Biology subjects

Alonso-Curbelo, D.

Publications and source records attributed to Alonso-Curbelo, D..

7 recordsLinked to original sources

bioRxiv2025

Oncogenic and tumor-suppressive forces converge on a progenitor-orchestrated niche to shape early tumorigenesis

The benign-to-malignant transition is a defining step in cancer progression. To investigate when and how malignancy initiation occurs and tissue reorganization proceeds, we combine single-cell and spatial transcriptomic profiling in mouse models of pancreatic ductal adenocarcinoma (PDAC) that capture spontaneous p53 loss. Among Kras-mutant cells, we find that oncogenic and tumor-suppressive programs, including those controlled by p53, CDKN2A, and SMAD4, are co-activated in a discrete progenitor-like population, engaging senescence-like responses. Using a framework we develop for spatial analysis, we show that a niche centered on these cells undergoes stepwise remodeling during tumor progression, mirroring invasive PDAC. Transient KRAS inhibition depletes progenitor-like cells and dismantles their niche, delaying malignancy initiation. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state at the convergence of cancer-driving mutations, plasticity and tissue remodeling, revealing a critical window for intercepting malignancy.

cancer biology↗

bioRxiv2024

Metastatic site influences driver gene function in pancreatic cancer

Driver gene mutations can increase the metastatic potential of the primary tumor1-3, but their role in sustaining tumor growth at metastatic sites is poorly understood. A paradigm of such mutations is inactivation of SMAD4 - a transcriptional effector of TGF{beta} signaling - which is a hallmark of multiple gastrointestinal malignancies4,5. SMAD4 inactivation mediates TGF{beta}s remarkable anti-to pro-tumorigenic switch during cancer progression and can thus influence both tumor initiation and metastasis6-14. To determine whether metastatic tumors remain dependent on SMAD4 inactivation, we developed a mouse model of pancreatic ductal adenocarcinoma (PDAC) that enables Smad4 depletion in the pre-malignant pancreas and subsequent Smad4 reactivation in established metastases. As expected, Smad4 inactivation facilitated the formation of primary tumors that eventually colonized the liver and lungs. By contrast, Smad4 reactivation in metastatic disease had strikingly opposite effects depending on the tumors organ of residence: suppression of liver metastases and promotion of lung metastases. Integrative multiomic analysis revealed organ-specific differences in the tumor cells epigenomic state, whereby the liver and lungs harbored chromatin programs respectively dominated by the KLF and RUNX developmental transcription factors, with Klf4 depletion being sufficient to reverse Smad4s tumor-suppressive activity in liver metastases. Our results show how epigenetic states favored by the organ of residence can influence the function of driver genes in metastatic tumors. This organ-specific gene-chromatin interplay invites consideration of anatomical site in the interpretation of tumor genetics, with implications for the therapeutic targeting of metastatic disease.

cancer biology↗

bioRxiv2022

Chromosome 9p21.3 Coordinates Cell Intrinsic and Extrinsic Tumor Suppression

Somatic chromosomal deletions are prevalent in cancer, yet their functional contributions remain ill-defined. Among the most prominent of these events are deletions of chromosome 9p21.3, which disable a cell intrinsic barrier to tumorigenesis by eliminating the CDKN2A/B tumor suppressor genes. However, half of 9p21.3 deletions encompass a cluster of 16 type I interferons (IFNs) whose co-deletions have not been functionally characterized. To dissect how 9p21.3 and other genomic deletions impact cancer, we developed MACHETE (Molecular Alteration of Chromosomes with Engineered Tandem Elements), a genome engineering strategy that enables flexible modeling of megabase-sized deletions. Generation of 9p21.3-syntenic deletions in a mouse model of pancreatic cancer revealed that concomitant loss of Cdkn2a/b and the IFN cluster led to immune evasion and metastasis compared to Cdkn2a/b-only deletions. Mechanistically, IFN co-deletion disrupted type I IFN signaling, altered antigen-presenting cells, and facilitated escape from CD8+ T cell surveillance in a cell extrinsic manner requiring loss of interferon epsilon (Ifne). Our results establish co-deletions of the IFN cluster as a pervasive route to tumor immune evasion and metastasis, revealing how deletions can disable physically linked cell intrinsic and extrinsic tumor suppression. Our study establishes a framework to dissect the functions of genomic deletions in cancer and beyond.

cancer biology↗

bioRxiv2022

Epigenetic plasticity cooperates with emergent cell-cell interactions to drive neoplastic tissue remodeling in the pancreas

