This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from July 16 through July 31.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing ericd_schuller@dfci.harvard.edu.
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Annals of Oncology
Trastuzumab Deruxtecan (T-DXd) in HER2-Low Metastatic Breast Cancer Treatment
Tarantino P, Tolaney SM
We are grateful with Wei et al for their comments on our manuscript reporting the ESMO Expert Consensus Statements (ECS) on HER2-low breast cancer. The authors argue that, based on the inclusion criteria of the ASCENT and DESTINY-Breast04 phase 3 trials, trastuzumab deruxtecan (T-DXd) should be prioritized over sacituzumab govitecan (SG) as second-line treatment for patients with HER2-low metastatic triple-negative breast cancer (mTNBC). Although we agree that T-DXd represents an important treatment option for this population of patients, we believe that the currently available data supports utilizing SG first.
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Blood
MYD88L265P Augments Proximal B-Cell Receptor Signaling in Large B-Cell Lymphomas Via an Interaction with DOCK8
Mandato E, Yan Q, Paczkowska J, Bojarczuk K, Hansen J, Chapuy B, Rodig SJ, Khan SJ, Redd RA, Shipp MA
Diffuse large B-cell lymphoma (DLBCL) is a clinically and genetically heterogeneous disease comprised of at least 5 recognized molecular subtypes. Cluster 5/ MCD tumors frequently exhibit concurrent alterations of the Toll-like receptor (TLR) and B-cell receptor (BCR) pathway members, MYD88L265P and CD79B, and have a less favorable prognosis. In normal B cells, the synergy between TLR and BCR signaling pathways integrates innate and adaptive immune responses and augments downstream NF-kB activation. Additionally, physiologic TLR9 pathway engagement, via MYD88, PYK2 and DOCK8, increases proximal BCR signaling in normal murine B cells. Although MCD/ Cluster 5 DLBCLs are selectively sensitive to BTK inhibition in in vitro studies and certain clinical trials, the role of mutated MYD88 in proximal BCR signaling remains undefined. Using engineered DLBCL cell line models, we find that concurrent MYD88L265P and CD79B alterations significantly increase the magnitude and duration of proximal BCR signaling, at the level of SYK and BTK, and augment PYK2-dependent DOCK8 phosphorylation. MYD88L265P DLBCLs have significantly increased colocalization of DOCK8 with both MYD88 and the proximal BCR-associated Src kinase, LYN, in comparison to MYD88WT DLBCLs, implicating DOCK8 in MYD88L265P/ proximal BCR crosstalk. Additionally, DOCK8 depletion selectively decreases proximal BCR signaling, cellular proliferation and viability of DLBCLs with endogenous MYD88L265P/CD79BY196Falterations and increases the efficacy of BTK blockade in these lymphomas. Therefore, MYD88L265P/DOCK8-enhanced proximal BCR signaling is a likely mechanism for the increased sensitivity of MCD/ Cluster 5 DLBCLs to BTK blockade.
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Blood
Single-Cell Profiling in Multiple Myeloma: Insights, Problems, and Promises
Samur MK, Munshi NC
In a short time, single-cell platforms have become the norm in many fields of research, including multiple myeloma (MM). In fact, the large amount of cellular heterogeneity in MM makes single-cell platforms particularly attractive because bulk assessments can miss valuable information about cellular subpopulations and cell-to-cell interactions. The decreasing cost and increasing accessibility of single-cell platform, combined with breakthroughs in obtaining multiomics data for the same cell and innovative computational programs for analyzing data, have allowed single-cell studies to make important insights into MM pathogenesis; yet, there is still much to be done. In this review, we will first focus on the types of single-cell profiling and the considerations for designing a single-cell profiling experiment. Then, we will discuss what have learned from single-cell profiling about myeloma clonal evolution, transcriptional reprogramming, and drug resistance, and about the MM microenvironment during precursor and advanced disease.
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Cell
cGLRs are a Diverse Family of Pattern Recognition Receptors in Innate Immunity
Li Y, Slavik KM, Toyoda HC, Morehouse BR, Mears KS, Liu J, Kranzusch PJ
Cyclic GMP-AMP synthase (cGAS) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2'3'-cGAMP that activates STING-dependent downstream immunity. Here, we discover that cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in innate immunity. Building on recent analysis in Drosophila, we identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screening of 150 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of isomers of the nucleotide signals cGAMP, c-UMP-AMP, and c-di-AMP. Combining structural biology and in vivo analysis in coral and oyster animals, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.
