bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022‒03‒06
fifteen papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Nat Commun. 2022 Mar 01. 13(1): 1100
      Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.
  2. Nat Cancer. 2022 Feb;3(2): 232-250
      Models that recapitulate the complexity of human tumors are urgently needed to develop more effective cancer therapies. We report a bank of human patient-derived xenografts (PDXs) and matched organoid cultures from tumors that represent the greatest unmet need: endocrine-resistant, treatment-refractory and metastatic breast cancers. We leverage matched PDXs and PDX-derived organoids (PDxO) for drug screening that is feasible and cost-effective with in vivo validation. Moreover, we demonstrate the feasibility of using these models for precision oncology in real time with clinical care in a case of triple-negative breast cancer (TNBC) with early metastatic recurrence. Our results uncovered a Food and Drug Administration (FDA)-approved drug with high efficacy against the models. Treatment with this therapy resulted in a complete response for the individual and a progression-free survival (PFS) period more than three times longer than their previous therapies. This work provides valuable methods and resources for functional precision medicine and drug development for human breast cancer.
  3. Cell Rep. 2022 Mar 01. pii: S2211-1247(22)00174-7. [Epub ahead of print]38(9): 110447
      Breast cancer is accompanied by systemic immunosuppression, which facilitates metastasis formation, but how this shapes organotropism of metastasis is poorly understood. Here, we investigate the impact of mammary tumorigenesis on regulatory T cells (Tregs) in distant organs and how this affects multi-organ metastatic disease. Using a preclinical mouse mammary tumor model that recapitulates human metastatic breast cancer, we observe systemic accumulation of activated, highly immunosuppressive Tregs during primary tumor growth. Tumor-educated Tregs show tissue-specific transcriptional rewiring in response to mammary tumorigenesis. This has functional consequences for organotropism of metastasis, as Treg depletion reduces metastasis to tumor-draining lymph nodes, but not to lungs. Mechanistically, we find that Tregs control natural killer (NK) cell activation in lymph nodes, thereby facilitating lymph node metastasis. In line, an increased Treg/NK cell ratio is observed in sentinel lymph nodes of breast cancer patients compared with healthy controls. This study highlights that immune regulation of metastatic disease is highly organ dependent.
    Keywords:  NK cells; T(regs); breast cancer; immunosuppression; lymph nodes; metastasis; organotropism
  4. Cell Rep Med. 2022 Feb 15. 3(2): 100525
      Mechanisms of therapeutic resistance and vulnerability evolve in metastatic cancers as tumor cells and extrinsic microenvironmental influences change during treatment. To support the development of methods for identifying these mechanisms in individual people, here we present an omic and multidimensional spatial (OMS) atlas generated from four serial biopsies of an individual with metastatic breast cancer during 3.5 years of therapy. This resource links detailed, longitudinal clinical metadata that includes treatment times and doses, anatomic imaging, and blood-based response measurements to clinical and exploratory analyses, which includes comprehensive DNA, RNA, and protein profiles; images of multiplexed immunostaining; and 2- and 3-dimensional scanning electron micrographs. These data report aspects of heterogeneity and evolution of the cancer genome, signaling pathways, immune microenvironment, cellular composition and organization, and ultrastructure. We present illustrative examples of how integrative analyses of these data reveal potential mechanisms of response and resistance and suggest novel therapeutic vulnerabilities.
    Keywords:  human tumor atlas; metastatic breast cancer; personalized medicine; precision oncology
  5. Drug Resist Updat. 2022 Feb 18. pii: S1368-7646(22)00020-6. [Epub ahead of print]61 100821
      Despite the rapid advancement in the introduction of new drugs for cancer therapy, the frequent emergence of drug resistance leads to disease progression or tumor recurrence resulting in dismal prognosis. Given that genetic mutations are thought to be important drivers of anti-cancer drug resistance, it is of paramount importance to pin-point mutant genes that mediate drug resistance and elucidate the underlying molecular mechanisms in order to develop novel modalities to surmount chemoresistance and achieve more efficacious and durable cancer therapies. Cumulative evidence suggests that epigenetic alterations, especially those mediated by epigenetic enzymes with high mutation rates in cancer patients, can be a crucial factor in the development of chemoresistance. Mutant epigenetic enzymes have altered enzymatic activity which may directly or indirectly affect the level of histone modifications. This can change chromatin structure and function hence altering the expression of target genes and eventually lead to chemoresistance. In the current review, we summarize epigenetic enzyme mutations and the consequent mechanisms of drug resistance in pre-clinical drug-resistance models and relapsed cancer patient specimens. We also introduce previously unreported mutation sites in the DOT1 domain of DOT1L, which are related to lung cancer drug resistance. It is worth noting that mutations occur not only in domains with enzymatic activity but also in non-catalytic regions. Each protein domain is an evolutionarily conserved region with independent functional properties. This may provide a rationale for the potential development of small molecule inhibitors which target various functional domains of epigenetic enzymes. Finally, based on the multitude of mechanisms of drug resistance, we propose several therapeutic strategies to reverse or overcome drug-resistance phenotypes, with the aim to provide cancer patients with novel efficacious combination therapeutic regimens and strategies to improve patient prognosis.
