Harvard Medical School

Permanent URI for this communityhttps://dash.harvard.edu/handle/1/4454685

This community provides open access to material created by faculty, staff, and students of the Harvard Medical School. All material in the repository is also harvested by search engines (such as Google Scholar) and Open Archives Initiative data harvesters.

Browse

Filters

2010 - 201923.6K2020 - 20252K

Settings

Search Results

Now showing 1 - 10 of 25558
  • No Thumbnail Available
    Publication
  • No Thumbnail Available
    Publication
    Crypt density and recruited enhancers underlie intestinal tumour initiation
    (Springer Science and Business Media LLC, 2025-01-08) Gaynor, Liam; Singh, Harshabad; Tie, Guodong; Badarinath, Krithika; Madha, Shariq; Mancini, Andrew; Bhattacharya, Swarnabh; Hoshino, Mikio; de Sauvage, Frederic J.; Murata, Kazutaka; Jadhav, Unmesh; Shivdasani, Ramesh; tie, guodong
    Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence. Mutation of Adenomatous polyposis coli (Apc), the most common initiating event in conventional adenomas, activates Wnt signalling, hence conferring fitness on mutant intestinal stem cells (ISCs). Apc mutations may occur in ISCs that arose by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar, it is unclear if both generate tumours equally well in uninjured intestines. Also unknown is whether cis-regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here, we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc-null ISCs not associated with adenomas. These cis-elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumourigenesis.
  • No Thumbnail Available
    Publication
    Neuropeptide signaling orchestrates T cell differentiation
    Hou, Yu; Sun, Lin-Yu; LaFleur, Martin; Huang, Linglin; Lambden, Conner; Thakore, Pratiksha; Geiger-Schuller, Kathryn; Kimura, Kimitoshi; Tang, Ruihan; Shi, Jingwen; Deng, Liwen; Subramanian, Ayshwarya; Wallrapp, Antonia; Choi, Hee Sun; Kye1, Yoon-Chul; Ashenberg, Orr; Schiebinger, Geoffrey; Doench, John; Chiu, Isaac; Regev, Aviv; Sharpe, Arlene; Kuchroo, Vijay
  • No Thumbnail Available
    Publication
    Deciphering the impact of genomic variation on function
    (Springer Science and Business Media LLC, 2024-09-04) Van Buren, Eric; Price, Alkes; Ham, Alexandra; Price, Alkes; Hall, Amelia; Carpenter, Anne; Yadav, Anupama; Durvasula, Arun; Becerra, Basheer; Kleinstiver, Benjamin; Cimini, Beth; Bradley, Bernstein; White, Cassandra; Epstein, Charles; Bauer, Daniel; Hill, David; Donnard, Elisa; Gaskell, Elizabeth; Roberts, Elizabeth; Gibbs, Ellie; King, Emily; Mattei, Eugenio; Koch, Evan; Jagoda, Evelyn; Duarte, Fabiana; Laval, Florent; Coppin, Georges; Munson, Glen; Barreto Corona, Guillermo; Zhou, Hufeng; Buenrostro, Jason; Ryu, Jayoung; Engreitz, Jesse; Ray, Judhajeet; Babu, Juliana; Fan, Kaili; Spirohn-Fitzgerald, Kerstin; Dong, Kevin; Dey, Kushal; Blaine, Logan; Pinello, Luca; Ferreira, Lucas; Murphy, Maddie; Kellis, Manolis; Vidal, Marc; Haghighi, Marzieh; Francoeur, Matthew; Tixhon, Maxime; Knudson, Mei; Calderwood, Michael; Kim, Nahye; Durand, Neva; Farrell, Nina; Shoresh, Noam; Vinh Phan, Quang; Savage, Rachel; Sherwood, Richard; Sakaue, Saori; Sunyaev, Shamil; Singh, Shantanu; Wekhande, Siddarth; Raychaudhuri, Soumya; Song, Susie; Jones, Thouis; Wu, Ting; Hao, Tong; Singh, Vasundhara; Xi, Wang; Li, Xihao; Lin, Xihong; Patel, Zain; Li, Zhijian; Yang, Zhipeng
  • No Thumbnail Available
    Publication
    Spatial multiomic landscape of the human placenta at molecular resolution
    (Springer Science and Business Media LLC, 2024-11-20) Ounadjela, Johain R.; Zhang, Ke; Kobayashi-Kirschvink, Koseki J.; Jin, Kang; J. C. Russell, Andrew; Lackner, Andreas I.; Callahan, Claire; Viggiani, Francesca; Dey, Kushal K.; Jagadeesh, Karthik; Maxian, Theresa; Prandstetter, Anna-Maria; Nadaf, Naeem; Gong, Qiyu; Raichur, Ruth; Zvezdov, Morgan L.; Hui, Mingyang; Simpson, Mattew; Liu, Xinwen; Min, Wei; Knöfler, Martin; Chen, Fei; Haider, Sandra; Shu, Jian
  • No Thumbnail Available
    Publication
    Molecular control of macroscopic forces drives formation of the vertebrate hindgut
    (Springer Science and Business Media LLC, 2019-01) Nerurkar, Nandan; Lee, ChangHee; Mahadevan, Lakshminarayanan; Tabin, Clifford