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Cell
Modeling Epigenetic Lesions that Cause Gliomas
Rahme GJ, Javed NM, Puorro KL, Xin S, Hovestadt V, Johnstone SE, Bernstein BE
Epigenetic lesions that disrupt regulatory elements represent potential cancer drivers. However, we lack experimental models for validating their tumorigenic impact. Here, we model aberrations arising in isocitrate dehydrogenase-mutant gliomas, which exhibit DNA hypermethylation. We focus on a CTCF insulator near the PDGFRA oncogene that is recurrently disrupted by methylation in these tumors. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. We show that a second lesion, methylation-dependent silencing of the Cdkn2a tumor suppressor, cooperates with insulator loss in OPCs. Coordinate inactivation of the Pdgfra insulator and Cdkn2a drives gliomagenesis in vivo. Despite locus synteny, the insulator is CpG-rich only in humans, a feature that may confer human glioma risk but complicates mouse modeling. Our study demonstrates the capacity of recurrent epigenetic lesions to drive OPC proliferation in vitro and gliomagenesis in vivo.
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Journal of Clinical Oncology
Safety and Activity of Immune Checkpoint Inhibitors in People Living with HIV and Cancer: A Real-World Report from the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium
El Zarif T, Adib E, Huang J, Freeman D, Xie W, Choueiri TK, Baden LR
PURPOSE: Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer.
METHODS: This retrospective study included PWH treated with anti-PD-1- or anti-PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC).
RESULTS: Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti-PD-1/anti-PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was -0.06 months (95% CI, -5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, -4.02 to 8.48; P = .48) for OS.
CONCLUSION: Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.
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Nature Cancer
SIGLEC9 Tips the Myeloid Balance in Glioblastoma
Guerriero JL
Glioblastoma is an aggressive brain tumor with a highly immunosuppressive environment that responds poorly to immune checkpoint inhibitors. A study shows that SIGLEC9+ monocyte-derived macrophages are enriched in glioblastomas that do not respond to immune checkpoint inhibitors, and targeting this receptor synergizes with immunotherapy.
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Nature Communications
Adipose Tissue and Skeletal Muscle Wasting Precede Clinical Diagnosis of Pancreatic Cancer
Babic A, Rosenthal MH, Brais LK, Loftus M, Caplan L, Denning S, Gurung A, Harrod J, Schawkat K, Yuan C, Wang QL, Lee AA, Biller LH, Yurgelun MB, Ng K, Nowak JA, Aguirre AJ, Bhatia SN, Vander Heiden MG, Wolpin BM
Patients with pancreatic cancer commonly develop weight loss and muscle wasting. Whether adipose tissue and skeletal muscle losses begin before diagnosis and the potential utility of such losses for earlier cancer detection are not well understood. We quantify skeletal muscle and adipose tissue areas from computed tomography (CT) imaging obtained 2 months to 5 years before cancer diagnosis in 714 pancreatic cancer cases and 1748 matched controls. Adipose tissue loss is identified up to 6 months, and skeletal muscle wasting is identified up to 18 months before the clinical diagnosis of pancreatic cancer and is not present in the matched control population. Tissue losses are of similar magnitude in cases diagnosed with localized compared with metastatic disease and are not correlated with at-diagnosis circulating levels of CA19-9. Skeletal muscle wasting occurs in the 1-2 years before pancreatic cancer diagnosis and may signal an upcoming diagnosis of pancreatic cancer.
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Nature Communications
Cryo-EM Structure of a RAS/RAF Recruitment Complex
Park E, Rawson S, Schmoker A, Kim BW, Oh S, Jeon H, Eck MJ
RAF-family kinases are activated by recruitment to the plasma membrane by GTP-bound RAS, whereupon they initiate signaling through the MAP kinase cascade. Prior structural studies of KRAS with RAF have focused on the isolated RAS-binding and cysteine-rich domains of RAF (RBD and CRD, respectively), which interact directly with RAS. Here we describe cryo-EM structures of a KRAS bound to intact BRAF in an autoinhibited state with MEK1 and a 14-3-3 dimer. Analysis of this KRAS/BRAF/MEK1/14-3-3 complex reveals KRAS bound to the RAS-binding domain of BRAF, captured in two orientations. Core autoinhibitory interactions in the complex are unperturbed by binding of KRAS and in vitro activation studies confirm that KRAS binding is insufficient to activate BRAF, absent membrane recruitment. These structures illustrate the separability of binding and activation of BRAF by RAS and suggest stabilization of this pre-activation intermediate as an alternative therapeutic strategy to blocking binding of KRAS.