The response to tumor-initiating inflammatory and genetic insults can vary amongst morphologically indistinguishable cells, suggesting yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we perform single-cell analyses on normal, inflamed, pre-malignant and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identify heterogeneous cell-states that are primed for diverse late-emerging neoplastic fates and link these to chromatin remodeling at cell-cell communication loci. Using a new inference approach, we reveal signaling gene modules and tissue-level crosstalk, including a neoplasia-driving feedback loop between discrete epithelial and immune cell populations that we validate by genetic perturbation in mice. Our results uncover a neoplasia-specific tissue remodeling program that may be exploited for pancreas cancer interception. One-Sentence SummarySingle-cell analysis reveals that enhanced epigenetic plasticity drives pro-neoplastic crosstalk in early pancreatic cancer.

cancer biology↗

bioRxiv2022

Senescence rewires microenvironment sensing to facilitate anti-tumor immunity

Cellular senescence involves a stable cell cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune competent tumor model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels cell surface proteome to alter how they sense environmental factors, as exemplified by Type II interferon gamma (IFN-{gamma}). Compared to proliferating cells, senescent cells upregulate IFN-{gamma} receptor, become hypersensitized to microenvironmental IFN-{gamma}, and more robustly induce antigen presenting machinery -effects also recapitulated in human tumor cells treated with senescence-inducing drugs. Disruption of the IFN-{gamma} sensing by senescent cells blunts their immune-mediated clearance without disabling their characteristic secretory program or immune cell recruitment. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals, and imply that each process is required for their effective immune surveillance. SIGNIFICANCEOur work identifies a novel interplay between tissue remodeling and tissue sensing programs that can be engaged by senescence in advanced cancers to render tumor cells more visible to the adaptive immune system. This new facet of senescence establishes reciprocal heterotypic signaling interactions that can be induced therapeutically to enhance anti-tumor immunity.

cancer biology↗

bioRxiv2019

Antimetastatic dsRNA mimics identified by live imaging of pathogenic neolymphangiogenesis

The crosstalk between cancer cells and the lymphatic vasculature has long been proposed to define competency for metastasis. Nevertheless, the discovery of selective blockers of lymphovascular niches has been compromised by the paucity of experimental systems for whole-body analyses of tumor progression. Here we present immunocompetent and immunodeficient mouse models for live imaging of melanoma-induced neolymphangiogenesis (driven by Vegfr3) as a cost-effective platform for drug screening in vivo. Spatio-temporal analyses in autochthonous melanomas and patient-derived xenografts identified double stranded RNA mimics (dsRNA nanoplexes) as potent repressors of lymphangiogenesis and metastasis. Mechanistically, dsRNA nanoplexes were found to suppress lymphangiogenic drivers in both tumor cells and their associated lymphatic vasculature (via MIDKINE and Vegfr3, respectively). This dual inhibitory action, driven by type I interferon, was not shared by FDA-approved antimelanoma treatments or by lymphangiogenic blockers in clinical testing. These results underscore the power of Vegfr3-lymphoreporters for pharmacological testing in otherwise aggressive cancers. RELEVANCEAlthough tumor-induced lymphangiogenesis has long been associated with metastasis, selective targeting of this process has been compromised by the paucity of experimental platforms for whole-body imaging of tumor progression and drug response. Here we present animal models engineered for spatio-temporal analyses of neolymphangiogenesis in clinically relevant autochthonous melanomas and patient-derived xenografts, and identify a unique action of double stranded-RNA nanoplexes as potent repressors of lymphatic dissemination and metastatic relapse.

cancer biology↗

bioRxiv2019

An in vivo KRAS allelic series reveals distinct phenotypes of common oncogenic variants

KRAS is the most frequently mutated oncogene in cancer. Tumor sequencing has revealed a complex spectrum of KRAS mutations across different cancer types, yet there is little understanding how specific KRAS alterations impact tumor in initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new LSL-Kras mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRASG12C), pancreas (KRASG12R) and colon (KRASG13D) cancers. Induction of each mutation in the developing mouse pancreas reveal striking quantitative and qualitative differences in the degree of ductal transformation and pre-malignant progression. Further, using organoid models we show that KRASG13D mutants respond to EGFR inhibition, while the anti-proliferative effect of KRASG12C-selective inhibitors can be overcome by upstream EGFR signaling. Together, these new mouse strains provide an ideal for investigating KRAS biology in vivo, and for developing pre-clinical precision oncology models of KRAS-mutant pancreas (G12R), colon (G13D), and lung (G12C) cancers.

cancer biology↗