    The embryonic gut tube is a cylindrical structure from which the respiratory and gastrointestinal tracts arise 1. Despite investigations into early emergence of the endoderm as an epithelial sheet 2,3 and later morphogenesis of the definitive digestive and respiratory organs 4–6, the intervening process of gut tube formation has been severely understudied, particularly over the past 45 years 7,8. Here we investigate the molecular control of macroscopic forces underlying early morphogenesis of the gut tube in the chick embryo. The gut tube has been described as forming from two endodermal invaginations – the Anterior Intestinal Portal (AIP) towards the rostral end of the embryo and the Caudal Intestinal Portal (CIP) at the caudal end – that migrate toward one another, internalizing the endoderm until they meet at the yolk stalk (umbilicus in mammals) 1,6. Migration of the AIP to form foregut has been descriptively characterized 9,10, yet the hindgut likely forms by a distinct mechanism that has not been fully elucidated 11. We find that the hindgut forms by collective cell movements through a stationary CIP, rather than via movement of the CIP itself. Moreover, combining in vivo imaging, biophysics, and mathematical modeling with molecular and embryological approaches, we identify a contractile force gradient that drives cell movements in the hindgut-forming endoderm, permitting tissue-scale posterior extension of the forming hindgut tube. The force gradient, in turn, is established in response to a morphogenic gradient of FGF signaling. As a result, we propose that an important positive feedback arises, whereby contracting cells draw passive cells from low to high FGF levels, recruiting them to contract and pull more cells into the elongating hindgut. In addition to providing new insight into the early gut development, these findings illustrate how large-scale tissue level forces can be traced to developmental signals during vertebrate morphogenesis.
  • No Thumbnail Available
    Publication
    SKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO
    (Springer Science and Business Media LLC, 2025-02-05) Borck, Patricia C.; Boyle, Isabella; Jankovic, Kristina; Bick, Nolan; Foster, Kyla; Lau, Anthony C.; Parker-Burns, Lucy I.; Lubicki, Daniel A.; Li, Tianxia; Borah, Ashir A.; Lofaso, Nicholas J.; Das Sharma, Sohani; Chan, Tessla; Kishen, Riya V.; Adeagbo, Anisah; Raghavan, Srivatsan; Aquilanti, Elisa; Prensner, John R.; Krill-Burger, J. Michael; Golub, Todd R.; Campbell, Catarina D.; Dempster, Joshua M.; Chan, Edmond M.; Vazquez, Francisca
    Cancer genome alterations often lead to vulnerabilities that can be used to selectively target cancer cells. Various inhibitors of such synthetic lethal targets are FDA-approved or in clinical trials, highlighting the potential of this approach.1–3 Here, we analyzed large-scale CRISPR knockout screening data and identified a new synthetic lethal target, pelota mRNA surveillance and ribosome rescue factor (PELO), for two independent molecular subtypes of cancer: biallelic deletion of chromosomal region 9p21.3 (9p21.3-/-) or microsatellite instability-high (MSI-H). In 9p21.3-/- cancers, PELO dependency emerges from biallelic deletion of the 9p21.3 gene focadhesin (FOCAD), a stabilizer of the superkiller complex (SKIc). In MSI-H cancers, PELO is required due to MSI-H-associated mutations in tetratricopeptide repeat domain 37 (TTC37), a critical component of the SKIc. We show that both cancer subtypes converge to destabilize the SKIc, which extracts mRNA from stalled ribosomes. In SKIc-deficient cells, PELO depletion induces the unfolded protein response (UPR), a stress response to accumulated misfolded or unfolded nascent polypeptides. Together, our findings nominate PELO as a promising therapeutic target for a large patient population with cancers characterized as MSI-H with deleterious TTC37 mutations or with biallelic 9p21.3 deletions involving FOCAD.
  • No Thumbnail Available
    Publication
    Programs, Origins, and Niches of Immunomodulatory Myeloid Cells in Gliomas