    Keywords:  Cancer; Chemoresistance; Drug resistance; Epigenetic enzymes; Mutations; Surmounting drug resistance; Targeted interventions; Therapy
  6. Nature. 2022 Mar 02.
      RAS family members are the most frequently mutated oncogenes in human cancers. Although KRAS(G12C)-specific inhibitors show clinical activity in patients with cancer1-3, there are no direct inhibitors of NRAS, HRAS or non-G12C KRAS variants. Here we uncover the requirement of the silent KRASG60G mutation for cells to produce a functional KRAS(Q61K). In the absence of this G60G mutation in KRASQ61K, a cryptic splice donor site is formed, promoting alternative splicing and premature protein termination. A G60G silent mutation eliminates the splice donor site, yielding a functional KRAS(Q61K) variant. We detected a concordance of KRASQ61K and a G60G/A59A silent mutation in three independent pan-cancer cohorts. The region around RAS Q61 is enriched in exonic splicing enhancer (ESE) motifs and we designed mutant-specific oligonucleotides to interfere with ESE-mediated splicing, rendering the RAS(Q61) protein non-functional in a mutant-selective manner. The induction of aberrant splicing by antisense oligonucleotides demonstrated therapeutic effects in vitro and in vivo. By studying the splicing necessary for a functional KRAS(Q61K), we uncover a mutant-selective treatment strategy for RASQ61 cancer and expose a mutant-specific vulnerability, which could potentially be exploited for therapy in other genetic contexts.
  7. J Clin Invest. 2022 Mar 01. pii: e141797. [Epub ahead of print]132(5):
      Cancer stem-like cells (CSLCs) acquire enhanced immune checkpoint responses to evade immune cell killing and promote tumor progression. Here we showed that signal regulatory protein γ (SIRPγ) determined CSLC properties and immune evasiveness in a small population of lung adenocarcinoma (LUAD) cancer cells. A SIRPγhi population displayed CSLC properties and transmitted the immune escape signal through sustaining CD47 expression in both SIRPγhi and SIRPγlo/- tumor cells. SIRPγ bridged MST1 and PP2A to facilitate MST1 dephosphorylation, resulting in Hippo/YAP activation and leading to cytokine release by CSLCs, which stimulated CD47 expression in LUAD cells and consequently inhibited tumor cell phagocytosis. SIRPγ promoted tumor growth and metastasis in vivo through YAP signaling. Notably, SIRPγ targeting with genetic SIRPγ knockdown or a SIRPγ-neutralizing antibody inhibited CSLC phenotypes and elicited phagocytosis that suppressed tumor growth in vivo. SIRPG was upregulated in human LUAD and its overexpression predicted poor survival outcome. Thus, SIRPγhi cells serve as CSLCs and tumor immune checkpoint-initiating cells, propagating the immune escape signal to the entire cancer cell population. Our study identifies Hippo/YAP signaling as the first mechanism by which SIRPγ is engaged and reveals that targeting SIRPγ represents an immune- and CSLC-targeting strategy for lung cancer therapy.
    Keywords:  Cancer; Immunology
  8. Nat Cancer. 2022 Feb;3(2): 173-187
      Radiotherapy is one of the most effective approaches to achieve tumor control in cancer patients, although healthy tissue injury due to off-target radiation exposure can occur. In this study, we used a model of acute radiation injury to the lung, in the context of cancer metastasis, to understand the biological link between tissue damage and cancer progression. We exposed healthy mouse lung tissue to radiation before the induction of metastasis and observed a strong enhancement of cancer cell growth. We found that locally activated neutrophils were key drivers of the tumor-supportive preconditioning of the lung microenvironment, governed by enhanced regenerative Notch signaling. Importantly, these tissue perturbations endowed arriving cancer cells with an augmented stemness phenotype. By preventing neutrophil-dependent Notch activation, via blocking degranulation, we were able to significantly offset the radiation-enhanced metastases. This work highlights a pro-tumorigenic activity of neutrophils, which is likely linked to their tissue regenerative functions.
  9. Nat Cancer. 2022 Feb;3(2): 156-172
      The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.
  10. Nat Biomed Eng. 2022 Mar 03.
      Immune checkpoint blockade (ICB) therapy does not benefit the majority of treated patients, and those who respond to the therapy can become resistant to it. Here we report the design and performance of systemically administered protease activity sensors conjugated to anti-programmed cell death protein 1 (αPD1) antibodies for the monitoring of antitumour responses to ICB therapy. The sensors consist of a library of mass-barcoded protease substrates that, when cleaved by tumour proteases and immune proteases, are released into urine, where they can be detected by mass spectrometry. By using syngeneic mouse models of colorectal cancer, we show that random forest classifiers trained on mass spectrometry signatures from a library of αPD1-conjugated mass-barcoded activity sensors for differentially expressed tumour proteases and immune proteases can be used to detect early antitumour responses and discriminate resistance to ICB therapy driven by loss-of-function mutations in either the B2m or Jak1 genes. Biomarkers of protease activity may facilitate the assessment of early responses to ICB therapy and the classification of refractory tumours based on resistance mechanisms.
