling and its downstream effectors in PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2874
  15. Clin Cancer Res. 2021 Jan 14. pii: clincanres.3752.2020. [Epub ahead of print]
    Clinical Proteomics of Metastatic Melanoma Reveals Profiles of Organ-Specificity and Treatment Resistance.
    Tamar Geiger, Lir Beck, Michal Harel, Shun Yu, Ettai Markovits, Ben Boursi, Gal Markel.
      PURPOSE: Treatment of metastatic melanoma has dramatically improved in recent years thanks to the development of immunotherapy and BRAF-MEK targeted therapies. However, these developments revealed marked heterogeneity among patient response, which is yet to be fully understood. In this work, we aimed to associate the proteomic profiles of metastatic melanoma with the patient clinical information, to identify protein correlates with metastatic location and prior treatments.EXPERIMENTAL DESIGN: We performed mass-spectrometry-based proteomic analysis of 185 metastatic melanoma samples and followed with bioinformatic analysis to examine the association of metastatic location, BRAF status, survival and immunotherapy response with the tumor molecular profiles.
    RESULTS: Bioinformatic analysis showed high degree of functional heterogeneity associated with the site of metastasis. Lung metastases presented higher immune-related proteins, and higher mitochondrial-related processes, which were previously shown to be associated with better immunotherapy response. In agreement, epidemiological analysis of data from the National Cancer Database showed improved response to anti-PD1, mainly in patients with lung metastasis. Focus on lung metastases revealed prognostic and molecular heterogeneity and highlighted potential tissue-specific biomarkers. Analysis of the BRAF mutation status and prior treatments with MAPK inhibitors proposed the molecular basis of the effect on immunotherapy response and suggested coordinated combination of immunotherapy and targeted therapy may increase treatment efficacy.
    CONCLUSIONS: Altogether, the proteomic data provided novel molecular determinants of critical clinical features, including the effects of sequential treatments and metastatic locations. These results can be the basis for development of site-specific treatments toward treatment personalization.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-3752
  16. Cancers (Basel). 2021 Jan 07. pii: E179. [Epub ahead of print]13(2):
    Deciphering the Role of Ca2+ Signalling in Cancer Metastasis: From the Bench to the Bedside.
    Abeer Alharbi, Yuxuan Zhang, John Parrington.
      Metastatic cancer is one of the major causes of cancer-related mortalities. Metastasis is a complex, multi-process phenomenon, and a hallmark of cancer. Calcium (Ca2+) is a ubiquitous secondary messenger, and it has become evident that Ca2+ signalling plays a vital role in cancer. Ca2+ homeostasis is dysregulated in physiological processes related to tumour metastasis and progression-including cellular adhesion, epithelial-mesenchymal transition, cell migration, motility, and invasion. In this review, we looked at the role of intracellular and extracellular Ca2+ signalling pathways in processes that contribute to metastasis at the local level and also their effects on cancer metastasis globally, as well as at underlying molecular mechanisms and clinical applications. Spatiotemporal Ca2+ homeostasis, in terms of oscillations or waves, is crucial for hindering tumour progression and metastasis. They are a limited number of clinical trials investigating treating patients with advanced stages of various cancer types. Ca2+ signalling may serve as a novel hallmark of cancer due to the versatility of Ca2+ signals in cells, which suggests that the modulation of specific upstream/downstream targets may be a therapeutic approach to treat cancer, particularly in patients with metastatic cancers.
    Keywords:  Ca2+ signals; calcium; cancer; metastasis
    DOI:  https://doi.org/10.3390/cancers13020179
  17. J Clin Invest. 2021 Jan 14. pii: 131698. [Epub ahead of print]
    Concerted roles of PTEN and ATM in controlling hematopoietic stem cell fitness and dormancy.
    Jerome Fortin, Christian Bassi, Parameswaran Ramachandran, Wanda Y Li, Ruxiao Tian, Ida Zarrabi, Graham Hill, Bryan E Snow, Jillian Haight, Chantal Tobin, Kelsey Hodgson, Andrew Wakeham, Vuk Stambolic, Tak W Mak.
      In order to sustain proficient life-long hematopoiesis, hematopoietic stem cells (HSCs) must possess robust mechanisms to preserve their quiescence and genome integrity. DNA-damaging stress can perturb HSC homeostasis by affecting their survival, self-renewal and differentiation. Ablation of the kinase ATM, a master regulator of the DNA damage response, impairs HSC fitness. Paradoxically, we show here that loss of a single allele of Atm enhances HSC functionality in mice. To explain this observation, we explored a possible link between ATM and the tumor suppressor PTEN, which also regulates HSC function. We generated and analyzed a knock-in mouse line (PtenS398A/S398A), in which PTEN cannot be phosphorylated by ATM. Similar to Atm+/-, PtenS398A/S398A HSCs have enhanced hematopoietic reconstitution ability, accompanied by resistance to apoptosis induced by genotoxic stress. Single-cell transcriptomic analyses and functional assays revealed that dormant PtenS398A/S398A HSCs aberrantly tolerate elevated mitochondrial activity and the accumulation of reactive oxygen species, which are normally associated with HSC priming for self-renewal or differentiation. Our results unveil a molecular connection between ATM and PTEN, which couples the response to genotoxic stress and dormancy in HSC.
    Keywords:  DNA repair; Hematology; Hematopoietic stem cells; Stem cells
    DOI:  https://doi.org/10.1172/JCI131698
  18. Cancer Res. 2021 Jan 13. pii: canres.2222.2020. [Epub ahead of print]
    Multiomics characterization of low-grade serous ovarian carcinoma identifies potential biomarkers of MEK inhibitor sensitivity and therapeutic vulnerability.
    Raunak Shrestha, Marta Llaurado Fernandez, Amy Dawson, Joshua Hoenisch, Stanislav Volik, Yen-Yi Lin, Shawn Anderson, Hannah Kim, Anne M Haegert, Shane Colborne, Nelson K Y Wong, Brian McConeghy, Robert H Bell, Sonal Brahmbhatt, Cheng-Han Lee, Gabriel E DiMattia, Stephane Le Bihan, Gregg B Morin, Colin C Collins, Mark S Carey.
      Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates in patients with metastatic disease. There is a pressing need to develop effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here we use multiomics integration of whole exome sequencing, RNA sequencing, and mass spectrometry-based proteomics on fourteen LGSOC cell lines to elucidate novel biomarkers and therapeutic vulnerabilities. Comparison of LGSOC cell line data to LGSOC tumor data enabled predictive biomarker identification of MEK inhibitor (MEKi) efficacy, with KRAS mutations found exclusively in MEKi-sensitive cell lines and NRAS mutations found mostly in MEKi-resistant cell lines. Distinct patterns of COSMIC mutational signatures were identified in MEKi-sensitive and MEKi-resistant cell lines. Deletions of CDKN2A/B and MTAP genes were more frequent in cell lines than tumor samples and possibly represent key driver events in the absence of KRAS/NRAS/BRAF mutations. These LGSOC cell lines were representative models of the molecular aberrations found in LGSOC tumors. For prediction of in vitro MEKi efficacy, proteomic data provided better discrimination than gene expression data. Condensin, MCM, and RFC protein complexes were identified as potential treatment targets in MEKi-resistant cell lines. This study suggests that CDKN2A/B or MTAP deficiency may be exploited using synthetically lethal treatment strategies, highlighting the importance of using proteomic data as a tool for molecular drug prediction. Multiomics approaches are crucial to improving our understanding of the molecular underpinnings of LGSOC and applying this information to develop new therapies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2222
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