    (Nature, 2023-10-27) Miller, Tyler E.; Farran, Chadi A. El; Couturier, Charles P.; Chen, Zeyu; D’Antonio, Joshua P.; Verga, Julia; Villanueva, Martin A.; Castro, L. Nicolas Gonzalez; Tong, Yuzhou Evelyn; Saadi, Tariq Al; Chiocca, Andrew N.; Fischer, David S.; Heiland, Dieter Henrik; Guerriero, Jennifer L.; Petrecca, Kevin; Suva, Mario L.; Shalek, Alex K.; Bernstein, Bradley
    ABSTRACTGliomas are incurable malignancies notable for an immunosuppressive microenvironment with abundant myeloid cells whose immunomodulatory properties remain poorly defined. Here, utilizing scRNA-seq data for 183,062 myeloid cells from 85 human tumors, we discover that nearly all glioma-associated myeloid cells express at least one of four immunomodulatory activity programs: Scavenger Immunosuppressive, C1Q Immunosuppressive, CXCR4 Inflammatory, and IL1B Inflammatory. All four programs are present in IDH1 mutant and wild-type gliomas and are expressed in macrophages, monocytes, and microglia whether of blood or resident myeloid cell origins. Integrating our scRNA-seq data with mitochondrial DNA-based lineage tracing, spatial transcriptomics, and organoid explant systems that model peripheral monocyte infiltration, we show that these programs are driven by microenvironmental cues and therapies rather than myeloid cell type, origin, or mutation status. The C1Q Immunosuppressive program is driven by routinely administered dexamethasone. The Scavenger Immunosuppressive program includes ligands with established roles in T-cell suppression, is induced in hypoxic regions, and is associated with immunotherapy resistance. Both immunosuppressive programs are less prevalent in lower-grade gliomas, which are instead enriched for the CXCR4 Inflammatory program. Our study provides a framework to understand immunomodulatory myeloid cells in glioma, and a foundation to develop more effective immunotherapies.
  • No Thumbnail Available
    Publication
    A vision–language foundation model for precision oncology
    (Springer Science and Business Media LLC, 2025-01-08) Xiang, Jinxi; Wang, Xiyue; Zhang, Xiaoming; Xi, Yinghua; Eweje, Feyisope; Chen, Yijiang; Li, Yuchen; Bergstrom, Colin; Gopaulchan, Matthew; Kim, Ted; Yu, Kun-Hsing; Willens, Sierra; Olguin, Francesca Maria; Nirschl, Jeffrey J.; Neal, Joel; Diehn, Maximilian; Yang, Sen; Li, Ruijiang
  • No Thumbnail Available
    Publication
    A γδ T cell–IL-3 axis controls allergic responses through sensory neurons
    (Springer Science and Business Media LLC, 2024-09-04) Flayer, Cameron; Kernin, Isabela J.; Matatia, Peri R.; Zeng, Xiangsunze; Yarmolinsky, David A.; Han, Cai; Naik, Parth R.; Buttaci, Dean R.; Aderhold, Pamela A.; Camire, Ryan B.; Zhu, Xueping; Tirard, Alice J.; McGuire, John T.; Smith, Neal P.; McKimmie, Clive S.; McAlpine, Cameron S.; Swirski, Filip K.; Woolf, Clifford J.; Villani, Alexandra-Chloe; Sokol, Caroline L.
    In naïve individuals, sensory neurons directly detect and respond to allergens, leading both to the sensation of itch and the activation of local innate immune cells, which initiate the allergic immune response. In the setting of chronic allergic inflammation, immune factors prime sensory neurons, causing pathologic itch. While these bidirectional neuroimmune circuits drive responses to allergens, whether immune cells regulate the set-point for neuronal activation by allergens in the naïve state is unknown. Here we describe a gd T cell-IL-3 signaling axis that controls the allergen responsiveness of cutaneous sensory neurons. We define a poorly characterized epidermal gd T cell subset, termed GD3 cells, that produces its hallmark cytokine IL-3 to promote allergic itch and the initiation of the allergic immune response. Mechanistically, IL-3 acts on Il3ra-expressing sensory neurons in a JAK2-dependent manner to lower their threshold for allergen activation without independently eliciting itch. This gd T cell-IL-3 signaling axis further acts via STAT5 to promote neuropeptide production and the initiation of allergic immunity. These results reveal an endogenous immune rheostat that sits upstream of and governs sensory neuronal responses to allergens upon first exposure. This pathway may explain individual differences in allergic susceptibility and opens novel therapeutic avenues for treating allergic diseases.