  11. Oncogene. 2022 Mar 02.
      Dual-specificity mitogen-activated protein kinase phosphatase-1 (MKP-1/DUSP1/CL-100) has been documented to promote breast cancer cell survival and chemoresistance. MKP-1 is an unstable protein that is ubiquitinated and degraded via the ubiquitin-proteasome system. However, it is not clear how MKP-1 protein stability is regulated in breast cancer. In this study, we performed a genome-wide siRNA library screen of deubiquitinases (DUBs) and identified STAMBPL1 as an MKP-1 DUB in breast cancer cells. STAMBPL1 interacts with MKP-1 and stabilizes MKP-1 via deubiquitination. Both STAMBPL1 and MKP-1 depletion sensitize breast cancer cells to cisplatin in vitro and in vivo, and ectopic overexpression of MKP-1 partially rescues STAMBPL1 depletion-induced cisplatin sensitivity. Furthermore, STAMBPL1 and MKP-1 depletion increased breast cancer sensitivity to cisplatin by increasing the phosphorylation and activation of c-Jun N-terminal protein kinase (JNK). Collectively, our findings not only identify STAMBPL1 as an MKP-1 DUB but also reveal a critical mechanism that regulates MKP-1 expression in breast cancer. Our findings indicate that the STAMBPL1/MKP-1 axis represents a potential therapeutic target in breast cancer.
  12. Cell Rep. 2022 Mar 01. pii: S2211-1247(22)00168-1. [Epub ahead of print]38(9): 110441
      Gα13 transduces signals from G-protein-coupled receptors. While Gα13 functions as a tumor suppressor in lymphomas, it is not known whether Gα13 is pro-tumorigenic or tumor suppressive in genetically engineered mouse (GEM) models of epithelial cancers. Here, we show that loss of Gα13 in the Kras/Tp53 (KPC) GEM model promotes well-differentiated tumors and reduces survival. Mechanistically, tumors developing in KPC mice with Gα13 loss exhibit increased E-cadherin expression and mTOR signaling. Importantly, human pancreatic ductal adenocarcinoma (PDAC) tumors with low Gα13 expression also exhibit increased E-cadherin expression and mTOR signaling. Treatment with the mTOR inhibitor rapamycin decreases the growth of syngeneic KPC tumors with Gα13 loss by promoting cell death. This work establishes a tumor-suppressive role of Gα13 in pancreatic tumorigenesis in the KPC GEM model and suggests targeting mTOR in human PDAC tumors with Gα13 loss.
    Keywords:  E-cadherin; Gα13; KC mouse model; KPC mouse model; human PDAC tumors; mTOR; rapamycin
  13. Nat Rev Cancer. 2022 Mar 03.
      Senescence is a cellular response to a variety of stress signals that is characterized by a stable withdrawal from the cell cycle and major changes in cell morphology and physiology. While most research on senescence has been performed on non-cancer cells, it is evident that cancer cells can also mount a senescence response. In this Review, we discuss how senescence can be induced in cancer cells. We describe the distinctive features of senescent cancer cells and how these changes in cellular physiology might be exploited for the selective eradication of these cells (senolysis). We discuss activation of the host immune system as a particularly attractive way to clear senescent cancer cells. Finally, we consider the challenges and opportunities provided by a 'one-two punch' sequential treatment of cancer with pro-senescence therapy followed by senolytic therapy.
  14. Cell Stem Cell. 2022 Mar 03. pii: S1934-5909(22)00058-3. [Epub ahead of print]29(3): 350-352
      Adaptive aberrant gene regulation is a hallmark of malignant growth and therapy resistance in acute myeloid leukemia (AML). In this issue of Cell Stem Cell, Eagle et al. identified oncogenic enhancer-driven overexpression of selenophosphate synthetase 2 (SEPHS2) as an opportunity for targeted mitigation of malignant cell growth in AML.
  15. Nat Rev Cancer. 2022 Mar 02.
      Genomic analyses in cancer have been enormously impactful, leading to the identification of driver mutations and development of targeted therapies. But the functions of the vast majority of somatic mutations and copy number variants in tumours remain unknown, and the causes of resistance to targeted therapies and methods to overcome them are poorly defined. Recent improvements in mass spectrometry-based proteomics now enable direct examination of the consequences of genomic aberrations, providing deep and quantitative characterization of tumour tissues. Integration of proteins and their post-translational modifications with genomic, epigenomic and transcriptomic data constitutes the new field of proteogenomics, and is already leading to new biological and diagnostic knowledge with the potential to improve our understanding of malignant transformation and therapeutic outcomes. In this Review we describe recent developments in proteogenomics and key findings from the proteogenomic analysis of a wide range of cancers. Considerations relevant to the selection and use of samples for proteogenomics and the current technologies used to generate, analyse and integrate proteomic with genomic data are described. Applications of proteogenomics in translational studies and immuno-oncology are rapidly emerging, and the prospect for their full integration into therapeutic trials and clinical care seems bright.