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Nature Genetics
Landscape of mSWI/SNF Chromatin Remodeling Complex Perturbations in Neurodevelopmental Disorders
Valencia AM, Sankar A, Satterstrom FK, Fu J, Talkowski ME, Kadoch C
DNA sequencing-based studies of neurodevelopmental disorders (NDDs) have identified a wide range of genetic determinants. However, a comprehensive analysis of these data, in aggregate, has not to date been performed. Here, we find that genes encoding the mammalian SWI/SNF (mSWI/SNF or BAF) family of ATP-dependent chromatin remodeling protein complexes harbor the greatest number of de novo missense and protein-truncating variants among nuclear protein complexes. Non-truncating NDD-associated protein variants predominantly disrupt the cBAF subcomplex and cluster in four key structural regions associated with high disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core ARID-armadillo repeat (ARM) module insertion site, the Arp module and DNA-binding domains. Although over 70% of the residues perturbed in NDDs overlap with those mutated in cancer, ~60% of amino acid changes are NDD-specific. These findings provide a foundation to functionally group variants and link complex aberrancies to phenotypic severity, serving as a resource for the chromatin, clinical genetics and neurodevelopment communities.
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Molecular Cell
Oncogenic K-Ras Suppresses Global miRNA Function
Shui B, Beyett TS, Gazlay WM, Eck MJ, Haigis KM
K-Ras frequently acquires gain-of-function mutations (K-RasG12D being the most common) that trigger significant transcriptomic and proteomic changes to drive tumorigenesis. Nevertheless, oncogenic K-Ras-induced dysregulation of post-transcriptional regulators such as microRNAs (miRNAs) during oncogenesis is poorly understood. Here, we report that K-RasG12D promotes global suppression of miRNA activity, resulting in the upregulation of hundreds of targets. We constructed a comprehensive profile of physiological miRNA targets in mouse colonic epithelium and tumors expressing K-RasG12D using Halo-enhanced Argonaute pull-down. Combining this with parallel datasets of chromatin accessibility, transcriptome, and proteome, we uncovered that K-RasG12D suppressed the expression of Csnk1a1 and Csnk2a1, subsequently decreasing Ago2 phosphorylation at Ser825/829/832/835. Hypo-phosphorylated Ago2 increased binding to mRNAs while reducing its activity to repress miRNA targets. Our findings connect a potent regulatory mechanism of global miRNA activity to K-Ras in a pathophysiological context and provide a mechanistic link between oncogenic K-Ras and the post-transcriptional upregulation of miRNA targets.
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Clinical Cancer Research
Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer
Singh H, Kapner KS, Dilly J, Raghavan S, Yuan C, Cohen EF, Tolstorukov M, Andrews E, Brais LK, da Silva A, Perez K, Rubinson DA, Surana R, Giannakis M, Ng K, Clancy TE, Yurgelun MB, Schlechter BL, Clark JW, Shapiro GI, Rosenthal MH, Hornick JL, Nardi V, Li YY, Gupta H, Cherniack AD, Meyerson M, Cleary JM, Nowak JA, Wolpin BM, Aguirre AJ
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European Urology Oncology
Stereotactic Magnetic Resonance-guided Adaptive Radiation Therapy for Localized Kidney Cancer: Early Outcomes from a Prospective Phase 1 Trial and Supplemental Cohort
Yim K, Hsu SH, Nolazco J, Cagney D, Mak RH, D'Andrea V, Singer L, Williams C, Huynh E, Han Z, Martin N, Nguyen P, Kibel AS, Choueiri TK, Chang SL, Leeman JE
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International Journal of Radiation Oncology, Biology, Physics
Assessing the Feasibility of Utilizing Artificial Intelligence-Segmented Dominant Intraprostatic Lesion for Focal Intraprostatic Boost with External Beam Radiation Therapy
Tsui JMG, Kehayias CE, Leeman JE, Nguyen PL, Peng L, Yang DD, Moningi S, Martin N, Orio PF, D'Amico AV, Bredfeldt JS, Lee LK, Guthier CV, King MT
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Transplantation and Cellular Therapy
Medication Adherence in Patients with Hematologic Malignancies who are Hematopoietic Stem Cell Transplantation Survivors: A Qualitative Study
Amonoo HL, Deary EC, Wang A, Newcomb RA, Daskalakis E, Weber D, Holmbeck KE, Choe JJ, Nabily A, Cutler C, Traeger LN, El-Jawahri A
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